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Prophylactic Abciximab in Elective Coronary Stenting: Results of a Randomized Trial
February 2002
Recent large randomized trials have shown that abciximab [a potent inhibitor of platelet aggregation via glycoprotein (GP) IIb/IIIa blockade] is a safe and effective drug in reducing the incidence of death, myocardial infarction and the need for urgent revascularization after percutaneous transluminal coronary balloon angioplasty or coronary stent deployment.1,2 Furthermore, the use of abciximab in “high-risk” coronary angioplasty was associated with a significant reduction in target lesion revascularization at 6-month3 and 3-year follow-up.4
Intracoronary stents have been demonstrated to improve early (post-procedural) and late (6-month) target lesion lumen diameter and reduce the incidence of binary angiographic restenosis compared with balloon angioplasty.5 However, acute and subacute stent thrombosis,6 acute ischemic complications7 and late in-stent restenosis8 remain significant issues, particularly in complex (multiple, long or unplanned) stent subsets. Furthermore, despite advances in catheter technology and adjunctive pharmacology, treatment of lesions with complex morphology, particularly long lesions9 with long10,11 or multiple12 stents, is still associated with worse immediate and long-term outcomes.13,14
Moreover, there is evidence that thrombus,15 inflammation and neointimal cell proliferation and remodeling after stent implantation play key roles in the vascular response to intracoronary stenting, and may thus affect clinical outcomes.16,17 As abciximab demonstrates affinity for cellular receptors specific to each of these processes (thrombus: platelet GP IIb/IIIa;18 inflammation: white cell CD 11b;18,19 neointimal proliferation: smooth muscle avb3)20 it could potentially modify the vascular response to stent deployment, and thus, clinical events in stented patients.
Although prophylactic administration of abciximab has been demonstrated to improve clinical outcomes in patients having elective or unplanned coronary stent deployment and reduces target vessel revascularization in stented patients with diabetes mellitus, the utility of abciximab in patients undergoing stenting for long coronary stenoses is unknown.
The purpose of this study was to assess the safety of prophylactic abciximab administration in the treatment of long coronary lesions requiring implantation of long or multiple overlapping coronary stents and to evaluate the effect of abciximab treatment on ischemic adverse outcomes and late restenosis in this patient population.
METHODS
Patients and study protocol. This is a single-center, open-label, randomized study of patients selected from the percutaneous transluminal coronary angioplasty population of the Interventional Unit at the University Hospital of Catania. Patients with demonstrable reversible ischemia and severe (> 70%) de novo native coronary stenoses requiring implantation of either a stent longer than 20 mm or of multiple overlapping stents were included. Patients were excluded if they had a saphenous graft lesion, bleeding diathesis, thrombocytopenia ( 180 mmHg, diastolic blood pressure > 100 mmHg), major surgery or trauma within 6 weeks.
Between October 1996 and February 1998, a total of 512 percutaneous coronary interventions were performed. An intracoronary stent implantation was performed in 368 patients (72%). One-hundred and seven patients (29%) treated with elective implantation of either a stent longer than 20 mm or of multiple overlapping stents form the intent-to-treat population of the study. The randomization to study medication was performed with a standard list of random numbers. All patients had a complete blood cell count and cardiac enzyme checks at 6, 12, 24, 36 and 48 hours post-procedure and at discharge. They were regularly followed at 1, 3 and 6 months to obtain clinical information after the procedure and to perform repeat angiography in case of recurrent angina. All patients underwent 6-month angiographic follow-up. The protocol was approved by the ethical committee of our hospital.
Study medication and adjunctive therapy. All patients received 325 mg aspirin orally the day before the procedure, and daily thereafter. Ticlopidine 250 mg twice daily was started the day before the intervention and was prescribed to all patients for four weeks following the procedure. Patients were randomly assigned to one of the two study medication treatment groups: 1) placebo with standard dose, weight-adjusted heparin [100 U/kg bolus to a maximum of 100,000 units with supplemental heparin to target a procedural activated clotting time (ACT) of Randomization. Randomization was performed with the use of closed envelopes. A research nurse was asked to open the envelop every time a case was enrolled. Interventionalists were not blinded to the randomization, but they had no control over the group assignment even when more than one case per day was randomized.
Stent implantation procedure. Procedures were performed via the femoral artery using 8 French (Fr) guiding catheters as previously described.21 Briefly, different types of slotted tubular and coil stents were used according to the characteristics of the lesions and availability in the catheterization laboratory. All stents were implanted after predilation of the lesion. Post-deployment high-pressure balloon inflations (> 16 atm) using non-compliant balloons were then performed to achieve a final angiographic result of Angiographic analysis. Coronary angiograms before stenting, immediately after stenting and at follow-up were analyzed by two experienced angiographers not involved in the procedure and blinded to the study medication treatment. Patients received intracoronary nitroglycerin (2 mg) before baseline and final angiograms to achieve maximal coronary vasodilation. Stenoses were measured on manual calipers in end-diastolic frames on two orthogonal views. The guiding catheter was used as the reference object for measurement of vessel length and diameter. The following parameters were calculated from the angiographic analysis: acute gain [minimal luminal diameter (MLD) post-stenting minus MLD pre-stenting], late loss (MLD after stenting minus MLD at follow-up) and net gain (MLD at follow-up minus MLD pre-stenting). Lesion severity at the baseline angiogram was characterized according to the modified American College of Cardiology/American Heart Association classification.22
Objectives. The primary objective of the study was to assess the safety (bleeding and vascular complications) of prophylactic abciximab and its efficacy in reducing major in-hospital adverse cardiac events related to the procedure (death, myocardial infarction and urgent revascularization) during elective implantation of long or multiple overlapping coronary stents. The secondary objective was to evaluate the efficacy of abciximab in reducing death, myocardial infarction, or target lesion revascularization (TLR) and angiographic binary restenosis in such a complex setting to 6 months of follow-up.
Definitions. Angiographic success: final post-procedural diameter stenosis of 5 g/dL or hematocrit > 15%) or minor (spontaneous hematuria or hematemesis, observed hemorrhage producing a fall in hemoglobin > 3 g/dL or a decrease in hemoglobin > 4 g/dL with no identified bleeding site) in accordance with the Thrombolysis in Myocardial Infarction (TIMI) criteria. Vascular complications: occurrence of bleeding or hematoma formation at the puncture site requiring transfusion or vascular repair or prolonged (> 30 minute) external compression. Death: all causes. Myocardial infarction (MI): Q-wave myocardial infarction (occurrence of new pathological Q-waves in conjunction with elevation in creatine kinase levels > 3 times the upper limit of normal); non-Q wave MI (elevation of the cardiac enzymes to greater than three times the normal value without new pathologic Q-wave development). Urgent revascularization: interventions (coronary artery bypass surgery or repeated PTCA) performed during the hospitalization. Target lesion revascularization: non-emergency surgical or percutaneous procedure performed for symptomatic restenosis. Acute or subacute stent thrombosis: stent occlusion or the finding of TIMI I or II flow associated with an intraluminal filling defect occurring following successful stent deployment. Stent restenosis: >= 50% luminal reduction immediately adjacent to (marginal) or within the stent site at follow-up angiogram irrespective of clinical symptoms of the patient.
Statistical analysis. All variables were expressed as means ± standard deviation. All variables in the two treatment arms were compared with the Student’s t-test for all continuous data and with the Chi-square test for all qualitative data. A probability of RESULTS
A total of 107 patients were randomized to the heparin group (n = 53) or the abciximab group (n = 54). Baseline demographic, clinical and angiographic characteristics are shown (Tables 1 and 2). There were no substantial differences between randomized groups in clinical variables.
The stent type, number of stents per lesion and the rate of hybrid stenting (overlapping of different stent types) were also similar between the 2 groups (Table 3). The stent/lesion ratio was 1.4; lesions shorter than 20 mm were included only when treated with 2 overlapping stents.
The acute and follow-up angiographic results are shown in Table 4. Angiographic success was obtained in 100% of cases. One patient in the heparin group experienced acute stent thrombosis ten minutes after stent deployment in the right coronary artery and was successfully treated with further balloon inflations and a bail-out infusion of abciximab. He had an uneventful recovery and no restenosis was observed at 6-month angiographic follow-up. Despite similar acute gain (2.5 ± 0.8 mm in heparin group versus 2.3 ± 0.3 mm in the abciximab group; p = not significant), a significant greater late loss at follow-up was observed in the heparin group as compared to the abciximab group (1.7 ± 0.4 mm versus 0.9 ± 0.8 mm, respectively; p 50% diameter stenosis) was observed in 9 out of 54 patients (17%) treated with abciximab and in 18 out of 53 patients (34%) with a standard dose of heparin (p = 0.03).
Major in-hospital and 6-month adverse cardiac events are shown in Table 5. One patient with post-infarctional angina in the heparin group died following an unexpected ventricular fibrillation occurring 20 hours after stent deployment in the proximal segment of the left anterior descending coronary artery (LAD). Another patient in the heparin group had a lateral myocardial infarction 10 hours after stent implantation in the left circumflex coronary artery. Repeat coronary angiography was not performed in the patient because of the complexity of the target vessel and a limited extent of infarction. A total of three patients (5.6%) in the heparin group and two patients (3.7%) in the abciximab group experienced a non-Q wave MI. One patient in the heparin group suffered an acute stent thrombosis, which was documented angiographically. None of the patients underwent urgent target lesion revascularization. Overall, composite in-hospital events were recorded in 6 patients (11.3%) in the heparin group and 2 patients (3.7%) in the abciximab group (p = 0.13).
There were no deaths at 6-month follow-up of patients discharged from the hospital. One heparin-treated patient experienced subacute stent thrombosis 9 days after successful stent deployment in the proximal LAD. This patient had voluntarily discontinued ticlopidine and aspirin therapy. During follow-up, one patient in the heparin group presented with electrocardiographic changes consistent with a previous inferior MI. Follow-up angiography showed a functional stent occlusion due to diffuse, severe in-stent restenosis and percutaneous coronary intervention (PCI) was not attempted. Ten patients in the heparin group underwent TLR for symptomatic angina [6 PCI, 4 coronary artery bypass graft surgeries (CABG)]. In the abciximab group, 6 patients had TLR at follow-up (4 PCI, 2 CABG). The overall TLR rate was 21% in the heparin group and 11% in the abciximab group (p = 0.1). Composite follow-up events were encountered in 13 heparin-treated patients (24%) and 6 abciximab-treated patients (11%) (p = 0.06). Overall, the incidence of in-hospital and follow-up composite adverse events was significantly lower in abciximab patients versus heparin patients (14% versus 35%, respectively; p = 0.01).
Bleeding and vascular complications are shown in Table 6. No “major” bleeding complications or transfusions occurred in either group. In the heparin group, one patient suffered from hematemetis. In the abciximab group, two patients experienced minor bleeding (spontaneous hematuria, mild gingival bleeding). One heparin patient had a groin hematoma not requiring vascular repair. A case of thrombocytopenia (40,000 platelets/µL) was observed in one abciximab patient. No differences in bleeding or vascular complications were observed.
DISCUSSION
The major findings of this randomized, controlled trial of prophylactic abciximab administration to patients undergoing complex coronary stent deployment are the following: 1) peri-procedural use of abciximab with a low-dose weight-adjusted heparin regimen is safe because it does not cause an increased incidence of bleeding/vascular complications or adverse drug reactions compared to standard heparin regimen; 2) abciximab therapy is valuable and effective in patients with complex, long lesions requiring long or multiple overlapping coronary stent implantation because it is associated with a 68% reduction (p = 0.1) of the composite in-hospital adverse cardiac events and a significant reduction of the incidence of overall in-hospital and follow-up composite adverse events (p = 0.01); and 3) patients treated with abciximab had a better 6-month outcome than those receiving standard-dose heparin, especially with respect to target lesion revascularization (48% reduction; p 72 hours before the procedure to decrease the degree of activation of hemostasis.31 A premedication with ticlopidine for more than 72 hours before the procedure is rarely achieved in clinical practice; therefore, abciximab, which allows immediate blockade of platelet GP IIb/IIIa receptors, could be extremely valuable in reducing the incidence of major adverse cardiac events in a high-risk stenting patient population.
A trend toward a reduction in TLR has been shown in our study. Prophylactic adjunctive therapy with abciximab has been shown to significantly reduce 6-month TLR,7 with a particularly marked benefit in diabetics32 and patients undergoing complex coronary stenting.23
Furthermore, in our study, a significant reduction in angiographic restenosis rate was observed in the abciximab patients. In the EPIC trial (where only selected patients undergoing high-risk coronary angioplasty were enrolled),1 abciximab therapy was associated with a 26% reduction in the need for TLR at 6 months, leading to the hypothesis that this drug may inhibit the process of restenosis. Indeed, these findings were not confirmed in the EPILOG trial, where unselected patients undergoing elective balloon angioplasty were recruited.2
The ERASER study33 did not show a beneficial effect of abciximab in reducing angiographic in-stent restenosis (binary 50%), angiographic late loss or volumetric obstruction by intravascular ultrasound. Even in this elective population, a 53% reduction in the composite occurrence of death, myocardial infarction and TLR at 1 week was observed. It is difficult to explain our findings as compared to the ERASER results. However, abciximab’s ability to reduce the restenosis/TLR rate might have become more evident in a population with a higher likelihood of in-stent restenosis, such as long or multiple overlapping coronary stents.
Indeed, it has been shown that intracoronary stent implantation increases platelet responsiveness,34 activates dynamic expression of GP IIb/IIIa receptors on the platelet surface35 and promotes free thrombin generation, all of which predispose to thrombus formation. It has been reported that the degree of platelet activation directly correlates with the development of in-stent restenosis at 6 months after long stent implantation.36
Neointimal growth represents the main mechanism of in-stent restenosis in both experimental37,38 and clinical studies.39 The pathophysiology of restenosis is not fully understood, but histological studies in human stented coronary arteries have shown that thrombosis, inflammation with recruitment of monocytes and lymphocytes play an important role in the early phases after coronary stenting and their degree may be related to medial injury and lipid core penetration.40 Proliferation of smooth muscle cells and neointimal growth are late mechanisms, often related to the degree of thrombosis/inflammation.40–43 Moreover, overlapping stents produce more pronounced coronary vessel injury, resulting in more inflammation and neointimal hyperplasia compared to single stents.44
The avb3 receptors become up-regulated following deep arterial injury and play a key role in modulating the cellular proliferation phase of restenosis.45 Selective avb3 blockade results in a marked reduction of neointimal hyperplasia and percent diameter stenosis in a large-animal coronary restenosis model.46
Abciximab decreases thrombus formation after PCI,47 is effective in the treatment of acute stent thrombosis,48 binds avb3 receptors,20 reduces CD11b expression on leukocytes during coronary angioplasty and leukocyte-platelet interactions.19 All of the above are potential mechanisms that may explain the role of abciximab in the prevention of in-stent restenosis.
Study limitations. A possible drawback of this study is the method of angiographic analysis used. During recent years, the role of quantitative coronary arteriography in the trials analyzing restenosis has been widely recognized and the importance of achieving absolute values of luminal diameter has been underlined. However, even if we are aware of the limitations in accuracy that might derive from a “semiquantitative” analysis, we must emphasize that errors of measurement must be evenly distributed among the two groups (heparin and abciximab), since the reading of angiograms was blind to treatment. A larger cohort of patients would have been necessary to increase the statistical power of the study, and to clarify the direction of possible trends in outcome. The stent implantation procedure in this study was performed without intravascular ultrasound guidance. It cannot be determined whether the lack of such guidance might have resulted in sub-optimal stent expansion in some of our patients. However, randomization means that such occurrences must have been evenly distributed. This is a single-center study and there could have been bias reflecting local practices and prejudices.
Conclusion. Prophylactically administered adjunctive therapy with abciximab should be considered during percutaneous coronary interventions in patients with long lesions who may require the deployment of long or overlapping stents.
1. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956–961.
2. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689–1696.
3. Topol EJ, Califf RM, Weisman HF, et al., on behalf of the EPIC Investigators. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: Results at six months. Lancet 1994;343:881–886.
4. Topol EJ, Ferguson JJ, Weisman HF, et al. for the EPIC Investigator Group. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin b3 blockade with percutaneous coronary intervention. JAMA 1997;278:479–484.
5. Topol EJ. The stentor and the sea change. Am J Cardiol 1995;76:307–308.
6. Moussa I, Di Mario C, Reimers B, et al. Subacute stent thrombosis in the era of intravascular ultrasound-guided coronary stenting without anticoagulation: Frequency, predictors and clinical outcome. J Am Coll Cardiol 1997;29:6–12.
7. The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet 1998;352:87–92.
8. Kastrati A, Schömig A, Elezi S, et al. Predictive factors of restenosis after coronary stent placement. J Am Coll Cardiol 1997;30:1428–1436.
9. Kobayashi N, Finci L, Ferraro M, et al. Restenosis after coronary stenting — Clinical and angiographic predictors in 1,906 lesions (Abstr). J Am Coll Cardiol 1999;33(Suppl A):32A.
10. Kobayashi N, De Gregorio J, Kobayashi Y, et al. The treatment of long lesions: How does varying stent length affect outcome? (Abstr). Am J Cardiol 1988;82:56S.
11. Kornowski R, Bhargava B, Fuchs S, et al. Procedural results and late clinical outcomes following percutaneous interventions using long (> 25 mm) versus short (
