Author + information
- Received July 6, 2004
- Accepted August 23, 2004
- Published online December 7, 2004.
- David E. Kandzari, MD*,* (, )
- Peter B. Berger, MD*,
- Adnan Kastrati, MD†,
- Steven R. Steinhubl, MD‡,
- Julinda Mehilli, MD†,
- Franz Dotzer, MD§,
- Jurriën M. ten Berg, MD∥,
- Franz-Josef Neumann, MD¶,
- Hildegard Bollwein, MD#,
- Josef Dirschinger, MD#,
- Albert Schömig, MD†,#,
- ISAR-REACT Study Investigators
- ↵*Reprint requests and correspondence:
Dr. David E. Kandzari, Room 7063, Duke Clinical Research Institute, Durham, North Carolina 27705
Objectives We examined clinical outcomes in the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) trial based on the duration of pretreatment with a 600-mg loading dose of clopidogrel.
Background The influence of the treatment duration with a 600-mg dose of clopidogrel before percutaneous coronary revascularization on early outcomes remains uncertain.
Methods Among 2,159 patients with coronary disease who underwent percutaneous coronary intervention (PCI) in the ISAR-REACT trial, we examined clinical outcomes relative to the duration of pretreatment with a 600-mg dose of clopidogrel: (2 to 3 h, 3 to 6 h, 6 to 12 h, or >12 h). Patients were randomly assigned to adjunctive therapy with abciximab or placebo at the beginning of the study. The primary end point was a composite of death, myocardial infarction, or urgent revascularization within 30 days after randomization.
Results No significant differences were observed between patient groups regarding the duration of pretreatment, irrespective of assignment to abciximab or placebo (p = 0.27 for interaction among abciximab/clopidogrel and placebo/clopidogrel treatment at each time interval). Occurrence of major bleeding also did not differ according to time of initial clopidogrel dosing.
Conclusions For low-to-intermediate risk patients treated with a 600-mg loading dose of clopidogrel before PCI, incremental clinical benefit within the first 30 days from durations of pretreatment >2 to 3 h was not evident.
Combination antiplatelet therapy with aspirin and a thienopyridine has remarkably improved the outcome of patients after coronary artery stenting (1,2). Recently, the potential benefit of thienopyridine administration before percutaneous coronary intervention (PCI) has been examined. For patients at low-to-intermediate risk for early ischemic complications, treatment with clopidogrel at least several hours to days before PCI may reduce early adverse events and possibly lessen the benefit provided by glycoprotein (GP) IIb/IIIa antagonists (3–5). Recent trials have shown improved outcomes with earlier clopidogrel treatment before elective PCI, yet the appropriate dose and duration for pretreatment with clopidogrel remain uncertain.
More rapid platelet inhibition has been achieved with large loading doses of clopidogrel than with lower doses of clopidogrel or with ticlopidine, yet at least 3 to 6 h is necessary to achieve the maximal antiplatelet effect ex vivo with a 300-mg loading dose (6–9). In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, despite a nonsignificant 19% relative reduction in ischemic adverse events with clopidogrel treatment (300 mg) 3 to 24 h before PCI, a prespecified subgroup analysis revealed that patients receiving pretreatment for >6 h demonstrated a strong trend toward benefit, whereas those treated for shorter periods did not (4). Subsequent analysis of these data, however, have revealed that clinical events were not significantly reduced compared with placebo unless 300 mg of clopidogrel was given at least 15 h before PCI (10).
Accordingly, there may be adverse consequences if PCI is performed before achieving adequate platelet inhibition. A 600-mg loading dose of clopidogrel results in a maximal antiplatelet effect within 2 h of administration, as assessed by light transmission aggregometry (6,11,12). Further, we recently demonstrated that the addition of a GP IIb/IIIa antagonist may not provide measurable clinical benefit for patients receiving a 600-mg loading dose of clopidogrel at least 2 h before PCI (5). In the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) trial, the duration of clopidogrel pretreatment beyond 2 h was not further specified. We therefore examined clinical outcomes in ISAR-REACT based on the duration of pretreatment after a 600-mg loading dose of clopidogrel.
The ISAR-REACT trial has been previously described (5). Between May 2000 and February 2003, patients enrolled in the trial were treated with a 600-mg oral loading dose of clopidogrel at least 2 h before elective PCI. All patients gave written informed consent, and the study protocol was approved by the ethics committees of the participating centers. The major exclusion criteria were a myocardial infarction (MI) within 14 days, an acute coronary syndrome manifest by ST-segment deviation ≥0.1 mV in at least two electrocardiographic leads at rest, a troponin T level >0.03 ng/ml, or insulin-dependent diabetes mellitus. Other exclusion criteria were a target lesion that involved a venous bypass graft, chronic (>3 months) occlusion, or angiographically visible thrombus; left ventricular ejection fraction <30%; any hemodynamic instability; or treatment with an intravenous GP IIb/IIIa inhibitor within the preceding 14 days.
In addition to clopidogrel, all patients received 325 to 500 mg of aspirin. After diagnostic coronary angiography but before guide wire placement, patients were randomly assigned in a double-blinded fashion to adjunctive treatment with abciximab (0.250 mg/kg bolus, followed by a 0.125 μg/kg/min infusion [up to 10 μg/min] for 12 h) or placebo. Patients assigned to abciximab received 70 U/kg of unfractionated heparin compared with 140 U/kg for those assigned to placebo.
After stent placement, the protocol specified indefinite aspirin therapy (100 to 325 mg daily) and treatment with clopidogrel, 75 mg twice daily until discharge, but no longer than three days, followed by 75 mg daily for at least one month. Aside from in-hospital ascertainment of adverse events, follow-up was performed for patients experiencing ischemic symptoms within 30 days after randomization.
Study hypothesis and end points
The hypotheses, end point definitions, and results of the ISAR-REACT trial have been described (5). The hypothesis of this analysis was that, among all patients undergoing PCI (either with abciximab treatment or placebo), the composite 30-day end point of death, MI, or urgent repeat revascularization would not significantly differ based on the duration of pretreatment with clopidogrel. Hemorrhagic and hematologic complication rates were assessed. Myocardial infarction was defined as the development of pathologic Q waves in two or more contiguous electrocardiographic leads or an elevation of creatine kinase or creatine kinase-MB (≥3× the upper limit of normal [ULN], minimum of two samples). All events were classified and adjudicated by a committee blinded to the patients' treatment assignments.
Categorical variables were compared by the likelihood-ratio chi-square test. Continuous variables are presented as mean values ± SD and were compared by one-way analysis of variance. Logistic regression model analysis also was performed for the 30-day composite end point, to assess for an interaction between abciximab treatment and duration of clopidogrel pretreatment, as well as the independent role of duration of clopidogrel pretreatment. This model included all baseline characteristics (Table 1).Thirty-day outcomes were also assessed by the Kaplan-Meier method and compared by the log-rank test. All analyses were by intention-to-treat, and all p values are two-sided with significance level of 0.05.
Of 2,159 patients enrolled in the study, four patient groups were identified based on the duration of clopidogrel treatment before PCI: 2 to 3 h, n = 367; 3 to 6 h, n = 560; 6 to 12 h, n = 486; >12 h, n = 746 (Table 1). Patients were further divided according to whether they received abciximab or placebo. The median duration of clopidogrel pretreatment was 7.4 h (25th, 75th percentiles = 4.0, 19.0 h).
The mean age of the study population was 66 years, 40% had class III or IV angina, and 20% had type 2 diabetes mellitus (Table 1). Approximately 75% of patients had multivessel disease, and about 33% had experienced prior MI. Revascularization was performed on more than one lesion in 30% of patients (n = 652; p = 0.40 across groups).
The duration of clopidogrel therapy before PCI was not associated with differences in the composite 30-day clinical outcome or its individual components (Table 2).Patients treated with 600 mg clopidogrel 2 to 3 h before intervention had event rates similar to those of patients receiving earlier treatment (p = 0.79 across groups) (Fig. 1).Neither the occurrence of large MI (creatine kinase or creatine kinase-MB >5 times the ULN) nor any infarction differed between patient groups. In addition, by using a multivariable Cox regression model that examined 30-day adverse events, no independent role was observed for duration of clopidogrel pretreatment (p = 0.47) nor was there a significant interaction between duration of clopidogrel pretreatment and abciximab treatment (p = 0.27). At 30 days, the primary composite end point was 2.9% in the group pretreated for 2 to 3 h who did not receive abciximab versus 5.6% in those who did (p = 0.20).
Clopidogrel pretreatment appeared safe across all time points; as previously reported (5), no patient sustained an intracranial hemorrhage, and minor and major bleeding episodes did not differ between the four groups based on pretreatment duration. Mild thrombocytopenia and transfusion requirements increased with abciximab treatment (5), but did not differ among patients receiving clopidogrel alone, irrespective of treatment duration.
Clinical trials have suggested improved outcomes for patients undergoing elective percutaneous revascularization after pretreatment with clopidogrel (3,4), yet the appropriate dose and duration of clopidogrel pretreatment have remained uncertain. Our analysis indicates that, among patients at low-to-intermediate risk for early ischemic complications after elective PCI following pretreatment with a 600-mg loading dose of clopidogrel, increasing the pretreatment interval beyond 2 to 3 h is not associated with a measurable clinical benefit, irrespective of adjunctive treatment with abciximab.
Against the background of recent trials that have advanced our understanding of thienopyridine therapy as adjunctive treatment for PCI, two contemporary randomized trials have shown that 300 mg of clopidogrel given at the time of PCI followed by a daily 75-mg dose for at least two weeks is equivalent to conventional ticlopidine for preventing early ischemic events and is superior to ticlopidine with regard to hematologic and other side effects (13,14). In vitro studies using light transmission aggregometry have indicated that a 600-mg loading dose of clopidogrel accelerates inhibition of platelet aggregation, as compared with a 300-mg loading dose of clopidogrel or a 500-mg dose of ticlopidine, and this effect is demonstrable 2 h after drug administration (12,15).
The results in this analysis contrast with the findings from the CREDO trial that demonstrated a time-dependence in the clinical benefit of a 300-mg clopidogrel loading dose, with at least 15 h of pretreatment required to significantly reduce clinical events (10). These clinical results are in contrast with ex vivo studies suggesting that 300-mg of clopidogrel requires only 3 to 6 h to achieve maximal effect (6–9). Conversely, the findings in the present analysis support the hypothesis that rapid platelet inhibition when a 600-mg clopidogrel dose is administered is concordant with the absence of further clinical benefit beyond 2 to 3 h in the ISAR-REACT trial.
Because patients in the ISAR-REACT trial were not randomized according to the timing of clopidogrel pretreatment, a limitation of the trial design is the ability to definitively establish the absence of a time-dependent relationship beyond 2 to 3 h with a 600-mg clopidogrel loading dose. Although there were differences in baseline characteristics between the four study groups, patients with a longer interval between clopidogrel treatment and revascularization did not show a higher risk profile. The findings of the present study, however, inform the need for further prospective, randomized examination of the relationship between the clopidogrel dose and pretreatment duration with clinical outcomes.
When a 600-mg loading dose of clopidogrel is administered at least 2 h before PCI in patients considered at low or intermediate risk for ischemic complications, as in the ISAR-REACT trial, the likelihood of a successful procedural outcome and freedom from early adverse events is not further increased by prolonging the pretreatment interval of clopidogrel, regardless of the additional use of abciximab.
The ISAR-REACT trial was supported by research grants from Deutsches Herzzentrum, Klinik an der Technischen Universität, Munich, Germany (67-00 and 04-01), and by an unrestricted educational grant from Bristol-Myers Squibb GmbH, Munich, Germany.
- Abbreviations and acronyms
- Clopidogrel for the Reduction of Events During Observation trial
- Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment trial
- myocardial infarction
- percutaneous coronary intervention
- upper limit of normal
- Received July 6, 2004.
- Accepted August 23, 2004.
- American College of Cardiology Foundation
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