Glycoprotein IIb/IIIa Inhibitors during Rescue Percutaneous Coronary Intervention in Acute Myocardial Infarction

Fibrinolytic therapy for acute myocardial infarction, even with the most efficient regimens available, is fraught with a substantial proportion of failures to re-establish normal blood flow in the occluded vessel.^1,2 Failure to achieve prompt and complete restoration of TIMI 3 coronary blood flow after full-dose thrombolysis is associated with a poor prognosis.³ Although percutaneous coronary intervention (PCI), with or without stenting following full-dose thrombolytic therapy (rescue angioplasty), is a common procedure in these patients, data are scarce and there is ample controversy regarding the usefulness of the procedure.^4–6 Moreover, few data are available concerning the safety and efficacy of stenting in combination with glycoprotein (GP) IIb/IIIa inhibitors administration in these patients.^7–9 Even recent studies have failed to address the issue of GP IIb/IIIa inhibitor administration in these patients.¹⁰ The aim of the present study was to assess the impact of concomitant treatment with GP IIb/IIIa inhibitors on the clinical outcomes of acute myocardial infarction patients who underwent rescue PCI with stents. Methods Patient population. We retrospectively compared the 30-day outcomes in two cohorts of patients who underwent rescue PCI after full-dose thrombolytic therapy. All patients admitted with ST-segment elevation myocardial infarction were treated with either streptokinase (Streptase®, Aventis Behring, Marburg, Germany) or t-PA (Actilyse®, Boehringer Ingelheim, Rhein, Germany) and failed to show signs of reperfusion. A decision to perform emergency coronary angiography/PCI was included in the study. Failed thrombolysis was diagnosed one hour after the end of the thrombolytic infusion when there were no electrocardiographic signs of reperfusion, i.e., there was failure of the ST-segment to fall by > 50%. Although chest pain resolution and the appearance of reperfusion arrhythmias were also used adjunctively for the diagnosis of failed thrombolysis, they were not used independently as markers of reperfusion. After a diagnostic angiographic procedure was performed in 59 patients and a decision to intervene on the infarct-related artery was taken, 29 patients underwent percutaneous revascularization and were treated concomitantly with a GP IIb/IIIa inhibitor, whereas 30 patients did not receive a GP IIb/IIIa inhibitor during the revascularization procedure. Glycoprotein IIb/IIIa inhibitor therapy. A total of 29 patients were treated with one of the currently available GP IIb/IIIa inhibitors: abciximab (ReoPro®, Eli Lilly & Co., Indianapolis, Indiana) was administered as a 0.25 µg/kg bolus followed by a 12-hour infusion of 0.125 µg/kg/min; eptifibatide (Integrilin®, COR Therapeutics, South San Francisco, California) was given as a double bolus of 180 µg/kg administered 10 minutes apart, and as a continuous infusion of 2 µg/kg per minute started at the same time of the first bolus and continued for 18 to 24 hours; and tirofiban (Aggrastat®, Merck and Co., Inc., Whitehouse Station, New Jersey) as a 25 µg/kg bolus followed by an 18-hour infusion of 0.15 µg/kg, per routine protocol. The selection of the GP IIb/IIIa inhibitor was arbitrary and left to the discretion of the operator. All patients included in the study underwent stenting of the infarct-related lesion. Procedure. All patients underwent diagnostic coronary angiography and intervention according to current guidelines with conventional steerable guidewire systems via the femoral approach using 6 Fr guiding catheters.¹¹ All patients received aspirin 325 mg on diagnosis of acute myocardial infarction and daily after the procedure. Weight-adjusted heparin dosage was administered during the procedure as an intravenous bolus (100 IU/kg or 50–60 IU/kg, if a GP IIb/IIIa was administered). Heparin was routinely discontinued at the end of the procedure. Clopidogrel was administered at the end of the procedure (loading dose of 300 mg followed by 75 mg daily), and continued for at least 4 weeks per the routine protocol. Vascular access sheaths were routinely removed 4 hours after the procedure. Clinical success was defined as a successful revascularization in the absence of death, reinfarction or emergency coronary artery bypass graft surgery. Major bleeding was defined as a reduction in hemoglobin > 5 g/dL (or greater than or equal 15% in hematocrit), retroperitoneal bleeding or any intracranial bleeding. Vascular complications were defined as the need for surgical repair, large hematoma (diameter > 10 cm), pseudoaneurysm or fistula at the vascular access site. Reinfarction was determined as the development of new, abnormal Q-waves or creatine kinase, MB fraction or cardiac troponin re-elevation above the upper normal limit, and either chest pain or ischemic discomfort lasting > 20 minutes at rest. Statistical analysis. Statistical significance of the differences between treatment groups for the baseline clinical characteristics, the composite of events, individual endpoints, or bleeding complications were assessed by use of the Chi-square test (or Fisher’s exact test if small numbers were expected). Normally distributed variables (e.g., age) are presented as mean ± standard deviation (SD) and were compared using a two-sample t-test. A multivariate logistic regression model was used to determine the relative risk (with 95% confidence intervals) of developing the composite endpoint. The final model included selected baseline demographic and clinical characteristics which potentially could influence clinical events (GP IIb/IIIa inhibitors treatment, Killip class on admission, gender and age). Event-free curves were estimated by the Kaplan-Meier method, and curves were compared with the log-rank test. A p-value of less than 0.05 was considered to indicate statistical significance. Data were analyzed using the SPSS statistical software 11.1 (SPSS, Chicago, Illinois). Results Between January 2001 and August 2004, a total of 59 consecutive acute myocardial infarction patients who were treated with thrombolytic therapy and failed to show signs of reperfusion, underwent rescue PCI with stents at our institution. During the procedure, 29 patients (49.2%) were treated concomitantly with a GP IIb/IIIa inhibitor and 30 (50.8%) were not. The majority of these patients were treated with either abciximab or eptifibatide, reflecting different time periods, as abciximab is now seldom used during PCI at our institution. Baseline clinical characteristics are shown in Table 1. A significantly larger number of patients who received GP IIb/IIIa inhibitors had a prior history of coronary interventions. All other baseline clinical characteristics, location of the infarct, Killip class on arrival and the presence of multivessel disease, were similar between the two groups. Pharmacological treatment of patients on admission is shown in Table 2. The left anterior descending coronary artery was the infarct-related artery in 52% of patients treated with GP IIb/IIIa inhibitors and in 43% of those who were not treated, respectively (p = NS). As expected, the majority of patients had abnormal coronary blood flow on arrival to the catheterization laboratory. The procedure was technically successful in all patients in both groups, with successful restoration of normal TIMI 3 coronary blood flow in 90% of patients in both groups. All patients were treated with bare metal stents. In-hospital and 30-day outcomes. In-hospital outcomes are shown in Table 3. Hard endpoints such as death and the need for urgent target vessel revascularization (TVR) were numerically lower in patients treated with GP IIb/IIIa inhibitors compared to those who were not treated with the agent. The composite endpoint of death, reinfarction and urgent TVR was significantly lower in patients treated with GP IIb/IIIa inhibitors (p = 0.01). There was a slightly higher rate of major bleeding complications in patients who received GP IIb/IIIa inhibitors, but it did not achieve statistical significance. The 30-day Kaplan-Meier event-free survival curve is shown in Figure 1. Overall event-free survival was 96.7% versus 73.3% (p = 0.01). The composite endpoint of major bleeding, minor bleeding and vascular complications was similar in both groups, as shown in Table 3. By multivariate analysis, GP IIb/IIIa inhibitor administration was not an independent predictor of 30-day outcomes. The only independent predictors were age and Killip class on admission. Discussion In the present study we observed a significant reduction in the 30-day composite endpoint of death, reinfarction and urgent TVR in patients treated with GP IIb/IIIa inhibitors during rescue PCI following full-dose thrombolytic therapy. The additional use of GP IIb/IIIa inhibitors in these patients was not associated with an increase in bleeding (major or minor) or vascular complications. By multivariate analysis, GP IIb/IIIa inhibitor administration was not an independent predictor of better outcomes. Interestingly, despite the small number of patients in the study, baseline clinical characteristics for both groups were similar, probably reflecting the personal inclination of the operator regarding the use of GP IIb/IIIa inhibitors, and not a selection according to the severity of the case. Nevertheless, we cannot ignore the retrospective nature of this analysis and potential bias incurred by different operators regarding the administration of GP IIb/IIIa inhibitors after full-dose thrombolysis. There are scant data in the literature regarding the use of GP IIb/IIIa inhibitors in patients who undergo rescue PCI. As is, thrombolytic therapy restores patency of the infarct-related artery in 75% of patients at 90 minutes, but normal (TIMI 3) coronary blood flow in only half of all patients.1 Therefore, in medical institutions that have on-site cardiac catheterization facilities, rescue PCI is considered a viable option. The potential for major bleeding complications has been the main deterrent for the administration of GP IIb/IIIa inhibitors in patients who undergo rescue PCI. The administration of another potent pharmacological agent that interferes with normal coagulation in patients treated with aspirin and full-dose thrombolytic therapy has not been fully assessed and has been approached with trepidation. Previous studies conducted prior to the advent of GP IIb/IIIa inhibitors that compared balloon angioplasty versus conservative medical therapy showed a marginal benefit for patients randomized to rescue angioplasty. The most recent of these studies was the Middlesbrough Early Revascularization to Limit Infarction (MERLIN) trial.¹⁰ Despite the fact that this study enrolled patients between 1999 and 2002, only a small fraction (3.3%) of all the patients in the rescue angioplasty arm were concomitantly treated with GP IIb/IIIa inhibitors, and none were treated with the agent in the conservative arm.¹⁰ Although this study was not powered to show a benefit in mortality, it demonstrated a lower incidence of the 30-day composite secondary endpoint of death, reinfarction, stroke, repeat revascularization and heart failure. Nevertheless, patients enrolled in the rescue arm of the study had a significantly higher need for blood transfusions. A study by Petronio et al.9 randomized 89 consecutive patients who underwent rescue PCI to either abciximab and low-dose heparin (70 U/kg; n = 44), or placebo plus low-dose heparin (70 U/kg; n = 45). Abciximab treatment during rescue PCI was associated with a lower incidence of cardiac events at 30 days and at 6-month follow up (11% vs. 38%; p = 0.004). Furthermore, there was a significant improvement in left ventricular function at 6 months as assessed by wall motion score index by echocardiography in these patients. It is important to note that 71% of these patients were treated with stents. The incidence of major and minor bleeding complications was similar between the two groups. In a multicenter study by Jong et al.⁸ from Canada, 147 patients underwent PCI within 48 hours after thrombolytic therapy (rescue and urgent PCI). In this study, 57 patients (39%) treated with abciximab during the procedure. The combined primary endpoint of the study, major and minor bleeding complications occurred more frequently in the abciximab group (63%) than in the control group (39%; p = 0.004). There was a four-fold increase in the risk of major bleeding (12% vs. 3%; p = 0.03), and a two-fold increase in major and minor bleeding complications (54% vs. 38%; p = 0.05). Although the authors reported an 89% procedural success rate in both groups, they did not address clinical outcomes. Sundlof et al.¹² reported a 23% rate of major bleeding events in 22 patients who underwent rescue PCI within 15 hours of abciximab administration. Two of these cases were fatal. On the contrary, no bleeding complications were observed in patients who underwent the procedure more than 15 hours after thrombolysis. Both of these studies accentuated the need for a cautious approach in patients who undergo rescue PCI. Study limitations. The present study was a retrospective, nonrandomized analysis in a small number of patients, thus the results are limited by the shortcomings inherent in this type of study. The use of a non-fibrin specific agent (streptokinase) can also be considered as a limitation of the study. Given the small number of events, the multivariate analysis might not be sufficiently powered to show an independent effect of GP IIb/IIIa inhibitors on outcomes. The type of GP IIb/IIIa inhibitor administered was left to the discretion of the operator, and therefore was also possibly subject to selection bias. All bleeding complications were obtained from chart reviews and were thus subject to reporting limitations and biases. Conclusion Based on our limited experience, the administration of GP IIb/IIIa inhibitors during rescue PCI after failed thrombolysis in patients with ST-segment acute myocardial infarction was safe and may have a beneficial effect on 30-day event-free survival rates, without a significant increase in bleeding or vascular complications. These results warrant further investigation through larger, randomized studies.

1. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary artery patency, ventricular function and survival after acute myocardial infarction. N Engl J Med 1993;329:1615–1622. 2. The TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial: Phase 1 findings. N Engl J Med 1985;312:932–938. 3. Simes RJ, Topol EJ, Holmes DR, et al. for the GUSTO-1 Investigators. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Circulation 1995;91:1923–1928. 4. Ellis SG, da Silva ER, Heindryckx G, et al. Randomized comparison of rescue angioplasty with conservative management of patients with early failure of thrombolysis for acute anterior myocardial infarction. Circulation 1994;90:2280–2284. 5. Simoons ML, Arnold AE, Betriu A, et al. Thrombolysis with tissue plasminogen activator in acute myocardial infarction: No additional benefit from immediate percutaneous coronary angioplasty. Lancet 1988;1:197–203. 6. Prendergast BD, Shandall A, Buchalter MB. What do we do when thrombolysis fails? A United Kingdom survey. Int J Cardiol 1997;61:39–42. 7. Miller JM, Smalling R, Ohman EM, et al. Effectiveness of early coronary angioplasty and abciximab for failed thrombolysis (reteplase or alteplase) during acute myocardial infarction (results from the GUSTO III Trial). Am J Cardiol 1999;84:779–784. 8. Jong P, Cohen EA, Batchelor W, et al. Bleeding risks with abciximab after full-dose thrombolysis in rescue or urgent angioplasty for acute myocardial infarction. Am Heart J 2001;141:218–225. 9. Petronio AS, Musumeci G, Limbruno U, et al. Abciximab improves 6-month clinical outcome after rescue coronary angioplasty. Am Heart J 2002;143:334–341. 10. Sutton AG, Campbell PG, Graham R, et al. A randomized trial of rescue angioplasty versus a conservative approach for failed fibrinolysis in ST-segment elevation myocardial infarction: The Middlesbrough Early Revascularization to Limit INfarction (MERLIN) trial. J Am Coll Cardiol 2004;44:287–296. 11. Pepine CJ, Holmes DR, for the Cardiac Catheterization Committee. ACC Expert Consensus Group. Coronary artery stents. J Am Coll Cardiol 1996;28:782–794. 12. Sundlof DW, Rerkpattanapitat P, Wongpraparut N, et al. Incidence of bleeding complications associated with abciximab use in conjunction with thrombolytic therapy in patients requiring percutaneous transluminal coronary angioplasty. Am J Cardiol 1999;83:1569–1571, A7.