CLINICAL RESEARCH: ACUTE CORONARY SYNDROME
A Randomized Comparison of High Clopidogrel Loading Doses in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes
The ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) Trial
Gilles Montalescot, MD, PhD*,1,*,
Georges Sideris, MD ,
Catherine Meuleman, MD ,
Claire Bal-dit-Sollier, MB ,1,
Nicolas Lellouche, MD||,
Ph. Gabriel Steg, MD¶,1,
Michel Slama, MD#,
Olivier Milleron, MD**,
Jean-Philippe Collet, MD, PhD*,
Patrick Henry, MD,
Farzin Beygui, MD, PhD*,
Ludovic Drouet, MD, PhD,1 for the ALBION Trial Investigators
* Institut de Cardiologie–Pitié-Salpêtriére University Hospital, Assistence Publique Hôpiteux de Paris (APHP), Paris, France.
Service de Cardiologie–Lariboisiére University Hospital, APHP, Paris, France.
Service de Cardiologie–Saint-Antoine University Hospital, APHP, Paris, France.
Laboratoire d’Hémostase–Lariboisière University Hospital, APHP, Paris, France.
|| Service de Cardiologie–Henri-Mondor University Hospital, APHP, Paris, France.
¶ Service de Cardiologie–Hôpital Bichat-Claude Bernard, APHP, Paris, France.
# Service de Cardiologie–Antoine Béclère University Hospital, APHP, Paris, France.
** Service de Cardiologie–Ambroise Paré University Hospital, APHP, Paris, France.
Manuscript received September 26, 2005;
revised manuscript received April 20, 2006,
accepted April 25, 2006.
* Reprint requests and correspondence to: Dr. Gilles Montalescot, Institut de Cardiologie, Bureau 2-236, Pitié-Salpêtrière Hospital, 47 Boulevard de l’Hôpital, 75013 Paris, France. (Email: gilles.montalescot{at}psl.aphp.fr).
 |
Abstract
|
|---|
OBJECTIVES: We sought to compare the antiplatelet effects of three clopidogrel loading doses (LDs).
BACKGROUND: Administration of a 300-mg clopidogrel LD is beneficial in situations requiring rapid platelet inhibition. Whether higher LDs can provide further benefits remains unknown.
METHODS: Patients (n = 103) with non–ST-segment elevation acute coronary syndromes were randomized to receive a 300-mg, 600-mg, or 900-mg clopidogrel LD, given on top of other standard therapy (including acetylsalicylic acid). The main outcome measure was inhibition of adenosine diphosphate-induced inhibition of platelet aggregation (IPA); inhibition of platelet activation, inflammatory markers, troponin I release, and major adverse cardiac events also were evaluated; all measures were blindly evaluated.
RESULTS: Compared with the 300-mg LD, greater doses were associated with significantly greater platelet inhibition, with dose-effect relationships observed for onset of action, maximal plateau, 24-h areas under the curves of IPA, and rates of low IPA (<10% at 6 h), using 20 µmol/l major adverse cardiac events. A significant dose-response was also observed for the vasodilator-stimulated phosphoprotein index, a measure of P2Y12 receptor inhibition. Similar but nonsignificant trends were observed for troponin release and major adverse cardiac events. Bleeding rates were similar in each group.
CONCLUSIONS: In low-to-moderate risk patients with non–ST-elevation acute coronary syndromes, clopidogrel LDs >300 mg provide a faster onset of action, a higher IPA plateau, and greater reductions in platelet activation during the first 24 h. A 900-mg LD may induce a greater antiplatelet effect than 600 mg, when compared with the standard 300-mg regimen. These findings require further clinical confirmation.
|
Abbreviations and Acronyms
| | ADP = adenosine diphosphate | | ASA = acetylsalicylic acid | | AUC = area under the inhibition of platelet aggregation curve | | GP = glycoprotein | | IPA = inhibition of platelet aggregation | | LD = loading dose | | LMWH = low molecular weight heparin | | MACE = major adverse cardiac events | | MFI = median fluorescence intensity | | NSTE-ACS = non–ST-segment elevation acute coronary syndrome | | PA = platelet aggregation | | PAI = plasminogen activator inhibitor | | PCI = percutaneous coronary intervention | | PGE1 = prostaglandin E1 | | sCD40L = soluble CD40 ligand | | VASP = vasodilator-stimulated phosphoprotein | | vWF Ag = von Willebrand factor antigen |
|
Optimal and rapid inhibition of platelet function is an important therapeutic goal for the management of patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention (PCI). In the case of antiplatelet therapy with clopidogrel, a P2Y12 adenosine diphosphate (ADP)-receptor antagonist, this has traditionally been achieved by initiating treatment with a 300-mg oral loading dose (LD) to reduce the time to onset of action from a few days to a few hours (1), with a significant clinical benefit in addition to acetylsalicylic acid (ASA), in various situations (2–10).
However, the slow onset of action still remains a question in the urgent care setting and/or PCI and has led several groups to conduct small randomized studies evaluating greater LDs (i.e., 400 to 600 mg) of clopidogrel. Most of these studies have suggested that greater LDs reduce the time to achieve optimal inhibition of platelet aggregation (IPA) (11–13), although divergent results have also been published (14,15). Recent data also have suggested an incremental benefit of a 600-mg LD (compared with the standard 300-mg LD) on the release of cardiac markers after PCI (13,16). These studies typically have been single center and open label, with a limited number of sampling time points; all have used clopidogrel LDs  600 mg.
To address the question of the optimal clopidogrel LD rigorously, we performed a randomized, multicenter, parallel-group evaluation of the effects of three different clopidogrel LDs, testing a dose as high as 900 mg. In this dose-ranging study, multiple sampling time points were used to precisely determine the onset of action and the timing of the maximal effect on inhibition of platelet function with the different LDs. Although evaluation of platelet aggregation (PA) was the primary objective of the study, platelet activation and markers of inflammation and necrosis also were evaluated during the first 24 h. To avoid any interaction of PCI on the kinetics of all these markers, it was decided to study patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS) before they presented to the catheterization laboratory. Finally, ischemic and bleeding events were closely monitored during a month of follow-up.
|
Methods
|
|---|
Study design.
The ALBION (Assessment of the best Loading dose of clopidogrel to Blunt platelet activation, Inflammation and Ongoing Necrosis) trial was a randomized, parallel-group study of patients hospitalized with NSTE-ACS with a blinded evaluation of the primary end point and all biological secondary end points. The study was conducted at seven cardiology centers in Paris, France, according to the principles of the Helsinki Declaration and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines for Good Clinical Practice. Approval was obtained from the Pitié-Salpêtrière University Hospital Ethics Committee, and patients provided written informed consent.
Major inclusion criteria were: 1) age >18 and 85 years; 2) ischemic symptoms (onset <48 h) and at least one of the following: electrocardiogram ST-segment or T-wave changes or positive troponin; 3) treatment at hospital admission with 250 to 500 mg of oral or intravenous ASA and low molecular weight heparin (LMWH); and 4) an assignment for clopidogrel treatment.
Major exclusion criteria were: 1) catheterization performed before randomization or scheduled to be performed <24 h after randomization; 2) contraindication to LMWH, clopidogrel, or ASA; 3) severe hypertension; 4) platelet count <100,000/mm3; 5) neutrophil count <1800/mm3; 6) increased risk of bleeding; and 7) recent (within 10 days) or planned use of nonpermitted concomitant medications (any antiplatelet agent other than ASA, oral anticoagulants, hirudin, nonsteroidal anti-inflammatory drugs). In case of emergent PCI or glycoprotein (GP) IIb/IIIa inhibitor use during the 24-h study period, the patient was excluded from the analysis.
Treatment and follow-up.
Using central randomization, patients were allocated to receive a 300-, 600-, or 900-mg oral clopidogrel LD on the morning of day 1. Twenty-four hours after the LD, all patients were started on a regimen of clopidogrel 75 mg/day and ASA 100 mg/day. Low molecular weight heparin was administered twice daily. All study medication was administered on an open-label basis. Patients were followed up at 30 (±7) days to record clinical outcome and adverse event reporting.
Processing of samples.
To ensure prompt sample transfer and assaying, patients could only be randomized if the baseline blood sample was to be taken between 7 AM and 11 AM between Monday and Friday. The blood samples were transferred by the delivery service to the central laboratory, arriving within 1 h of venipuncture. Platelet aggregometry and flow cytometry tests were blindly performed immediately upon receipt.
Assay methods.
Aggregometry, flow cytometry, measurements of inflammatory biomarkers, and markers of myonecrosis at all time points during the 24 h were processed in the core laboratory that was blinded to the treatment received.
Adenosine diphosphate-induced platelet aggregation
Platelet-rich plasma was obtained by centrifugation of citrated whole blood at 100 g for 15 min at room temperature. Platelet-poor plasma was obtained by further centrifugation at 1000 g for 20 min. In vitro PA in platelet-rich plasma was measured at 37°C in an aggregometer (Model 490-4D, Chrono-Log Corporation, Kordia, the Netherlands) following the optical aggregometry method of Born (17). Platelet aggregation was induced by the addition of ADP (Chrono-Par, Kordia, the Netherlands) at final concentrations of 5 µmol/l and 20 µmol/l, and PA parameters were measured on samples obtained at baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, and 24 h. Inhibition of platelet aggregation (%) at time Tx was (intensity of aggregation at T baseline) – (intensity of aggregation at Tx)/(intensity of aggregation at T baseline).
Flow cytometry
Flow cytometry measurements were performed at the same nine time points. All flow cytometric studies were conducted on a FACScalibur flow cytometer (Becton Dickinson, Franklin Lakes, New Jersey) using CellQuest software (Becton Dickinson) for data acquisition and analysis. Analyses were performed on citrated whole blood diluted 1:4 in phosphate-buffered saline incubated with either PAC1 fluorescein isothiocyanate-conjugated monoclonal antibody (Becton Dickinson), anti-P-selectin phycoerythrin-conjugated monoclonal antibody (Becton Dickinson), or anti-fibrinogen fluorescein isothiocyanate-conjugated polyclonal antibody (Dako, Trappes, France). Platelet activation markers were measured in unstimulated platelets and after stimulation of platelets with ADP (5 µmol/l final concentration). In addition, the phosphorylation of vasodilator-stimulated phosphoprotein (VASP) was measured at 6 and 24 h by quantitative flow cytometry using a commercially available kit from Diagnostica Stago/Biocytex (Marseille, France). The VASP index was calculated from the median fluorescence intensity (MFI) of samples incubated with prostaglandin E1 (PGE1) and ADP according to the formula: VASP index = [(MFI(PGE1) – MFI(PGE1 + ADP))/MFI(PGE1)] x 100.
Inflammatory markers
Determinations were performed on samples obtained at baseline, 6 h, and 24 h using commercially available enzyme-linked immunosorbent assays. High-sensitivity C-reactive protein in serum was measured using a highly sensitive kit (Dade-Behring, Paris la Défense, France). von Willebrand factor antigen (vWF Ag) and plasminogen activator inhibitor (PAI)-1 antigen were measured in citrated plasma (Asserachrom, Stago, Asnières, France). Soluble CD40 ligand (sCD40L) was measured in serum (R&D Systems, Lille, France).
Troponin I
Troponin I measurements were performed on samples taken at baseline, 6 h, and 24 h, with serum concentrations measured by immunoassay using an AXSYM analyzer (Abbott, Rungis, France). Patients with an increasing troponin were defined as either patients with a negative troponin on admission becoming positive over the course of 24 h or patients with a positive troponin on admission increasing by  30%, during the first 24 h.
End points
The primary objective of the study was to evaluate changes in PA (IPA, %). The kinetic profile of clopidogrel-mediated IPA induced by 5 µmol/l ADP was compared across the three groups with respect to change from baseline to each time point and maximum effect. The same criteria were applied to the kinetic profile of inhibition of 20 µmol/l ADP-induced PA.
Among the secondary objectives of the study were the kinetics of inhibition of platelet activation (activated GP IIb/IIIa receptor complexes, P-selectin expression, fibrinogen binding, P-VASP); the frequency of low response (defined as IPA <10% at 6 h); the impact on markers of inflammation (C-reactive protein, vWF Ag, PAI-1 antigen, sCD40L); the effect on troponin I (a marker of myonecrosis); the incidence of death, myocardial infarction, or ischemic recurrences leading to revascularization and/or rehospitalization; and the safety profile using the GUSTO (Global Utilization of Streptokinase and TPA for Ocluded Arteries) (18) definitions of bleeding.
Statistical analyses
The time course of the change from baseline to the maximum intensity of PA induced by ADP was compared through an analysis of variance of the changes from baseline at each time point. A Student t test, using the common residual variance from the global analysis of variance, was used to make pairwise comparisons between the 300-mg group and each of the higher LDs at each time point. No adjustment for multiple comparisons was made. The following comparisons were performed: 300 mg versus 600 mg and 300 mg versus 900 mg. The area under the IPA curve (AUC) was calculated and compared across dosages using an analysis of variance. This AUC was a combination of the level of inhibition with the duration of the inhibition. The platelet activation parameters were analyzed using the same model of analysis of variance but after log transformation of the number of epitopes. Qualitative variables were compared using the Pearson chi-square test or the Fisher exact test when the calculated sample size of at least 1 cell of a table was <5.
|
Results
|
|---|
A total of 103 patients with NSTE-ACS were enrolled into the study. Baseline demographic characteristics are listed in Table 1. Overall, there were no statistically significant differences between the treatment groups.
Inhibition of platelet aggregation.
In the 300-mg LD group, maximal inhibition of 5 µmol/l ADP-induced PA was achieved by 6 h after the initiation of clopidogrel. Greater LDs were associated with a significantly faster onset of inhibition (within the first 6 h: p < 0.05 at 3 time points with both 600 mg and 900 mg vs. 300 mg) (Table 2). In addition, the greater clopidogrel LDs produced significantly greater maximal IPA compared with the 300-mg LD. For each of the higher LDs, this significant increment in platelet inhibition was still observed at 24 h (Fig. 1A, Table 2).
View larger version (24K):
[in this window]
[in a new window]
|
Figure 1 (A) Percentage inhibition of platelet aggregation after stimulation with 5 µmol/l adenosine diphosphate (ADP). (B) Percentage inhibition of platelet aggregation after stimulation with 20 µmol/l ADP.
|
|
Using 20 µmol/l ADP, the kinetics of IPA were faster with 900 mg, which produced already significantly greater IPA at 1 h after the administration of clopidogrel than with 300 mg (Fig. 1B). Within 2 h, the level of IPA obtained with 900 mg was greater than that obtained at the plateau of IPA with 300 mg. The onset of action of the 600-mg dose was intermediate between the 300- and 900-mg dose groups. A similar dose-effect relationship was found for the maximal plateau of IPA. Significantly higher inhibition was found at all time points from 1 to 24 h with 900 mg versus 300 mg. Intermediate levels were measured with 600 mg, which were only statistically different from 300 mg at the 4-h time point (p = 0.04) (Table 2).
Comparison of the 24-h AUCs for IPA suggested again a dose-response effect, with statistically significant higher AUCs in the 600-mg and 900-mg groups compared with the 300-mg group (Fig. 2).
View larger version (26K):
[in this window]
[in a new window]
|
Figure 2 Areas under the curves for inhibition of adenosine diphosphate (ADP)-induced platelet aggregation between 0 and 24 h. Error bars indicate standard deviations of the mean. AUC = area under the IPA curve.
|
|
Interestingly, although maximal IPA increased with increasing doses, it was obtained between 5 and 6 h in all three groups with both 5 and 20 µmol/l ADP-induced PA. Patients with less than 10% of IPA at 6 h, a time point when maximal IPA was reached in all 3 groups, were specifically analyzed. When using 5 µmol/l, the percentages of patients with a low response (IPA <10% at 6 h) were 28.6%, 17.2%, and 7.1% with 300, 600, and 900 mg, respectively (p = 0.20). When using 20 µmol/l, these rates were 46.4%, 20.7%, and 10.7% with 300, 600, and 900 mg, respectively (p = 0.007).
Platelet activation.
All clopidogrel LDs reduced platelet membrane expression of PAC-1, P-selectin, and fibrinogen after stimulation. Peak reductions in these markers occurred at 5 to 6 h after administration of each clopidogrel LD. At 6 h, stimulated PAC-1 expression was reduced significantly in both the 600- and 900-mg groups as compared to the 300-mg group (absolute changes: –2280, –3250, and –3540 standardized sites with 300, 600, and 900 mg, respectively); at 6 h, stimulated P-selectin was reduced significantly in the 900-mg group only as compared with the 300-mg group (absolute changes: –5180, –5370, and –5470 standardized sites with 300, 600, and 900 mg, respectively); at 6 h, stimulated fibrinogen binding to the platelet membrane decreased in all three study groups (–405, –490, and –489 fluorescence count in the 300-, 600-, and 900-mg groups, respectively, without significant differences between groups).
The absolute platelet content of phosphorylated VASP, as measured after the dual effect of PGE1 and ADP, increased after ADP inhibition of the adenylate cyclase pathway. This increase was dose dependent at 6 h (Fig. 3A), and similar results were observed at 24 h. The VASP index, which calculates the relative ADP-dependent inhibition of the platelet adenylate cyclase pathway, also exhibited a dose-response effect that favored the 900-mg group (Fig. 3B), a difference that was still present at 24 h.
View larger version (25K):
[in this window]
[in a new window]
|
Figure 3 (Left) Mean fluorescence intensity (MFI) after the coadministration of PGE1 and adenosine diphosphate (ADP) at 6 h after dosing. (Right) Vasodilator-stimulated phosphoprotein (VASP) index at 6 h after dosing. Error bars indicate standard deviations of the mean.
|
|
Kinetics of markers of inflammation and myonecrosis.
Temporal changes in markers of inflammation are shown in Table 3. At 24 h, there was a trend toward an increasing reduction from baseline in high-sensitivity C-reactive protein with greater clopidogrel LDs, although this effect was neither significant at 24 h nor apparent at 6 h. Levels of PAI-1, sCD40L, and vWF Ag were not significantly affected during the first 24 h by the administration of increasing LDs of clopidogrel.
Average troponin I or creatine kinase levels did not differ between groups at 6 h or 24 h, but this analysis is impaired by the important interindividual variability and a lack of sensitivity. However, on day 2, a trend was observed toward a lower incidence of increasing troponin I levels during the first 24 h with increasing clopidogrel LD (50.0% vs. 42.9% vs. 34.6% for 300-, 600-, and 900-mg treatment groups, respectively, p = NS) (Fig. 4).
Major adverse cardiac events (MACE).
No deaths occurred during the study. Compared with the standard 300-mg LD, the incidence of MACE was numerically lower in the higher LD groups (300 mg, 4 patients [1 nonfatal myocardial infarction, 1 nonplanned PCI, 2 hospitalizations for recurrent ischemia]; 600 mg, 2 patients [2 nonfatal myocardial infarctions); 900 mg, 0 patients) but these differences were not statistically significant.
Safety.
There were no episodes of severe bleeding during the trial (Table 4). The incidence of mild bleeding was comparable in the 3 treatment groups and mainly due to bleeding at puncture sites (e.g., oozing, hematoma, subcutaneous bleeding).
|
Discussion
|
|---|
To our knowledge, the ALBION trial is the largest randomized, direct pharmacodynamic comparison of 3 different clopidogrel LDs. Furthermore, it is the only trial to evaluate multiple time points during the first 24 h after dosing and perform blinded evaluation of biological end points in a core laboratory. The results of the ALBION trial demonstrate that clopidogrel doses >300 mg can provide faster onset of action and greater levels of IPA in patients presenting with NSTE-ACS. A dose-response effect across the three LDs was found for IPA using 20 µmol/l ADP and inhibition of platelet activation. Compared with a standard 300-mg LD, a 900-mg LD provides greater platelet inhibition within 1 h, an effect that persisted for at least 24 h. In addition, there was a trend to lower occurrence of myocardial necrosis with the higher LDs.
Clopidogrel-induced platelet inhibition is dose and time dependent. In healthy subjects, maximum inhibition of ADP-induced PA was obtained within 5 h after the administration of a first dose of 400-mg LD of clopidogrel, with no further inhibition observed with a 600-mg LD (11). Similar results were reported in coronary patients receiving clopidogrel pretreatment before PCI, with no difference in IPA detected between 450- and 600-mg LDs of clopidogrel (14). More intriguing was the absence of a difference in IPA between 300 and 600 mg in a recent study, despite greater inhibition of ADP-induced platelet activation (as assessed by flow cytometry) with 600 mg of clopidogrel (15). These data are in contrast to other convincing studies demonstrating a higher IPA after the administration of clopidogrel 600 mg compared with 300 mg (12,13), and evidence of reduced myocardial necrosis and/or periprocedural events with the greater LD (13,16).
Although never evaluated versus clopidogrel 300 mg in an adequately sized clinical trial, the 600-mg LD has been used as standard therapy in placebo-controlled trials designed to assess the incremental benefit of GP IIb/IIIa inhibitors (19–21), and recent European guidelines have considered 600 mg to be an acceptable LD strategy in PCI (22). Moreover, there has been no dose-ranging study conducted so far and it was still unknown whether 600 mg was the optimal strategy to reach the maximal antiplatelet effect as early as possible. Our results suggest a gradual benefit of 600 mg and 900 mg to achieve more complete P2Y12 receptor antagonism than 300 mg, translating into more inhibition of both platelet activation and aggregation. The ADP concentrations used to induce aggregation influence the degree of IPA, and low ADP concentrations can sometimes elicit only the primary and reversible phase of aggregation. It has been suggested that this concentration may artificially blunt the drug or dose effect, reduce the number of poor responders, and may lack clinical relevance (23–25). On the other hand, greater ADP concentrations can recruit more P2Y12 receptors, recruit the platelet P2Y1 receptor, and may be more representative of highly thrombogenic clinical situations. From the ADP content of platelets, it is possible to calculate that a local ADP concentration of 20 µmol/l can be easily achieved in the context of in vivo platelet activation (26). Indeed, 20 µmol/l ADP was more effective than 5 µmol/l in unmasking the dose-effect relationship in the present study. Although we acknowledge the numerous factors contributing to the variability of PA measurements, the multiplicity of sampling times with consistent differences at all time points suggest strongly that 900 mg provides the most complete P2Y12 receptor occupancy. That dose impacts not only on the rapidity of action but also on the level of maximum IPA. Although it was reasonable to predict a more rapid onset of action with increasing doses, a higher maximal IPA during the first 24 h of observation with increasing doses, persisting beyond the 6-h timepoint, is quite interesting. The maximal plateau IPA was reached between 5 and 6 h in all three groups, and the curves remained parallel during the course of the 24-h sampling period, with a persistent advantage for the 900-mg group at 24 h. The impact of higher doses also clearly reduced the number of patients with a lower response in a dose-related manner. In these patients, 900 mg was associated with a 4-fold decrease in low IPA response compared with 300 mg, whatever the concentration of ADP. Our data underscore the importance of both the dose and sampling time when evaluating the degree of platelet response to clopidogrel.
These aggregation findings are reinforced by data on platelet activation. Measurements of activated GP IIb/IIIa receptor, fibrinogen binding, and P-selectin expression indicated less activation with the 2 higher doses of clopidogrel. The VASP phosphorylation assay, which is the most rational evaluation of ADP-induced platelet P2Y12 receptor activation and, as a consequence, a specific marker of the clopidogrel effect, demonstrated a dose-effect relationship across the 3 doses of clopidogrel. The mean of the absolute fluorescence intensity measured on activated platelets (PGE1 + ADP), which increases with the degree of platelet inhibition via the P2Y12 receptors, was substantially increased in a dose-related fashion with increasing doses of clopidogrel. Calculation of the VASP index, a measure of P2Y12-dependent platelet reactivity, confirmed the greater inhibition obtained with increasing doses of clopidogrel.
An additional supportive line of evidence was the observation that troponin I release was blunted in a dose-related manner with increasing doses of clopidogrel. This trend, which was measured during the 24-h period of medical treatment preceding catheterization, was nonsignificant but seems to confirm similar findings seen in prior PCI studies (13,16,27).
At 30 days, the incidence of MACE was asymmetrically split between the three LD groups, with a trend favoring the highest LD of clopidogrel. There was no excess of severe or moderate bleeding with the higher doses. A larger trial with adequate statistical power would be required to confirm these findings.
Finally, and in contrast to previous reports suggesting a potential anti-inflammatory effect of clopidogrel, we did not observe significant reductions in markers of inflammation. At 24 h, there was a nonsignificant trend toward increasing reduction from baseline in high-sensitivity C-reactive protein with greater clopidogrel LDs, but no evidence from the other inflammatory markers tested. This result is likely to be related to the short period of observation as well as to the absence of PCI (28,29).
The recent ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) study also compared the antiplatelet effects of the same 3 LDs (30). In this trial, which enrolled 60 stable patients, platelet aggregometry measurements were restricted to baseline and 4 h after administration of the LD. Incremental benefit was observed across the 3 doses, with statistical significance limited to the comparison between 600 and 300 mg with similar findings for the levels of the active clopidogrel metabolite. However, with only a single post-treatment measurement of PA, the ISAR-CHOICE investigators had little possibility of detecting differences in the onset of action according to the LD. In contrast, the present study used eight consecutive blood samples during the first 6 h, which demonstrated a dose-effect relationship for the onset of IPA as well as for platelet activation as measured by VASP, a direct measure of the action of the active clopidogrel metabolite. These 2 studies should stimulate further investigations to determine the optimal LD of clopidogrel.
Study limitations.
Although our study is the largest pharmacodynamic evaluation of 3 different LDs of clopidogrel, it remains small in size and, therefore, low power may be the explanation for lack of significance for some of the comparisons; moreover, our sample size does not allow interpretation of clinical events, which have been provided here only for information. The unblinded nature of the study is another limitation, although the primary end point (IPA) and all biological endpoints were blindly and centrally evaluated.
Conclusions.
The present study has shown that in moderate-risk patients with non–ST-segment elevation acute coronary syndromes, LDs of clopidogrel >300 mg provide a more rapid onset of action, a greater IPA plateau, less-frequent low response, and greater reductions in platelet activation during the first 24 h, which all are suggestive of a dose-effect relationship. Favorable trends also were seen on troponin release and ischemic events with higher doses, with no apparent adverse effects on safety. Our study suggests that 900 mg might induce a greater antiplatelet effect than 600 mg, when compared with the standard 300-mg regimen. These findings require further clinical evaluation in a larger, randomized, clinical-end point trial, ideally using a double-blind design.
|
Footnotes
|
|---|
This study was supported by a grant from Sanofi-Aventis and Bristol-Myers Squibb. Some conflict of interest with Sanofi Aventis and BMS exists.
1 Dr. Montalescot, Ms. Bal-dit-SoAllier, Dr. Steg, and Dr. Drouet declare that they have been consultants for and/or have received research grants from Sanofi-Aventis. 
|
References
|
|---|
1. Bal dit Sollier C, Mahé I, Berge N, Simoneau G, Bergmann JF, Drouet L. Reduced thrombus cohesion in an ex vivo human model of arterial thrombosis induced by clopidogrel treatmentkinetics of the effect and influence of single and double loading-dose regimens. Thromb Res 2003;111:19-27.[CrossRef][Web of Science][Medline]2. Dalby M, Montalescot G, Bal dit Sollier C, et al. Eptifibatide provides additional platelet inhibition in non-ST-elevation myocardial infarction patients already treated with aspirin and clopidogrel. Results of the platelet activity extinction in non–Q-wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study J Am Coll Cardiol 2004;43:162-168.[Abstract/Free Full Text] 3. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation N Engl J Med 2001;345:494-502.[Abstract/Free Full Text] 4. Sabatine MS, Cannon CP, Gibson CM, et al. CLARITY-TIMI 28 Investigators Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation N Engl J Med 2005;352:1179-1189.[Abstract/Free Full Text] 5. Mehta SR, Yusuf S, Peters RJ, et al. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary interventionthe PCI-CURE study. Lancet 2001;358:527-533.[CrossRef][Web of Science][Medline] 6. Steinhubl SR, Berger PB, Mann 3rd JT, et al. CREDO Investigators Early and sustained dual oral antiplatelet therapy following percutaneous coronary interventiona randomized controlled trial. JAMA 2002;288:2411-2420.[Abstract/Free Full Text] 7. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines(Committee on the Management of Patients with Unstable Angina) J Am Coll Cardiol 2002;40:1366-1374.[Free Full Text] 8. Bertrand ME, Simoons ML, Fox KAA, et al. The Task Force on the Management of Acute Coronary Syndromes of the European Society of Cardiology Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation Eur Heart J 2002;23:1809-1840.[Free Full Text] 9. Harrington RA, Becker RC, Ezekowitz M, et al. Antithrombotic therapy for coronary artery disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest 2004;126:513S-548S.[Abstract/Free Full Text] 10. Popma JJ, Berger P, Ohman EM, Harrington RA, Grines C, Weitz JI. Antithrombotic therapy during percutaneous coronary interventionthe Seventh ACCP Conference on antithrombotic and thrombolytic therapy. Chest 2004;126(Suppl 3):576S-599S.[Abstract/Free Full Text] 11. Thébault JJ, Kieffer G, Cariou R. Single-dose pharmacodynamics of clopidogrel Semin Thromb Hemost 1999;25(Suppl 2):3-8. 12. Müller I, Seyfarth M, Rudiger S, et al. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement Heart 2001;85:92-93.[Free Full Text] 13. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets. Results of the Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study Circulation 2005;111:1153-1159.[Abstract/Free Full Text] 14. Nikhil J, Reis M, Phillips AM, et al. A randomized comparison of the effects of a high versus conventional loading dose of clopidogrel on platelets aggregation (PA) prior to percutaneous coronary intervention (PCI)(abstr) Circulation 2001;104(Suppl):347. 15. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. High clopidogrel loading dose during coronary stentingeffects on drug response and interindividual variability. Eur Heart J 2004;25:1903-1910.[Abstract/Free Full Text] 16. Patti G, Collonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading doses of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention. Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty) study Circulation 2005;111:2099-2106.[Abstract/Free Full Text] 17. Born GVR. Aggregation of blood platelets by adenosine diphosphate and its reversal Nature (Lond) 1962;194:927-929.[Medline] 18. The GUSTO Investigators An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction N Engl J Med 1993;329:673-682.[Abstract/Free Full Text] 19. Kandzari DE, Berger PB, Kastrati A, et al. ISAR-REACT Study Investigators Influence of treatment duration with a 600-mg dose of clopidogrel before percutaneous coronary revascularization J Am Coll Cardiol 2004;44:2133-2136.[Abstract/Free Full Text] 20. Schömig A, Schmitt C, Dibra A, et al. Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment Study Investigators One year outcomes with abciximab vs. placebo during percutaneous coronary intervention after pre-treatment with clopidogrel Eur Heart J 2005;26:1379-1384.[Abstract/Free Full Text] 21. Mehilli J, Kastrati A, Schuhlen H, et al. Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) Study Investigators Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel Circulation 2004;110:3627-3635.[Abstract/Free Full Text] 22. Silber S, Albertsson P, Aviles FF, et al. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology Guidelines for percutaneous coronary interventions Eur Heart J 2005;26:804-847.[Free Full Text] 23. Jaremo P, Lindahl TL, Fransson SG, Richter A. Individual variations of platelet inhibition after loading doses of clopidogrel J Intern Med 2002;252:233-238.[CrossRef][Web of Science][Medline] 24. Mobley JE, Bresee SJ, Wortham DC, Craft RM, Snider CC, Carroll RC. Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization Am J Cardiol 2004;93:456-458.[CrossRef][Web of Science][Medline] 25. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrela review of the evidence. J Am Coll Cardiol 2005;45:1157-1164.[Abstract/Free Full Text] 26. Valles J, Santos MT, Aznar J, et al. Erythrocytes metabolically enhance collagen-induced platelet responsiveness via increased thromboxane production, adenosine diphosphate release, and recruitment Blood 1991;78:154-162.[Abstract/Free Full Text] 27. Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease Circulation 2000;101:570-580.[Free Full Text] 28. Chew DP, Bhatt DL, Robbins MA, et al. Effect of clopidogrel added to aspirin before percutaneous coronary intervention on the risk associated with C-reactive protein Am J Cardiol 2001;88:672-674.[CrossRef][Web of Science][Medline] 29. Vivekananthan DP, Bhatt DL, Chew DP, et al. Effect of clopidogrel pretreatment on periprocedural rise in C-reactive protein after percutaneous coronary intervention Am J Cardiol 2004;94:358-360.[CrossRef][Web of Science][Medline] 30. von Beckerath N, Taubert D, Pogatsa-Murray G, Schömig E, Kastrati A, Schömig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel. Results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose between 3 High Oral doses for Immediate Clopidogrel Effect) trial Circulation 2005;112:2946-2950.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
S. Schulz, T. Schuster, J. Mehilli, R. A. Byrne, J. Ellert, S. Massberg, J. Goedel, O. Bruskina, K. Ulm, A. Schomig, et al.
Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period
Eur. Heart J.,
November 2, 2009;
30(22):
2714 - 2721.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Dangas, R. Mehran, G. Guagliumi, A. Caixeta, B. Witzenbichler, J. Aoki, J. Z. Peruga, B. R. Brodie, D. Dudek, R. Kornowski, et al.
Role of Clopidogrel Loading Dose in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Angioplasty: Results From the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) Trial
J. Am. Coll. Cardiol.,
October 6, 2009;
54(15):
1438 - 1446.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Wallentin, R. C. Becker, A. Budaj, C. P. Cannon, H. Emanuelsson, C. Held, J. Horrow, S. Husted, S. James, H. Katus, et al.
Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes
N. Engl. J. Med.,
September 10, 2009;
361(11):
1045 - 1057.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. P. Bonaca, P. G. Steg, L. J. Feldman, J. F. Canales, J. J. Ferguson, L. Wallentin, R. M. Califf, R. A. Harrington, and R. P. Giugliano
Antithrombotics in acute coronary syndromes.
J. Am. Coll. Cardiol.,
September 8, 2009;
54(11):
969 - 984.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-P. Collet and G. Montalescot
Review: Platelet Function Testing and Implications for Clinical Practice
Journal of Cardiovascular Pharmacology and Therapeutics,
September 1, 2009;
14(3):
157 - 169.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. O'Donoghue, E. M. Antman, E. Braunwald, S. A. Murphy, P. G. Steg, A. Finkelstein, W. F. Penny, V. Fridrich, C. H. McCabe, M. S. Sabatine, et al.
The efficacy and safety of prasugrel with and without a glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes undergoing percutaneous intervention: a TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38) Analysis.
J. Am. Coll. Cardiol.,
August 18, 2009;
54(8):
678 - 685.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Wallentin
P2Y12 inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use
Eur. Heart J.,
August 2, 2009;
30(16):
1964 - 1977.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Verstuyft, T. Simon, and R. B. Kim
Personalized medicine and antiplatelet therapy: ready for prime time?
Eur. Heart J.,
August 2, 2009;
30(16):
1943 - 1963.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Witkowski, P. Maciejewski, W. Wasek, L. A. Malek, M. Niewada, B. Kaminski, J. Drzewiecki, M. Kosmider, J. Kubica, W. Ruzyllo, et al.
Influence of different antiplatelet treatment regimens for primary percutaneous coronary intervention on all-cause mortality
Eur. Heart J.,
July 2, 2009;
30(14):
1736 - 1743.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Prasad and D. R Holmes
Update on dual antiplatelet therapy for percutaneous coronary intervention
Heart,
June 1, 2009;
95(11):
861 - 865.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Tousoulis, A. Briasoulis, S. S Dhamrait, C. Antoniades, and C. Stefanadis
Effective platelet inhibition by aspirin and clopidogrel: where are we now?
Heart,
May 1, 2009;
95(10):
850 - 858.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. W. Hamm, H. Möllmann, J.-P. Bassand, and F. van de Werf
CHAPTER 16 Acute Coronary Syndromes
ESC Textbook of Cardiovascular Medicine,
January 1, 2009;
2(1):
med-9780199566990-chapter - med-9780199566990-chapter.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Authors/Task Force Members, F. Van de Werf, J. Bax, A. Betriu, C. Blomstrom-Lundqvist, F. Crea, V. Falk, G. Filippatos, K. Fox, K. Huber, et al.
Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology:
Eur. Heart J.,
December 1, 2008;
29(23):
2909 - 2945.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Gladding, M. Webster, I. Zeng, H. Farrell, J. Stewart, P. Ruygrok, J. Ormiston, S. El-Jack, G. Armstrong, P. Kay, et al.
The Antiplatelet Effect of Higher Loading and Maintenance Dose Regimens of Clopidogrel: The PRINC (Plavix Response in Coronary Intervention) Trial
J. Am. Coll. Cardiol. Intv.,
December 1, 2008;
1(6):
612 - 619.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. S. Kleiman
Searching for the Ceiling: New Reflections on the Disposition and Metabolism of Clopidogrel
J. Am. Coll. Cardiol. Intv.,
December 1, 2008;
1(6):
628 - 630.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Aleil, L. Jacquemin, F. De Poli, M. Zaehringer, J.-P. Collet, G. Montalescot, J.-P. Cazenave, M.-C. Dickele, J.-P. Monassier, and C. Gachet
Clopidogrel 150 mg/day to Overcome Low Responsiveness in Patients Undergoing Elective Percutaneous Coronary Intervention: Results From the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) Randomized Study
J. Am. Coll. Cardiol. Intv.,
December 1, 2008;
1(6):
631 - 638.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. O. Williams and J. D. Abbott
What to Do With Patients Receiving Long-Term Clopidogrel: Reload or Relax?
Circulation,
September 16, 2008;
118(12):
1219 - 1222.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-P. Collet, J. Silvain, A. Landivier, M.-L. Tanguy, G. Cayla, A. Bellemain, N. Vignolles, S. Gallier, F. Beygui, A. Pena, et al.
Dose Effect of Clopidogrel Reloading in Patients Already on 75-mg Maintenance Dose: The Reload With Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term With Dual Antiplatelet Therapy (RELOAD) Study
Circulation,
September 16, 2008;
118(12):
1225 - 1233.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Bonello, L. Camoin-Jau, F. Dignat-George, and F. Paganelli
A threshold of platelet reactivity for ischaemic events?
Eur. Heart J.,
September 1, 2008;
29(17):
2185 - 2186.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Kastrati, F.-J. Neumann, J. Mehilli, R. A. Byrne, R. Iijima, H. J. Buttner, A. A. Khattab, S. Schulz, J. C. Blankenship, J. Pache, et al.
Bivalirudin versus Unfractionated Heparin during Percutaneous Coronary Intervention
N. Engl. J. Med.,
August 14, 2008;
359(7):
688 - 696.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C Coons and S. Battistone
2007 Guideline Update for Unstable Angina/Non-ST-Segment Elevation Myocardial Infarction: Focus on Antiplatelet and Anticoagulant Therapies
Ann. Pharmacother.,
July 1, 2008;
42(7):
989 - 1001.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Widimsky, Z. Motovska, S. Simek, P. Kala, R. Pudil, F. Holm, R. Petr, D. Bilkova, H. Skalicka, P. Kuchynka, et al.
Clopidogrel pre-treatment in stable angina: for all patients >6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI? A randomized multicentre trial PRAGUE-8
Eur. Heart J.,
June 2, 2008;
29(12):
1495 - 1503.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Hjemdahl
Should we monitor platelet function during antiplatelet therapy?
Heart,
June 1, 2008;
94(6):
685 - 687.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T Geisler, M Kapp, K Gohring-Frischholz, K Daub, C Dosch, B Bigalke, H Langer, C Herdeg, and M Gawaz
Residual platelet activity is increased in clopidogrel- and ASA-treated patients with coronary stenting for acute coronary syndromes compared with stable coronary artery disease
Heart,
June 1, 2008;
94(6):
743 - 747.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Patrono, C. Baigent, J. Hirsh, and G. Roth
Antiplatelet Drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Chest,
June 1, 2008;
133(6_suppl):
199S - 233S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Harrington, R. C. Becker, C. P. Cannon, D. Gutterman, A. M. Lincoff, J. J. Popma, G. Steg, G. H. Guyatt, and S. G. Goodman
Antithrombotic Therapy for Non-ST-Segment Elevation Acute Coronary Syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Chest,
June 1, 2008;
133(6_suppl):
670S - 707S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. G. Goodman, V. Menon, C. P. Cannon, G. Steg, E. M. Ohman, and R. A. Harrington
Acute ST-Segment Elevation Myocardial Infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Chest,
June 1, 2008;
133(6_suppl):
708S - 775S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-P. Bassand
Unmet needs in antiplatelet therapy
Eur. Heart J. Suppl.,
May 1, 2008;
10(suppl_D):
D3 - D11.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Bonello, L. Camoin-Jau, S. Arques, C. Boyer, D. Panagides, O. Wittenberg, M.-C. Simeoni, P. Barragan, F. Dignat-George, and F. Paganelli
Adjusted Clopidogrel Loading Doses According to Vasodilator-Stimulated Phosphoprotein Phosphorylation Index Decrease Rate of Major Adverse Cardiovascular Events in Patients With Clopidogrel Resistance: A Multicenter Randomized Prospective Study
J. Am. Coll. Cardiol.,
April 8, 2008;
51(14):
1404 - 1411.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Kereiakes and P. A. Gurbel
Peri-Procedural Platelet Function and Platelet Inhibition in Percutaneous Coronary Intervention
J. Am. Coll. Cardiol. Intv.,
April 1, 2008;
1(2):
111 - 121.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Serebruany, V. Pasceri, G. Patti, G. Di Sciascio, F. von Lewinski, J. Riggert, W. Paulus, S. D. Wiviott, E. Braunwald, E. M. Antman, et al.
Prasugrel versus Clopidogrel
N. Engl. J. Med.,
March 20, 2008;
358(12):
1298 - 1301.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. L. L'Allier, G. Ducrocq, N. Pranno, S. Noble, R. Ibrahim, J. C. Gregoire, F. Azzari, A. Nozza, C. Berry, S. Doucet, et al.
Clopidogrel 600-mg double loading dose achieves stronger platelet inhibition than conventional regimens: results from the PREPAIR randomized study.
J. Am. Coll. Cardiol.,
March 18, 2008;
51(11):
1066 - 1072.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Comerota and S. Thakur
Antiplatelet Therapy for Vascular Interventions
Perspectives in Vascular Surgery and Endovascular Therapy,
March 1, 2008;
20(1):
28 - 35.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. D. Michelson
P2Y12 Antagonism: Promises and Challenges
Arterioscler Thromb Vasc Biol,
March 1, 2008;
28(3):
s33 - s38.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. E. Kip, K. Hollabaugh, O. C. Marroquin, and D. O. Williams
The Problem With Composite End Points in Cardiovascular Studies The Story of Major Adverse Cardiac Events and Percutaneous Coronary Intervention.
J. Am. Coll. Cardiol.,
February 19, 2008;
51(7):
701 - 707.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Wallentin, C. Varenhorst, S. James, D. Erlinge, O. O Braun, J. A. Jakubowski, A. Sugidachi, K. J. Winters, and A. Siegbahn
Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease
Eur. Heart J.,
January 1, 2008;
29(1):
21 - 30.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Bode and K. Huber
Antiplatelet therapy in percutaneous coronary intervention
Eur. Heart J. Suppl.,
January 1, 2008;
10(suppl_A):
A13 - A20.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. F. Storey
Variability of response to antiplatelet therapy
Eur. Heart J. Suppl.,
January 1, 2008;
10(suppl_A):
A21 - A27.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Gachet and B. Aleil
Testing antiplatelet therapy
Eur. Heart J. Suppl.,
January 1, 2008;
10(suppl_A):
A28 - A34.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. D. Wiviott, D. Trenk, A. L. Frelinger, M. O'Donoghue, F.-J. Neumann, A. D. Michelson, D. J. Angiolillo, H. Hod, G. Montalescot, D. L. Miller, et al.
Prasugrel Compared With High Loading- and Maintenance-Dose Clopidogrel in Patients With Planned Percutaneous Coronary Intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation Thrombolysis in Myocardial Infarction 44 Trial
Circulation,
December 18, 2007;
116(25):
2923 - 2932.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. D. Wiviott, E. Braunwald, C. H. McCabe, G. Montalescot, W. Ruzyllo, S. Gottlieb, F.-J. Neumann, D. Ardissino, S. De Servi, S. A. Murphy, et al.
Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes
N. Engl. J. Med.,
November 15, 2007;
357(20):
2001 - 2015.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. P. Giugliano and E. Braunwald
The Year in Non ST-Segment Elevation Acute Coronary Syndrome
J. Am. Coll. Cardiol.,
October 2, 2007;
50(14):
1386 - 1395.
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. J. Weerakkody, J. A. Jakubowski, J. T. Brandt, C. D. Payne, H. Naganuma, and K. J. Winters
Greater Inhibition of Platelet Aggregation and Reduced Response Variability With Prasugrel Versus Clopidogrel: An Integrated Analysis
Journal of Cardiovascular Pharmacology and Therapeutics,
September 1, 2007;
12(3):
205 - 212.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al.
ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine
J. Am. Coll. Cardiol.,
August 14, 2007;
50(7):
e1 - e157.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. Dixon, C. L. Grines, and W. W. O'Neill
The Year in Interventional Cardiology
J. Am. Coll. Cardiol.,
July 17, 2007;
50(3):
270 - 285.
[Full Text]
[PDF]
|
|
|
|
|
|
|
Authors/Task Force Members, J.-P. Bassand, C. W. Hamm, D. Ardissino, E. Boersma, A. Budaj, F. Fernandez-Aviles, K. A.A. Fox, D. Hasdai, E. M. Ohman, et al.
Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology
Eur. Heart J.,
July 1, 2007;
28(13):
1598 - 1660.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. A. Meadows and D. L. Bhatt
Clinical Aspects of Platelet Inhibitors and Thrombus Formation
Circ. Res.,
May 11, 2007;
100(9):
1261 - 1275.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Angiolillo, A. Fernandez-Ortiz, E. Bernardo, F. Alfonso, C. Macaya, T. A. Bass, and M. A. Costa
Variability in Individual Responsiveness to Clopidogrel: Clinical Implications, Management, and Future Perspectives
J. Am. Coll. Cardiol.,
April 10, 2007;
49(14):
1505 - 1516.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Dudek, A. Dziewierz, B. Chyrchel, L. Polonski, J. Legutko, and J. S. Dubiel
Antiplatelet treatment in non-ST-segment elevation acute coronary syndrome patients undergoing percutaneous coronary intervention (ISAR-REACT 2 insight)
Eur. Heart J. Suppl.,
February 1, 2007;
9(suppl_A):
A25 - A31.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. O'Donoghue and S. D. Wiviott
Clopidogrel Response Variability and Future Therapies: Clopidogrel: Does One Size Fit All?
Circulation,
November 28, 2006;
114(22):
e600 - e606.
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Hochholzer, D. Trenk, H.-P. Bestehorn, B. Fischer, C. M. Valina, M. Ferenc, M. Gick, A. Caputo, H. J. Buttner, and F.-J. Neumann
Impact of the Degree of Peri-Interventional Platelet Inhibition After Loading With Clopidogrel on Early Clinical Outcome of Elective Coronary Stent Placement
J. Am. Coll. Cardiol.,
November 7, 2006;
48(9):
1742 - 1750.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Hirose
ICVTS on-line discussion A
Interactive CardioVascular and Thoracic Surgery,
October 1, 2006;
5(5):
636 - 636.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. Mehta
Clopidogrel in non-ST-segment elevation acute coronary syndromes
Eur. Heart J. Suppl.,
October 1, 2006;
8(suppl_G):
G25 - G30.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods