Prophylactic Abciximab in Elective Coronary Stenting: Results of a Randomized Trial
- Volume 14 - Issue 2 - February, 2002
- Posted on: 8/1/08
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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 < 0.001). The net gain was significantly greater in the abciximab group than in the heparin group (1.4 ± 0.2 mm versus 0.7 ± 0.5 mm, respectively; p < 0.001). All patients underwent follow-up angiography. Late restenosis (> 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.
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 < 0.1). Follow-up angiographic results showed a significant reduction in late loss and in the restenosis rate in the abciximab group.
The results of this study are consistent with those reported by the EPISTENT Investigators7 and by Kereiakes and colleagues23 in patients undergoing elective and unplanned stent implantation, respectively. In both series, no increase in bleeding complications was observed in patients treated with abciximab and a significant reduction in adverse cardiac events (death, myocardial infarction, urgent revascularization) at 30 days was reported.
The use of the combined antiplatelet regimen of ticlopidine and aspirin has been associated with a significant reduction in the incidence of cardiac ischemic events at 1 month, not only in a low to intermediate risk population,24–27 but also in patients with a high risk profile.28,29 However, in the setting of complex coronary stenting, the risk of major adverse coronary events is far from negligible. In the STARS registry,29 in which patients with sub-optimal results were included (29% with severe dissection, 35% with more than 2 stents), the incidence of stent thrombosis was significantly higher (3%) than for patients in the randomized cohort of STARS trial (0.5%), despite the use of combined antiplatelet therapy and the use of abciximab in only 9% of the patients. Moreover, in the MATTIS trial, in which high-risk patients (bail-out stent implantation, sub-optimal result, long segment stented) were enrolled, the primary composite endpoint (occurrence of cardiovascular death, MI or repeat revascularization) was reached in 5.6% of the patients treated with ticlopidine and aspirin. Berger et al. have demonstrated that the risk of ischemic complications is significantly higher in the first 2 weeks after stent implantation.30 Even though the combined use of ticlopidine and aspirin markedly reduces the generation of thrombin and the activation of platelets, ticlopidine should be administered > 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.