Abciximab and Angiographic Restenosis After Coronary Stent Placement. Analysis of the Angiographic Substudy of ISAR-REACT
Helmut Sch?len, MD; Adnan Kastrati, MD; Julinda Mehilli, MD; Jörg Hausleiter, MD; Josef Dirschinger, MD; Franz Dotzer, MD; Hildegard Bollwein, MD; Albert Schömig MD 

Am Heart J.  2006;151(6):1248-1254.  ?2006 Mosby, Inc.
Posted 07/06/2006

Abstract and Introduction

Abstract

Background: ISAR-REACT was a trial designed to evaluate whether the glycoprotein IIb/IIIa inhibitor abciximab is beneficial in patients undergoing elective percutaneous coronary intervention (PCI) with stent placement after pretreatment with a 600 mg loading dose of clopidogrel. Objective for the angiographic substudy was to determine the impact of abciximab on angiographic restenosis after coronary stent placement. Previous analyses have suggested a reduction in the incidence of restenosis after the administration of abciximab.
Methods: The angiographic substudy comprises 1885 of 2159 patients enrolled in ISAR-REACT: 994 patients were randomly assigned to abciximab and 941 patients to placebo. All patients were scheduled for a routine angiographic follow-up after 6 months (performed in 80% of eligible patients). End points for the angiographic substudy were the rates of angiographic restenosis (≥50% diameter stenosis) and target lesion revascularization.
Results: The incidence of angiographic restenosis was 27% in the abciximab group and 29% in the placebo group (relative risk 0.92, 95% CI 0.79-1.06, P = .27). Late angiographic lumen loss was 0.95 ? 0.68 and 0.99 ? 0.70 mm, respectively (P = .25). Similar results were obtained in a subgroup analysis focusing on high-risk subsets. The rate of target lesion revascularization procedures was 22% in the abciximab group and 23% in the placebo group (relative risk 0.94, 95% CI 0.79-1.12, P = .52).
Conclusions: In low- to intermediate-risk patients who undergo elective PCI after pretreatment with a high loading dose of clopidogrel >2 hours before PCI, the additional administration of the glycoprotein IIb/IIIa inhibitor abciximab is not associated with a significant reduction in angiographic restenosis.

Introduction

The ISAR-REACT trial tested whether the glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor abciximab is beneficial in low- to intermediate-risk patients undergoing elective percutaneous coronary intervention (PCI) after pretreatment with clopidogrel.[1] The analysis of the primary end point, a composite of the incidence of death, myocardial infarction (MI), or urgent target vessel revascularization during the first 30 days after randomization, revealed that the additional administration of abciximab is not associated with a clinically measurable benefit if these patients received a loading dose of 600 mg of clopidogrel at least 2 hours before the procedure.[1] This primary analysis clearly focused on very early complications of PCI relating to the delayed onset of action of thienopyridines.[2,3] These drugs have become the mainstay of antithrombotic therapy after coronary artery stenting in conjunction with aspirin.[4,5] Based on earlier findings that a 600 mg loading dose of clopidogrel leads to most of the maximal antiplatelet effect within 2 to 4 hours,[6,7,8] ISAR-REACT suggests that this regimen, administered at least 2 hours before the procedure, minimizes or abolishes the known clinical benefit of abciximab of reducing early thrombotic complications.[9,10]

Apart from this effect of abciximab on the rate of early thrombotic complications as tested by this primary analysis of ISAR-REACT, previous experimental and clinical data also suggested a potential role of GPIIb/IIIa receptor blockade to reduce restenosis after PCI. Studies in animal models have indicated a direct link between platelet adhesion, aggregation, and thrombosis, and neointimal formation.[11,12,13] In addition to this attenuation of the platelet aggregation response inherent to all GPIIb/IIIa inhibitors, only abciximab inhibits also the vitronectin receptor, potentially interfering with a pathway that induces smooth muscle cell migration, leading to neointimal growth.[14] However, conflicting results have been found in clinical trials.[15,16,17,18]

Therefore, we designed the angiographic substudy of ISAR-REACT to assess whether the administration of abciximab is associated with a reduction in angiographic restenosis after PCI with coronary stent placement in patients with an optimized oral antithrombotic regimen of aspirin plus clopidogrel.

Methods

Patients

Detailed patient selection criteria for the ISAR-REACT trial have been described previously.[1] Briefly, patients with coronary artery disease were eligible for this study if they were to undergo elective PCI in native coronary vessels between May 2000 and February 2003, and had been pretreated with a high loading dose of clopidogrel (600 mg) at least 2 hours before PCI. The main exclusion criteria were recent MI within the prior 14 days, unstable angina with ST-segment changes and/or elevated troponin T levels, chronic total occlusions (>3 months), left ventricular ejection fraction <30%, insulin-dependent diabetes mellitus, or contraindications for the administration of a GPIIb/IIIa inhibitor. All patients provided written informed consent for participation in the study, and the study protocol was approved by the ethics committees of the participating centers.

The predefined angiographic substudy comprises all patients randomized at 3 centers, the Deutsches Herzzentrum M?chen, the 1 Medizinische Klinik at Klinikum rechts der Isar M?chen, and the Medizinische Klinik I in Garmisch-Partenkirchen. All patients from these 3 centers were scheduled for an angiographic follow-up at 6 months.

Study Protocol

All patients received clopidogrel 600 mg at least 2 hours before PCI. They also received 500 mg of aspirin intravenously at the beginning of the PCI procedure. Patients were randomized in a double-blind manner into 2 study groups. Patients in the abciximab group received abciximab (0.25 mg/kg bolus, followed by a 0.125 ?g/kg per minute [maximum of 10 ?g/min] infusion for 12 hours) along with 70 U of heparin per kilogram. Patients in the placebo group received a bolus of placebo, followed by a 12-hour infusion, and a bolus of 140 U of heparin per kilogram.

Coronary stenting was the target PCI procedure according to protocol. Therapy post-PCI included aspirin, 100 to 325 mg indefinitely; and clopidogrel, 75 mg twice a day until discharge (but for a maximum of 3 days), followed by daily administration of 75 mg for at least 1 month as indicated, as well as other cardiac medications as felt to be required by the patient's physician.

All patients in the angiographic substudy were asked to return for coronary angiography between 6 and 8 months after randomization or earlier if anginal symptoms had developed. Their clinical status was assessed over a period of 1 year.

Quantitative Coronary Angiography Evaluation

Coronary angiograms at baseline, after completion of PCI, and at follow-up were digitally recorded and sent for assessment to the Quantitative Angiographic Core Laboratory (Deutsches Herzzentrum, Munich, Germany). Analyses were performed by staff unaware of the assigned treatment arm. Digital angiograms were analyzed with the use of an automated edge detection system (CMS; Medis Medical Imaging Systems, Nuenen, the Netherlands). All measurements were performed on cineangiograms recorded after intracoronary nitroglycerin administration. The same projections were used at baseline and at the time of follow-up angiography. The contrast-filled nontapered catheter tip was used for calibration. The quantitative parameters that were measured included the reference diameter of the vessel, the minimal lumen diameter, and percentage of diameter stenosis. For patients who received stents, the quantitative analysis was performed in the "in-segment" area, including the stented segment, as well as both 5-mm margins proximal and distal to the stent.

Study end Points and Definitions

The end points of the whole ISAR-REACT trial have previously been reported.[1] The primary end point of the angiographic substudy was the incidence of binary angiographic restenosis defined as a diameter stenosis of ≥50% on follow-up angiography on the basis of the in-segment analysis. Secondary end point was the target lesion revascularization rate. A subgroup analysis was based on independent predictors of restenosis as defined by a previous analysis of patients with stent placement.[19] In addition, we assessed the incidence of target lesion revascularization due to angiographic restenosis and symptoms or signs of ischemia during the follow-up period.

Statistical Analysis

The data are presented as mean ? SD, median (25th, 75th percentiles), or as counts or proportions (percentage). The differences between the groups were assessed using a 2-sided χ2 test or Fisher exact test for categorical data, as appropriate. Student t test or nonparametric Wilcoxon rank sum test was used for comparing continuous data. Statistical significance was accepted for a 2-tailed P < .05.

Results

Study Population

Of a total of 2159 patients enrolled in ISAR-REACT, 1885 had been randomized at the 3 centers and have been enrolled in the angiographic substudy. Baseline clinical characteristics of these patients are displayed in Table I . No significant differences were observed between the 2 groups, nor did the population of this prespecified subgroup differ from the whole study population of ISAR-REACT. In these 1885 patients, a total of 2534 lesions were treated. In 321 patients of the abciximab group (34%), >1 lesion was treated compared to 328 in the placebo group (35%, P = .70). Baseline characteristics and procedural data for all treated lesions are displayed in Table II . At baseline, vessel size was significantly larger in the abciximab group (2.83 ? 0.56 vs 2.78 ? 0.57 mm in the placebo group, P = .021) and lesion length was longer (12.8 ? 6.7 vs 12.1 ? 7.0 mm, P = .013). Stent placement was the preferred procedure for this study and performed in 91% of lesions of both groups. Drug-eluting stents were used only in a small minority of procedures (4 and 5%); these were all sirolimus-eluting stents (Cypher; Cordis, Langenfeld, Germany). Unlike some dimensions measured before PCI, there was no significant difference in the angiographic measurements of the final results of the procedure.

In patients enrolled in the angiographic substudy, the primary end point of the whole ISAR-REACT trial (composite of death, MI, and urgent target vessel revascularization within the first 30 days[1]) was observed in 43 patients in the abciximab group (5%) and in 36 in the placebo group (4%, P = .43). These are almost identical figures for the angiographic substudy as for the whole study population (4% in both arms, P = .82).

Angiographic Follow-up

Of 1885 patients randomized, 24 patients were considered ineligible for follow-up angiography because of an unsuccessful procedure, death, or urgent target vessel revascularization within the first 30 days: 15 in the abciximab group and 9 in the placebo group. Of all eligible patients, 744 (80%) in the abciximab group and 749 (80%) in the placebo group had follow-up angiography; the median interval was 195 days (25th and 75th percentiles 175 and 214 days) and 195 days (25th and 75th percentiles 177 and 217 days), respectively (P = .54).

Table III lists the results of the quantitative analysis performed on follow-up angiograms, available in 1000 lesions in each group. Despite a small trend in all measurements favoring the abciximab group, no significant difference was observed. Figure 1 illustrates the cumulative curves for the minimal lumen diameter for the 2 groups, as measured at baseline before PCI, immediately after PCI, and at follow-up.

Figure 1. 

Cumulative curves of minimal lumen diameter of lesions before PCI, after PCI, and at follow-up angiography. FU, Follow-up angiography.

     

Restenosis Analysis

The primary end point of the angiographic substudy of ISAR-REACT, the incidence of angiographic restenosis, is illustrated in Figure 2. It was observed in 267 lesions (27%) in the abciximab group compared to 290 (29%) in the placebo group (relative risk 0.92, 95% CI 0.79-1.06, P = .27). Figure 3 illustrates the results for angiographic restenosis in subgroups with a high risk for restenosis identified by a previous analysis.[19] Although rates for angiographic restenosis was consistently higher in these subgroups, no significant difference was observed in any of these high-risk subsets. Only a nonsignificant trend was seen in the subgroup with diabetes mellitus (none of these patients were insulin treated because these were excluded from this trial).

Figure 2. 

Bars showing the incidence of angiographic restenosis and of target lesion revascularization in the abciximab and placebo groups of the study. Both comparisons yielded nonsignificant differences.

     

During follow-up, 217 lesions (22%) in the abciximab group and 230 (23%) in the placebo group were treated with a revascularization procedure (relative risk 0.94, 95% CI 0.79-1.12, P = .52). This was carried out predominantly by repeat PCI; only a minority was treated with coronary artery bypass surgery (2% in both groups).

Discussion

In the angiographic substudy of ISAR-REACT, we assessed whether the GPIIb/IIIa inhibitor abciximab reduces the rate of angiographic restenosis in low- to intermediate-risk patients undergoing elective PCI after pretreatment with clopidogrel. In these analyses, we found no significant differences in angiographic restenosis between the abciximab and the placebo group. The analysis complements the primary end point analysis of the entire study population of ISAR-REACT based on a composite of the incidence of death, MI, or urgent target vessel revascularization during the first 30 days after randomization.[1] This primary analysis related to the delayed onset of action of thienopyridines[2,3] and the known clinical benefit of abciximab of reducing early thrombotic complications.[9,10]

Abciximab and Restenosis

The rationale to perform the angiographic substudy was different. Early experimental data have suggested an important role of platelets in the development of restenosis.[21,22] Consequently, a direct link between platelet adhesion, aggregation, and thrombosis, and neointimal formation has been postulated.[11,12,13,23] Clinical trials on platelet inhibition with aspirin,[24] aspirin plus dipyridamole,[25] or aspirin plus ticlopidine[26] have not yielded a benefit of these regimen with respect to angiographic restenosis or rates of target lesion revascularization procedures. Therefore, the level of platelet inhibition, which can be achieved with these compounds, has no measurable effect on restenosis. Compounds binding to platelet αIIbβ3 (GPIIb/IIIa) receptors represent more potent platelet inhibitors.[27] Although this effect is inherent to all GPIIb/IIIa inhibitors, only abciximab inhibits in addition the αvβ3 (vitronectin) receptor. In animal models, it has been shown that vascular injury up-regulates β3 integrin expression, which induces smooth muscle cell proliferation.[14,28] Furthermore, the αvβ3 receptor has been demonstrated to be a significant modulator of leukocyte transmigration.[29] Abciximab also cross-reacts with the leukocyte integrins Mac-1 and intracellular adhesion molecule?1, both mediating inflammation after arterial injury.[30,31] In a rabbit model, it has been shown that selective αvβ3 receptor blockade reduces macrophage infiltration and restenosis after balloon angioplasty.[32] These pathways represent thrombus-independent mechanisms by which abciximab could reduce restenosis.

However, conflicting results have been found in clinical trials. In the EPIC trial, a significant 24% reduction of subsequent target vessel revascularization was reported at 6 months.[15] This observation was not confirmed in the larger EPILOG trial,[16] as well as in trials studying the role abciximab as adjunct to PCI for acute MI.[33,34] In the EPISTENT trial, an 18% reduction in the target vessel revascularization rate at 6 months was observed.[17] This finding, however, was largely confined to patients with diabetes mellitus with virtually identical rates for patients without diabetes but a >50% reduction in diabetic patients.[17] In the current analysis from the ISAR-REACT, we did not observe a significant difference in revascularization procedures between the abciximab and the placebo group (Figure 2).

Although rates of target lesion revascularization procedures reflect the clinical course of patients, a routine angiographic follow-up with detailed quantitative analysis yields a more precise measurement of restenosis development. The protocol for the EPISTENT trial included an angiographic substudy. There, a significantly higher net lumen gain was observed for patients with stent placement receiving abciximab but not for more common measures of restenosis development such as binary restenosis or late lumen loss.[17] The ERASER trial specifically looked at restenotic tissue volume by intravascular ultrasound at 6 months; in this relatively small trial (215 patients), no significant effect was observed in patients receiving abciximab;[18] a nonsignificant trend, however, was detected in the small subgroup with diabetes. The angiographic substudy of ISAR-REACT is the largest trial so far to specifically look at the potential effect of abciximab on angiographic restenosis. As illustrated, we did not observe a significant difference in any measurement at 6 months ( Table III ).

Diabetes

Like in several other trials mentioned previously, we did observe a nonsignificant trend in favor of abciximab. This was in particularly evident in the subgroup with diabetes mellitus but far less in any other subgroup with a known higher risk for restenosis (Figure 3). A similar effect limited to patients with diabetes had been observed in EPISTENT as outlined previously.[17] The ISAR-SWEET trial specifically addressed the issue if there is a benefit from the administration of abciximab in diabetic patients,[35] using a similar randomization and treatment protocol as ISAR-REACT. Although there was no significant benefit with respect to the primary end point, a composite of death and MI at 1 year, there was a significantly lower rate of angiographic restenosis in the abciximab group (28.9%) compared with the placebo group (37.8%, P = .01). This is in keeping with the angiographic analysis of diabetic substudy of EPISTENT.[36] In another small trial, the DANTE trial with 96 patients using IVUS, no significant benefit was seen for abciximab.[37]

Figure 3. 

Subgroup analysis for the rate of angiographic restenosis at follow-up, comparing lesions treated in patients assigned to receive abciximab to lesions in patients assigned to placebo. For analysis of long lesions, small vessels, and tight lesions, the respective median was used as cutoff value. n, Number of lesions; ACC/AHA, American College of Cardiology/American Heart Association; RD, reference diameter, MLDpre, minimal lumen diameter before PCI.

     

Study Limitations

The protocol for clopidogrel administration of ISAR-REACT was based on previous experience showing that a 600 mg loading dose of clopidogrel leads to most of the maximal platelet inhibition within 2 to 4 hours.[6,7,8] Still, a recent trial has demonstrated a considerable scatter in the level of platelet aggregation measured at time points between 0 to 10 hours after administration of 600 mg of clopidogrel; on the other hand, no significant change in platelet aggregation was observed after 2 hours in this trial.[38] Based on the currently available data, we cannot exclude that an optimized effect could be achieved with a higher or extended dosing protocol, nor should these data be extrapolated to a lower loading dose (ie, 300 mg) nor to a shorter pretreatment interval. This may be of particular importance if a 2-hour interval cannot be established because of organizational issues in busy catheterization laboratories.

Inferences from the results of the angiographic substudy are limited by the fact that power calculations and necessary cohort size of ISAR-REACT were guided by assumptions on the incidence of the primary end point of the entire study. In the angiographic substudy, an 8% reduction in the incidence of angiographic restenosis was observed. With our analysis based on 2000 lesions, this study had a power of 85% to detect a 20% reduction in this end point. Hence, we cannot exclude a smaller benefit missed because of a hypothetically inadequate trial size.

Two significant differences were observed in baseline angiographic characteristics ( Table II ). Vessel size had been significantly larger in the abciximab group. It is well known that restenosis rates decrease with increasing vessel size.[39] On the other hand, lesion length had been significantly longer in this group, which is a well-known risk factor for angiographic restenosis.[40] Although one can assume a somewhat divergent effect on the incidence of angiographic restenosis, patient groups in ISAR-REACT are too small to fully elucidate a differential role of these factors. Furthermore, 9% of patients in both groups were treated by angioplasty only, whereas 4% and 5% received drug-eluting stents. Although this illustrates some variability in the interventional procedure, patient groups are too small for an adequately sized subgroup analysis.

Conclusions

Based on the biggest cohort with angiographic follow-up so far, these data from the angiographic substudy of ISAR-REACT suggest that, in low- to intermediate-risk patients who undergo elective PCI after pretreatment with a high loading dose of clopidogrel >2 hours before elective PCI, the additional administration of the GPIIb/IIIa inhibitor abciximab is not associated with a significant reduction in angiographic restenosis. However, the results in the diabetic subgroup of this trial together with the observations from our dedicated diabetes trial, ISAR-SWEET,[35] consistently suggest that abciximab reduces the incidence of restenosis in diabetic patients undergoing elective PCI.

Table I. Patients Baseline Characteristics


Table I: Patients Baseline Characteristics

 

Table II. Baseline Lesion and Procedural Characteristics


Table II: Baseline Lesion and Procedural Characteristics

 

Table III. Quantitative Angiographic Analysis at Follow-up


Table III: Quantitative Angiographic Analysis at Follow-up

 



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Reprint Address

Helmut Sch?len, MD, Deutsches Herzzentrum M?chen, Lazarettstr. 36, 80636 M?chen, Germany. E-mail: schuehlen@dhm.mhn.de
Helmut Sch?len, MD,a Adnan Kastrati, MD,a Julinda Mehilli, MD,a Jörg Hausleiter, MD,a Josef Dirschinger, MD,b Franz Dotzer, MD,c Hildegard Bollwein, MD,b and Albert Schömig MD,a,b Munich and Garmisch-Partenkirchen, Germany

aDeutsches Herzzentrum, Munich, Germany
b1 Medizinische Klinik rechts derIsar, Munich, Germany
cMedizinische Klinik I, Garmisch-Partenkirchen, Germany
Financial Disclosure: This trial was supported by research grants by Deutsches Herzzentrum, Klinik an derTechnischen Universität, Munich, Germany (67-00 and 04-01), as well as by anunrestricted educational grant from Bristol-Myers Squibb GmbH, Munich, Germany.