One year outcomes with abciximab vs. placebo during percutaneous coronary intervention after pre-treatment with clopidogrel{dagger}

Albert Schömig1,2,*, Claus Schmitt1, Alban Dibra1, Julinda Mehilli1, Christian Volmer1, Helmut Schühlen2, Josef Dirschinger2, Franz Dotzer3, Jurriën M. ten Berg4, Franz-Josef Neumann5, Peter B. Berger6, Adnan Kastrati1 for the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment Study Investigators

1Deutsches Herzzentrum, Lazarettstr. 36, 80636 Munich, Germany
2Medizinische Klinik rechts der Isar, Munich, Germany
3Medizinische Klinik I, Garmisch-Partenkirchen, Germany
4St Antonius Ziekenhuis, Nieuwegein, Netherlands
5Herz-Zentrum, Bad Krozingen, Germany
6Duke University Medical Centre and Duke Clinical Research Institute, Durham, NC, USA

Received 11 October 2004; revised 13 January 2005; accepted 20 January 2005; online publish-ahead-of-print 25 February 2005.

* Corresponding author. Tel: +49 89 12184073; fax: +49 89 12184013. E-mail address: aschoemig{at}dhm.mhn.de


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims In the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment Trial, the use of abciximab in patients undergoing percutaneous coronary intervention (PCI) after pretreatment with 600 mg clopidogrel for >2 h was associated with no clinically measurable benefit at 30 days. We assessed whether there was any clinical benefit from abciximab at 1 year follow-up.

Methods and results After pre-treatment with 600 mg clopidogrel, a total of 2159 patients undergoing PCI for stable or unstable angina without marked ST-segment shifts or positive biomarkers were randomly assigned to receive abciximab or placebo. The occurrence of the composite endpoint of death, myocardial infarction, or target vessel revascularization was assessed at 1 year after randomization.

At 1 year, the composite endpoint occurred in 23.8% of the patients in each group [relative risk (RR), 1.01; 95% confidence interval (CI), 0.85–1.20; P=0.92]. The combined incidence of death and myocardial infarction was 6.0% in the abciximab group and 6.4% in the placebo group (RR, 0.94; 95% CI, 0.67–1.32; P=0.73). The mortality rate was 2.1% in the abciximab group and 2.4% in the placebo group (RR, 0.88; 95% CI, 0.50–1.54; P=0.66). No trend towards clinical benefit was observed with abciximab at 1 year in any subgroup analysed.

Conclusion In patients with a low-to-intermediate risk profile undergoing PCI after pre-treatment with a 600 mg clopidogrel for at least 2 h, the use of abciximab offers no additional clinical benefit at 1 year.

Key Words: Angina • Angioplasty • Platelets • Stents • Thrombosis


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Coronary thrombosis is a major protagonist in the acute coronary syndromes and early adverse events following percutaneous coronary interventions (PCI).1 Platelets play a primary role in the pathophysiology of coronary thrombosis and embolization both at the site of mechanically injured plaque and at the microcirculatory level.2,3 Adjunctive antiplatelet therapy, with aspirin as a cornerstone, has been shown to improve the outcome of patients undergoing PCI. The upstream use of inhibitors of platelet glycoprotein IIb/IIIa receptor in patients with an acute coronary syndrome has reduced adverse events both at short and at long term.4,5 Similarly, several studies have confirmed the efficacy of another class of antiplatelet drugs, thienopyridines.69 Within this class, clopidogrel has the advantage of a more favourable side-effect profile and more rapid onset of action. After a loading dose of 600 mg, maximum inhibition of aggregation is achieved within 2 h1013.

The Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) Trial was a randomized, double-blind, placebo-controlled trial which studied whether administration of abciximab provides additional clinical benefit in patients at low-to-intermediate risk undergoing elective PCI after pre-treatment with a 600 mg dose of clopidogrel for at least 2 h.14 The occurrence of the primary endpoint, which was the composite of death, myocardial infarction, or urgent target-vessel revascularization at 30 days, did not differ between the two study groups.

However, many believe that abciximab exerts a beneficial effect that extends beyond the first 30 days after its administration. In a previous meta-analysis of randomized studies on abciximab, Anderson et al.5 found that patients who received abciximab derived incremental benefit between 30 days and 1 year; this benefit was in addition to that obtained within the first 30 days after the index procedure.

Hence, we assessed whether there was any clinical benefit from abciximab at 1 year follow-up among patients enrolled in ISAR-REACT.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Patients
The design of the trial has been previously described in detail.14 In brief, between May 2000 and February 2003, we recruited 2159 patients with coronary artery disease undergoing PCI in native coronary vessels after pre-treatment with a 600 mg loading dose of clopidogrel for at least 2 h before the procedure. Exclusion criteria included myocardial infarction within the prior 14 days, unstable angina with ST-segment changes of at least 0.1 mV in at least two electrocardiographic leads at rest, a troponin T level of more than 0.03 µg/mL, a target lesion in a venous bypass graft or with angiographically visible thrombus, a coronary occlusion believed to be present for >3 months, a left ventricular fraction <30%, and insulin-dependent diabetes mellitus. All patients provided written informed consent for participation in the trial and 1 year follow-up. The study protocol was approved by the Ethics Committees of the participating centres and adhered to the Declaration of Helsinki.

Design and procedures
Patients enrolled in these study groups received 600 mg of clopidogrel at least 2 h before the PCI as well as 325–500 mg of aspirin. The treatment protocol has been described previously.14 Briefly, patients who were randomized to abciximab received abciximab [a bolus of 0.25 mg/kg of body weight followed by an infusion of 0.125 µg/kg per min (maximum, 10 µg/min) for 12 h] along with a bolus of 70 U heparin/kg. Patients who were randomized to placebo received a bolus of placebo, followed by a 12 h infusion, and a bolus of 140 U heparin/kg.

After intervention, all patients received aspirin (100–325 mg/day indefinitely) and clopidogrel (75 mg twice a day until discharge but no longer than 3 days, followed by a daily dose of 75 mg for at least 1 month as indicated) as well as other cardiac medications according to the physician's discretion. The follow-up protocol included a telephone interview at 30 days, 6 months, and 1 year after randomization. For all patients who reported cardiac symptoms during the telephone interview, at least one clinical and electrocardiographic check-up was performed at the outpatient clinic or by the referring physician.

Study endpoints and definitions
The cumulative incidence of death from any cause, myocardial infarction, or target-vessel revascularization at 1 year after randomization was the primary endpoint of this study. The diagnosis of myocardial infarction was based on either the development of new pathologic Q-waves in two or more contiguous electrocardiographic leads or an elevation of creatine kinase and its MB isoenzyme to at least three times the upper local limit of normal, in at least two blood samples. Target vessel revascularization was defined as coronary artery bypass surgery (CABG) involving the target vessel or PCI performed in the target lesion in the presence of restenosis-induced symptoms or signs of ischaemia.

Statistical analysis
The data are presented as mean±SD or as counts (per cent). A two-sided {chi}2 test for categorical data was used to assess the differences between the groups. Survival analysis was performed by applying the Kaplan–Meier method. Differences in survival were assessed by the use of log-rank test. The primary analysis was done by calculating the relative risk of the primary endpoint (with the 95% CI) associated with the use of abciximab, when compared with the use of placebo. In the secondary analysis, we studied abciximab in subgroups defined by older age (>70 years), sex, the presence of type 2 diabetes, the presence of angina class III–IV or a prior myocardial infarction, and the presence of the complex (type B2 or C) lesions. All tests performed were two-sided and a P-value <0.05 was considered to indicate statistical significance.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
The flow of patients through the ISAR-REACT trial is shown in Figure 1; baseline characteristics of the study population are displayed in Table 1. The median duration of pre-treatment with clopidogrel was 7.4 h (25th–75th percentiles, 4.0–19.1 h).



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Figure 1 Flow of patients through the ISAR-REACT trial.

 

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Table 1 Baseline characteristics
 
Clinical outcomes at 1 year
A 1 year follow-up was complete in all but 54 patients (2.5%) lost to follow-up: 23 in the abciximab group and 31 in the placebo group. The median length of follow up among patients with incomplete 1 year follow-up was 234 days (25th, 75th percentiles: 186, 286 days).

The incidence of the primary endpoint of the study, the composite of death, myocardial infarction, or target vessel revascularization, was identical among patients assigned to abciximab and those assigned to placebo (23.8% in each group; RR, 1.01; 95% CI, 0.85–1.20; P=0.92). Figure 2 shows the similar event-free survival curves during the first year. The combined incidence of death and myocardial infarction was 6.0% in the abciximab group and 6.4% in the placebo group (RR, 0.94; 95% CI, 0.67–1.32; P=0.73). The mortality rate was 2.1% in the abciximab group and 2.4% in the placebo group (RR, 0.88; 95% CI, 0.50–1.54; P=0.66). Within this period, myocardial infarctions occurred in 4.2% of the patients in the abciximab group and 4.3% of those in the placebo group (P=0.92). In 3.3% of the patients in the abciximab group and 3.1% of those in the placebo group, it was a Q-wave myocardial infarction (P=0.80). A reintervention (PCI or CABG) was performed in 19.3% of the patients in the abciximab group and 18.9% of those in the placebo group (P=0.82). A CABG was carried out in 2.3% of the patients in the abciximab group and 1.9% of the patients in the placebo group (P=0.55).



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Figure 2 1 year event-free survival curves in the two study groups.

 
Figure 3 shows the 1 year incidence of the primary endpoint in different subgroups of patients. In none of these subgroups was abciximab associated with a significant advantage at 1 year.



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Figure 3 1 year incidence of the composite of death, myocardial infarction, and target vessel revascularization in different subgroups according to study treatment and relative risk (95% CI) associated with the use of abciximab.

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
The 1 year follow-up results of ISAR-REACT trial show that after pre-treatment with a high loading dose of clopidogrel, the use of abciximab is associated with no incremental benefit among low-to-intermediate risk patients undergoing PCI. No advantage emerged, 1 year after study enrolment, with regard to death, myocardial infarction, or target vessel revascularization among patients who received abciximab.

In some studies, adjunctive use of abciximab has been associated with sustained beneficial effects, in particular, with a decreased rate of mortality at long term, among patients undergoing PCI.15 None of those studies required pre-treatment with a thienopyridine. In a previous meta-analysis of eight randomized trials evaluating abciximab in patients undergoing PCI, early myocardial infarction occurred in only 18% of patients who died at 1 year in the placebo arm.5 If true, this suggests benefit from abciximab unrelated to the prevention of procedural myocardial infarction. In the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) and Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trials, abciximab was associated with a lower revascularization rate at 6 months when compared with placebo.16,17 The explanation that has been provided for the clinical benefit of abciximab beyond the prevention of procedural infarction is the passivation of the injured plaque following PCI.18

Adjunctive antiplatelet therapy with thienopyridines derivatives, ticlopidine and clopidogrel, has also been associated with improved outcomes among patients undergoing PCI. Pre-treatment with either agent before PCI has been associated with a reduction of adverse events among patients in whom maximal inhibition of platelet aggregation were attained.68 The inhibition of platelet aggregation by ticlopidine and clopidogrel is dependent not only on their concentration but also on the duration of treatment.19 Data have shown that increasing large loading doses of clopidogrel up to 600 mg leads to a more rapid achievement of maximal inhibition of platelet aggregation.1012 On the basis of in vitro data on platelet inhibition with clopidogrel and abciximab, it could be supposed that antithrombotic protection achieved with a combination of clopidogrel and abciximab would be more effective than that of clopidogrel alone.11,20 However, the results of ISAR-REACT at both 30 days and now, with this report, 1 year reveal that the expected difference in in vitro inhibition of platelet aggregation did not translate into a difference in the clinical outcomes between patients treated with one vs. both agents. The disconnection between ex vivo antiplatelet effects and clinical outcome parallels that observed with aspirin.21 On the other hand, it is known that the greatest benefit from abciximab is among patients with acute coronary syndromes, especially those with abnormal troponin and diabetes.22 Perhaps, in part because these conditions are characterized by an increased platelet activation and aggregation, a high-level inhibition of glycoprotein IIb/IIIa receptor, as that offered by abciximab, may be required.23,24 Thus, in the C7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, the use of abciximab in patients with an elevated troponin significantly reduced the relative risk of death and nonfatal myocardial infarction; there was no benefit from treatment of patients without an elevated troponin.25 Additionally, according to a previous meta-analysis, the use of abciximab is associated with a reduction in mortality among diabetic patients.26 None of these issues could be addressed in the current study because high-risk subsets, such as those with acute coronary syndromes associated with marked ST-segment shifts or positive biomarkers, and patients with insulin-dependent diabetes, were excluded.

Abciximab, in addition to markedly reducing platelet aggregation, possesses anti-inflammatory properties and reduces CD40 ligand levels (a central inflammatory mediator) as well as CRP levels (a major inflammation marker with pro-inflammatory and pro-thrombotic properties).27,28 Elevated levels of CD40 ligand and C-reactive protein have been associated with increased long-term risk for adverse events.2931 However, similar anti-inflammatory properties have been demonstrated with clopidogrel. Clopidogrel also decreases CD40 ligand levels and reduces C-reactive protein levels in patients undergoing PCI.32,33 And in contrast to abciximab, which may increase expression of P-selectin, clopidogrel decreases P-selectin expression and platelet–leukocyte aggregate.34 High levels of P-selectin have been associated with increased risk for future cardiovascular events.35 Furthermore, in addition to preventing the transformation of glycoprotein IIb/IIIa receptor to the active form that binds fibrinogen, clopidogrel prevents platelet degranulation and release of several prothrombotic and inflammatory mediators.2 Platelet activation is not prevented by glycoprotein IIb/IIIa inhibitors.36 This spectrum of antithrombotic and anti-inflammatory effects may confer to clopidogrel, in synergism with aspirin, a role in the pharmacological plaque passivation;18 this could explain the lack of difference in the rate of adverse events observed at 1 year after PCI between patients treated with abciximab and placebo in our study.

Limitations
The sample size selected for the ISAR-REACT trial was based on the frequency with which the composite endpoint was expected to be reached at 30 days; the trial was certainly not powered to assess mortality either at 30 days or at 1 year. On the basis of the observed mortality at 1 year, the 95% CI for the true mortality associated with abciximab was between 1.4 and 3.2%. However, the lack of even a trend towards a reduction of the composite event rate or its individual components at 1 year, the inability to identify a subgroup in ISAR-REACT that appears to benefit from abciximab, 1 year outcomes in the TARGET trial suggesting no beneficial extra-platelet effects common only to the large monoclonal antibody abciximab, and the ability of clopidogrel to reduce not only inflammation (as can abciximab) but also platelet activation (which abciximab does not) lead us to believe that the results of this analysis, though derived from too small a trial (n=2159) to be conclusive, are indeed likely to be real. We also acknowledge that relying on the telephone interview at 1 year to collect data on patients' outcomes could have influenced our ability to detect patients who suffered a myocardial infarction during the follow-up period. However, this is common practice in clinical trials and the extent of its impact has not been estimated.

In summary, among patients with a low-to-intermediate risk profile undergoing PCI after pre-treatment with a 600 mg loading dose of clopidogrel at least 2 h before the procedure, the use of abciximab offers no additional clinical benefit at 1 year.


    Acknowledgements
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
The sources of support are research grants from Deutsches Herzzentrum, Klinik an der Technischen Universität, Munich, Germany (67-00 and 04-01) and an unrestricted educational grant from Bristol-Myers Squibb GmbH, Munich, Germany. F-J.N. reports having received research grants from Merck and speaker's fees from Centocor and Merck. P.B.B. reports having received research support from Bristol-Myers Squibb/Sanofi, Cordis/Johnson & Johnson, the Medicines Co., Genentech, Merck, Berlex, and Millennium; serving on a scientific advisory board for Cordis/Johnson & Johnson and Genentech; and speaking at scientific symposiums supported by Bristol-Myers Squibb/Sanofi, Merck, Aventis, and the Medicines Co. A.S. reports having received research grants for the Department of Cardiology from Bristol-Myers Squibb, Lilly, Boston Scientific, Cordis/Johnson & Johnson, and Guidant. None of the other authors has any conflict of interest to report.


    Footnotes
 
{dagger} A list of centres and investigators participating in the ISAR-REACT study has appeared in N Engl J Med 2004;350:232–238. Back


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