CORRESPONDENCE: RESEARCH CORRESPONDENCE
Effects of Clopidogrel on the Rebound Hypercoagulable State After Heparin Discontinuation in Patients With Acute Coronary Syndromes
Marcello Di Nisio, MD*,
Nick R. Bijsterveld, MD,
Joost C.M. Meijers, PhD,
Marcel Levi, MD,
Harry R. Büller, MD and
Ron J.G. Peters, MD
* Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, P.O. Box 22660, 1100 DD Amsterdam, the Netherlands (Email: marcellodinisio{at}hotmail.com).
To the Editor: Several studies have shown a clustering of recurrent ischemic events shortly after discontinuation of heparin treatment in patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS) (e.g., unstable angina and non–ST-segment elevation myocardial infarction) (1,2). Uncontrolled thrombin generation, partly facilitated through activated platelets, may be an important trigger for recurrent ischemic events as suggested by an increase in markers of thrombin activation within 24 h of heparin discontinuation (3,4). Antiplatelet agents can partially reduce such a prothrombotic tendency (1,2). The goal of this study was to evaluate the effects of adding clopidogrel to aspirin on the rebound increase of thrombin generation and activity after cessation of enoxaparin in NSTE-ACS patients.
The NSTE-ACS patients were eligible after stabilization by standard treatment, which included aspirin (100 mg/day) and enoxaparin (1 mg/kg twice daily subcutaneously). Patients were randomly assigned to receive clopidogrel 300 mg followed by 75 mg/day in addition to aspirin (clopidogrel group), or no clopidogrel (aspirin alone group). Glycoprotein IIb/IIIa inhibitors were not used in any patient. Clopidogrel was started at the time of the last enoxaparin administration and continued for at least 48 h. The time point at 12 h after the last enoxaparin dose was considered as the time of the loss of therapeutic enoxaparin levels and defined as time = 0. The study was approved by the institutional review board. Blood samples were collected during enoxaparin treatment just before the first clopidogrel dose, 12 h after the last enoxaparin administration (time = 0), and 3, 6, 12, 24, and 48 h thereafter. The sampling frequency was based on previously published data showing a rebound prothrombotic state approximately 5 to 10 h after heparin discontinuation (3,4). Concentrations of prothrombin fragment 1 and 2 (F1+2) and thrombin-antithrombin complexes (TAT) were measured by sandwich-type enzyme-linked immunosorbent assays (Dade-Behring, Marburg, Germany).
A sample size of 44 patients was estimated to have a 90% power to detect a 50% reduction of the rebound in plasmatic TAT and F1+2 levels. However, the introduction of clopidogrel as part of the standard initial management of NSTE-ACS patients precluded the completion of the study (5). Within a treatment group, the Wilcoxon test was performed to compare each of the eight time points relative to time 0. For comparisons between the two groups, the nonparametric Mann-Whitney test was used.
A total of 24 patients (12 per arm) were included. The distribution of cardiovascular risk factors such as hypertension, diabetes, dyslipidemia, body mass index, smoking, and a history of cardiovascular events was comparable between the study groups.
All patients received at least three doses of enoxaparin, except one patient in the clopidogrel group who received two doses. After loss of therapeutic plasma enoxaparin levels, the aspirin alone group showed a pronounced increase in TAT levels, with maximum levels at 12 and 24 h after cessation (Fig. 1).The TAT concentrations at 6, 12, and 24 h were significantly higher than baseline levels (Table 1). In contrast, TAT levels in the clopidogrel group showed no increase at any time point after cessation of enoxaparin, and remained similar to the baseline values. As compared with the aspirin alone group, patients in the clopidogrel group had a significantly lower increase in TAT levels from baseline to 12 h (p = 0.005). Both groups showed similar increases of plasma F1+2 as soon as 3 h after cessation of heparin (Table 1). The F1+2 levels at time points 3, 6, 12, and 24 h were significantly higher in both groups compared with their baseline levels, and maximum levels were reached at 24 h after cessation.
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Figure 1 Median thrombin-antithrombin levels at different time points during and after heparin treatment. Squares = no clopidogrel; triangles = clopidogrel. Hour 0 = 12 h after last enoxaparin dose.
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Table 1. Median Plasma Levels of Thrombin-Antithrombin Complex and of Prothrombin Fragment 1+2 in the Aspirin Plus Clopidogrel and Aspirin-Alone Groups
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In conclusion, this study confirms that in ACS patients, enoxaparin cessation results in a rapid increase of coagulation activity as early as 3 h after loss of therapeutic anticoagulation levels. This rebound state develops in spite of platelet inhibition by aspirin, but can be partially inhibited by the addition of clopidogrel. Patients on clopidogrel showed a less pronounced reactivation in coagulation activity, as reflected by absent increases of TAT complexes in contrast to the clear increase observed in patients treated with aspirin alone. Recently, Eikelboom et al. (6) found no differences in blood markers of coagulation activation seven days after cessation of heparin therapy in patients with NSTE-ACS treated with or without clopidogrel. However, this study did not investigate variation in these markers in the first 24 to 48 h after heparin discontinuation, when the rebound phenomenon occurs (3,4). Among the several mechanisms that might account for the rebound activation in coagulation after heparin discontinuation are the depletion of natural anticoagulants such as tissue factor pathway inhibitor or decreased activity in the protein C pathway. In this context, thrombin generation after cessation of heparin correlates inversely with tissue factor pathway inhibitor concentrations (3), whereas data regarding the heparin effects on the protein C pathway are discordant (7–9).
In the current study, the thrombin generation marker F1+2 in the clopidogrel group increased up to 24 h, whereas TAT, a marker of thrombin activity, remained stable. An explanation might be that clopidogrel could affect proteins that bind thrombin, such as thrombomodulin or protease-activated receptors, thus influencing the levels of circulating TAT.
In conclusion, rebound coagulation activity as reflected by increasing thrombin generation occurs within hours after discontinuation of low-molecular-weight heparin treatment. Clopidogrel reduces this reactivation, and this might partially account for the overall clinical benefits observed when adding clopidogrel to aspirin treatment in ACS patients.
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