Published online before print September 2, 2008, doi: 10.1161/CIRCULATIONAHA.108.776757
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(Circulation. 2008;118:1225-1233.)
© 2008 American Heart Association, Inc.
Coronary Heart Disease |
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
From the Institut de Cardiologie, Unité INSERM 856 (J.-P.C., J.S., A.L., G.C., A.B., N.V., S.G., F.B., A.P., G.M.), and Unité de Biostatistique (M.-L.T.), Pitié-Salpêtrière University Hospital (AP-HP), Paris, France.
Correspondence to Gilles Montalescot, MD, PhD, Bureau 236, Institut de Cardiologie, Hôpital Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75013, Paris, France. E-mail gilles.montalescot{at}psl.aphp.fr
Received February 29, 2008; accepted July 2, 2008.
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Abstract |
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Background— Clopidogrel loading has mostly been studied in clopidogrel-naïve patients. Whether clopidogrel-treated patients readmitted for an acute coronary syndrome or percutaneous coronary intervention can benefit from a new load of clopidogrel and at what dose remain unknown. Our aim was to evaluate the impact of 3 different strategies of administration of a loading dose of 900 mg clopidogrel in patients already treated with a maintenance dose of 75 mg clopidogrel for at least 7 days on residual platelet aggregation.
Methods and Results— Patients treated long term by clopidogrel 75 mg/d were assigned to receive a first loading dose of 300, 600, or 900 mg clopidogrel and 4 hours later a second loading dose of 600, 300, or 0 mg, respectively, to achieve a total loading dose of 900 mg in all patients. Platelet aggregation was evaluated at baseline, at 4 hours after the initial load (and before second load), and at 24 hours using light transmission aggregometry with 20 µmol ADP and the point-of-care assay VerifyNow P2Y12. The primary objective of the study was to evaluate the inhibition (relative change) of residual platelet aggregation (percentage of IRPA) between 600- and 900-mg first loading at 4 hours. IRPA at 24 hours also was evaluated as a secondary objective, as well as the rate of suboptimal response at 4 hours defined as IRPA <10%. We included 166 consecutive patients with acute coronary syndromes (n=80, 48%) or stable coronary artery disease (n=86, 52%). Baseline characteristics were similar in the 3 dose groups. A significant stepwise increase was found in percentage IRPA assessed at 4 hours in patients initially assigned to 300 versus 600 versus 900 mg (30.7% versus 40.3% versus 64.0%, respectively; P=0.0024). The difference in percentage IRPA at 4 hours was not significant between 300 and 600 mg but was significant between 600 and 900 mg and between 300 and 900 mg. Percentage IRPA assessed at 24 hours when all patients had received 900 mg did not differ between the 3 loading regimens. The rates of suboptimal response (IRPA <10% at 4 hours) were 23.6%, 20.4%, and 5.3% with 300, 600, and 900 mg, respectively (P=0.02 for all).
Conclusions— In patients treated long term with 75 mg clopidogrel, a new loading dose of 900 mg improves IRPA and reduces poor and/or slow response to clopidogrel significantly more than that obtained with 300 or 600 mg.
Key Words: clopidogrel • platelets • thrombosis • stents
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Introduction |
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The combination of aspirin and a thienopyridine has become the routine treatment for the prevention of ischemic events in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention (PCI).1 A loading dose (LD) of 300 mg accelerates inhibition of platelet aggregation compared with 75 mg without loading.
Editorial p 1219
Clinical Perspective p 1233
Several studies have shown increased inhibition, faster onset of action, and fewer poor responders with 600 mg clopidogrel compared with a 300-mg LD2–4 with better clinical outcomes.5,6 Subsequently, LDs >600 mg have been evaluated to further improve these parameters.4,6,7 In both the Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis (ALBION) study and the Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect (ISAR-CHOICE) study, clopidogrel 600 and 900 mg showed greater inhibition than 300 mg. An incremental benefit on inhibition of platelet aggregation, the vasodilator-stimulated phosphoprotein index, and troponin release from 300 to 900 mg was observed in ALBION.4,7 Recent studies have suggested that doses >900 mg are even more effective on platelet aggregation or vasodilator-stimulated phosphoprotein index.8,9 All these studies were conducted in clopidogrel-naïve patients presenting with acute coronary syndromes and eligible for elective/emergent PCI after acute loading, although evidence also suggests that variability exists in the maintenance phase of treatment with established prognostic implications.10,11
Clopidogrel at the approved maintenance dose of 75 mg achieves a modest antiplatelet effect, and up to one third of patients may continue to have elevated platelet reactivity.12,13 A few studies have shown improved platelet inhibition after a new load of 600 mg clopidogrel in patients already on 75-mg maintenance treatment, and it was suggested that the dose of 600 mg was the maximum dose that can be absorbed and/or metabolized.7 Whether this can result in improved clinical outcome is unknown. The present study sought to determine whether a dose-effect relationship could be seen across 3 LD regimens (300, 600, 900 mg) in clopidogrel-treated patients as previously observed in clopidogrel-naïve patients. The 900-mg effect was verified by a second phase in the study design using a second LD in the 2 lower-dose groups so that all patients finally reached the same total loading of 900 mg. This fractionation of the LD in the first 2 groups compared with a single loading in the third arm also allowed evaluation of whether differences exist in the absorption or metabolism of a 900-mg dose of clopidogrel.
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Methods |
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Patient Population
Patients were eligible for enrollment if they were at least 18 years old and if they were on a maintenance dose of clopidogrel for at least >7 days and scheduled to undergo cardiac catheterization because of unstable coronary artery disease or stable angina. Patients on a maintenance dose of 75 mg clopidogrel for
7 days; those with ongoing acute ST-elevation myocardial infarction; patients in whom catheterization was performed before randomization or was scheduled to be performed <24 hours after randomization; those with contraindication to the use of low-molecular-weight heparin, clopidogrel, or aspirin; patients with severe, uncontrolled hypertension; patients with low platelet count (<100 000/mm3); those with increased risk of bleeding, including recent surgical intervention (<3 weeks); patients with a history of severe systemic bleeding; and those with recent or planned use of nonpermitted concomitant medications (any antiplatelet agent other than aspirin or clopidogrel, oral anticoagulants, direct thrombin inhibitors, nonsteroidal antiinflammatory drugs) were excluded. All subjects provided written informed consent before participation.
Study Design
The REload with cLOpidegrel before coronary Angioplasty in subjects treated long term with Dual antiplatelet therapy (RELOAD) study (Figure 1) was conducted according to the principles of the Helsinki Declaration and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines for good clinical practice. Approval was obtained from the Pitié-Salpêtrière University Hospital ethics committee. Consecutive subjects were serially allocated to a first LD (LD1) of clopidogrel 300, 600, or 900 mg. The first patient was allocated to 300 mg, the second patient to 600 mg, and the third patient to 900 mg. This allocation was repeated in the same order for the following patients until the end of the study. Investigators were blinded to allocation, as were the staff in charge of all biological measurements. To maintain the blindness in the evaluation of this open-label study, investigators were different from treating physicians. Specifically trained clinical research nurses were responsible for delivering the exact dose of the study drug to the treating physicians and for checking the time of drug intake and blood draws according to the study protocol. Four hours after the first load, a second LD (LD2) was given so that all subjects received 900 mg clopidogrel in total. Those initially allocated to 300, 600, or 900 mg (LD1) were given 600, 300, or 0 mg (LD2) clopidogrel, respectively. Thereafter, all patients were on a regimen of clopidogrel 75 mg/d and aspirin 100 mg/d.
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All subjects were to have blood obtained for platelet measures before LD1 and LD2 and 24 hours after LD1. Patients were referred to the catheterization laboratory when the study was completed. Other study medications were administered on an open-label basis according to local practice.7 Patients were followed up at 30±7 days to record clinical outcome and to report adverse events.
Laboratory Procedures
Platelet measures were performed in <1 hour after venipuncture in a single laboratory where the investigators were blinded to the LD regimen assigned to study patients. Light transmission aggregometry (LTA) and the point-of-care assay VerifyNow were performed simultaneously. Blood was drawn into Becton-Dickinson 3.2% citrate vacuette tubes at baseline (before LD1), 4 to 6 hours after LD1 (before LD2), and 24 hours after LD1.
Platelet-rich plasma was obtained by centrifugation of citrated whole blood at 100g for 15 minutes at room temperature. Platelet-poor plasma was obtained by further centrifugation at 1000g for 20 minutes. In vitro platelet aggregation in platelet-rich plasma was measured at 37°C in an LTA (model 490-4D, Chrono-Log Corp, Kordia, the Netherlands) and was induced by the addition of ADP (Chrono-Par, Kordia, the Netherlands) at final concentrations of 5, 10, 20, and 50 µmol/L. Residual platelet aggregation (RPA) was selected because it is thought to be more specific than and to better reflect P2Y12 function than other measurements like maximal platelet aggregation (MPA) or inhibition of platelet aggregation (IPA).14,15 RPA corresponded to the level of aggregation curve (percentage) measured 6 minutes after induction of aggregation by ADP. Inhibition of RPA (IRPA in percentage) at time x was defined as follows: (intensity of RPA at baseline)–(intensity of RPA at time x)/(intensity of RPA at baseline). Evaluation of IRPA was calculated at 4 and 24 hours. Prespecified criteria to define nonevaluable samples were the lack of sufficient signal, hemolysis, plasma-rich protein platelet count <150 000/µL, and unstable baseline.
For the VerifyNow P2Y12 assay, samples were run locally according to the package insert at the same time points as for LTA. Percentage inhibition is reported and corresponds to 100x(P2Y12 reaction units)/thrombin receptor activating peptide–stimulated aggregation). P2Y12 reaction units were correlated to RPA at each time point. Absolute changes in percentage of inhibition were assessed to evaluate the impact of the 3 reloading strategies. Serum concentrations of troponin I were measured by immunoassay using an AXSYM analyzer (Abbott, Rungis, France) at baseline (before LD1), after PCI, and before discharge.
End Points
All end points were prespecified in the study protocol and statistical analysis plan. The analyses considered only subjects with evaluable measurements available for a given time point. The primary end point of the study was the comparison of IRPA measured 6 minutes after induction by 20 µmol/L ADP at 4 hours between 600 and 900 mg of LD1.
The kinetic profile of clopidogrel-mediated IRPA also was compared across the 3 groups with respect to change from baseline at the 4- and 24-hour time points. IRPA also was evaluated at the same time points with ADP concentrations of 5, 10, and 50 µmol/L.
Suboptimal response to a maintenance dose of 75 mg clopidogrel therapy on admission was defined as a baseline RPA >50% according to previous studies.12,16 Suboptimal response to clopidogrel loading also was evaluated at 4 and 24 hours according to the 3 dose regimens and was defined as an IRPA <10% based on previous work.4
An inhibition <15% at baseline was considered as a suboptimal response with the point-of-care VerifyNow.17,18 Absolute changes in the percentage of inhibition also were determined according to the 3 LD regimens at different time points.
Clinical end points, including cardiovascular death, myocardial infarction, and stroke over 30 days, were monitored. The primary safety measure was non–coronary artery bypass graft–related Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding in the treated subjects through the 30-day visit.
Statistical Analyses
A sample size of 50 evaluable patients per group was expected to yield 80% power to demonstrate a 10% absolute difference in IRPA with 20 µmol/L ADP 4 hours after LD1 of 600 versus 900 mg. We estimated an SD of 15% (variance, 225) on the basis of previous studies.4,13 The 
level was set at 0.05.
Means and SDs were used to describe the platelet function measures (IRPA, MPA, VerifyNow P2Y12 measurements). For IRPA measures, data were included for subjects with evaluable RPA measurements taken before treatment and at 4 and 24 hours. Data were analyzed using a 1-way ANOVA on treatment group. The time course of the change from baseline of intensity of platelet aggregation induced by ADP measured at 6 minutes was compared through the use of ANOVA at the 4- and 24-hour time point.
All tests were 2 sided and conducted at the =0.017 level of significance (Bonferroni correction) given multiple comparisons according to both primary and secondary study end points. Categorical data were compared by use of the Fisher exact test. A multivariable logistic regression analysis was performed to identify independent correlates of slow and suboptimal response as defined above. The LD regimen was entered into the model for identifying slow and suboptimal independent correlates. Correlations between quantitative variables were assessed with Spearman correlation coefficients. The analyses were performed by the Department of Statistics at Pitié-Salpêtrière University Hospital with SAS version 8.2 (SAS Institute, Inc, Cary, NC).
All the authors had full access to and take full responsibility for the integrity of the data. All the authors have read and agree to the manuscript as written.
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Results |
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One-hundred-sixty-six subjects were enrolled with baseline features well matched between the 3 loading regimens (Table 1). Subjects presented either with non–ST-elevation acute coronary syndromes or with stable coronary artery disease and proven myocardial ischemia. Half had a prior history of PCI or myocardial infarction.
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The vast majority of patients had been treated with clopidogrel 75 mg QD for >1 month. Aspirin was given for >6 months in the vast majority of patients (see Table 1). Only 5 patients were not treated long term with aspirin and were loaded with 500 mg IV before enrollment in the study. The number of evaluable subjects (n=151) was similar in each of the 3 dose groups. The flow of subjects through the trial and the number evaluable for the key efficacy measures are shown in Figure 1.
Residual Platelet Aggregation
The primary end point (IRPA with 20 µmol/L ADP at 4 hours after LD1) was significantly greater after clopidogrel 900 mg compared with clopidogrel 600 mg (64.0±38.4% versus 40.3±53.8%; P=0.017) (Figure 2A). The square mean difference was 24% (SD, 12.0%; P=0.045). In addition to a greater antiplatelet effect (higher mean IRPA), patients loaded with 900-mg LD1 had more consistent levels of inhibition with significant lower intersubject variability compared with 600-mg LD1 (0.13 versus 0.29; F test=2.186; P testing equality of variance=0.006).
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The highest LD1 also showed greater antiplatelet effect as assessed by the higher absolute change in RPA to 20 µmol/L ADP at 4 hours compared with 600 mg (19.2±12.5% versus 9.7±13.7%; P=0.003) (Figure 3), with a least square mean difference of 9.5% (SD, 3.1%; P=0.001).
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The greater antiplatelet effect of the 900-mg load regimen measured by IRPA with 20 µmol/L ADP was confirmed at 24 hours when all dosing strategies displayed the same antiplatelet effect (Figure 2B). No difference was measured between 900 mg QD and 300+600 or 600+300 mg 4 hours apart.
IRPA to 20 µmol/L ADP after LD1 (ie, at 4 hours) was significantly greater in subjects receiving clopidogrel 900 mg (64.0±38.4%) compared with clopidogrel 300 mg (30.7±57.3%), with a least square mean difference of 33.2% (SD, 11.6%; P=0.002) (Figure 2A). The RPA results also were consistent between the treatments groups with different concentrations of ADP used for LTA (Table 2).
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The VerifyNow P2Y12
Correlations between RPA measured with LTA and P2Y12 reaction units measured with the VerifyNow P2Y12 assay at baseline (
=0.69; P<0.0001), 4 hours (=0.73; P<0.0001), and 24 hours (=0.83; P<0.0001) were robust and consistent. Absolute changes in the percentage of inhibition were significantly different between the 3 doses of LD1 (Table 2).
Suboptimal Response
The rate of suboptimal responders to a maintenance dose of clopidogrel measured at baseline was 15.3% (23 of 153 with RPA >50%) using LTA versus 11.1% (17 of 153 with inhibition <15%) using VerifyNow P2Y12 assay. We found a poor concordance between the 2 assays (
=0.20; 95% confidence interval (CI), 0.06 to 0.40) to define poor responders.
Whatever the definition used, fewer poor responders were found among patients reloaded with 900 mg than with 600 and 300 mg when assessed 4 hours after LD1 using LTA with 20 µmol ADP (Figure 4A). We found a significant decrease in the rate of suboptimal response with increasing LD1 (Figure 4A). At 24 hours, the rate of suboptimal response was similar between the 3 loading strategies regardless of the biological method (Figure 4B). After multivariable analysis, diabetes mellitus, hypertension, and platelet count were nonsignificantly associated with suboptimal response to clopidogrel (IPA <10%). The 900 mg clopidogrel LD1 was the only significant independent correlate of an optimal biological response at 4 hours to reloading with clopidogrel (odds ratio, 5.29; 95% CI, 1.41 to 19.81; P=0.01).
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Using the American College of Cardiology/American Heart Association PCI statement that indicates that MPA >50% is not desirable after PCI,1 we found that 27.6% of all patients at baseline (on long-term clopidogrel treatment) were above this limit, with this number decreasing to 5% at 24 hours after a full load of 900 mg clopidogrel.
Clinical End Points
No difference in clinical safety or efficacy was found between the different reloading strategies. The 3 reloading strategies were well tolerated. No TIMI major bleeds were observed during the study period. Four subjects (0.7%) allocated to the 300-mg, 3 subjects (0.55%) allocated to the 600-mg, and 3 subjects (0.52%) allocated to 900-mg reloading group experienced a TIMI minor bleeding during the entire follow-up period.
Major adverse cardiac event end points also were infrequent. Two deaths occurred, one related to aortic dissection (300-mg group) and the other to cancer (900-mg group). One subject in the 600-mg reloading group had experienced a periprocedural myocardial infarction, and 1 subject allocated to the 900-mg reloading group required urgent target vessel revascularization. No strokes occurred in the whole study population during the follow-up period.
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Discussion |
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In the present trial, we have compared the effects of 3 reloading-dose strategies on laboratory measures of platelet function in patients treated with a maintenance dose of 75 mg clopidogrel and scheduled for PCI. A 2-step design allowed a double evaluation of the effect of 900 mg compared with lower doses. Using RPA, a more sensitive biological measure to identify suboptimal response to clopidogrel compared with MPA,15 we found a significantly greater platelet inhibition at 4 hours with 900 mg compared with 600 or 300 mg clopidogrel. This highly significant difference 4 hours after the first load totally disappeared when the 2 lower-dose groups were loaded a second time to complete a full dose of 900 mg. At 24 hours, all patients displayed a similar level of platelet inhibition regardless of the 3 reloading strategies, suggesting also that no absorption- or metabolism-limiting factor was present when 900 mg was taken at one time. Fewer subjects also had suboptimal response at 4 hours when they received 900 mg for the first load.
The RELOAD study is the first prospective evaluation of clopidogrel reloading with 3 different regimens in patients already on a maintenance dose of clopidogrel. The dose of 900 mg was chosen on the basis of previous studies that have shown increased inhibition, faster onset of action, and fewer poor responders with clopidogrel LDs 
600 mg compared with 300 mg.2,3,19 In both the ALBION and ISAR-CHOICE studies, clopidogrel 600 and 900 mg showed greater inhibition than 300 mg.4,7 In subjects treated long term with clopidogrel, RELOAD shows an incremental benefit from 600 to 900 mg clopidogrel as suggested in the ALBION study in clopidogrel-naïve patients. This difference is even larger in RELOAD than in ALBION, but the core laboratory, the biological end point, and the populations differ, and indirect comparisons are speculative only. The results of RELOAD also are consistent with those of Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty (ARMYDA-4), which suggested that pre-PCI loading with 600 mg only confers neither significant additional inhibition in platelet reactivity nor additional clinical benefit compared with no reloading in patients eligible for elective PCI who are treated long term with 75 mg clopidogrel. Other studies suggest that the dose-effect relationship still exists for doses >900 mg.8,9
On the basis of blood levels of clopidogrel and its active metabolite measured in 40 patients receiving 600 or 900 mg clopidogrel in the ISAR-CHOICE study,4,7 the dose of 600 mg was assumed to be the maximum dose that can be absorbed and/or metabolized. Fractionation of the LD was done on purpose in the RELOAD study to further test this hypothesis. The absence of difference in the level of IRPA between a single LD of 900 mg given at enrollment and a 2-step loading strategy with either 300-mg LD1 plus 600-mg LD2 or 600-mg LD1 plus 300-mg LD2 4 hours apart further supports the absence of saturable absorption and/or metabolism in this range of clopidogrel dosing. This also is supported by the dramatic decrease in the rate of suboptimal response at 24 hours that was similar regardless of the loading strategies.
Other studies since have tended to confirm that doses >900 mg can be absorbed and metabolized, leading to better control of platelet aggregation. Indeed, a double bolus of 600 mg (1200 mg) clopidogrel has been shown to provide a higher level of IPA than 600 mg.8 Bonello et al9 administered >2 g clopidogrel in some patients to improve response to the drug according to the vasodilator-stimulated phosphoprotein monitoring index.
The findings of the RELOAD study have relevant implications for clinicians with regard to dosing issues of clopidogrel.19–21 It was only recently suggested that an LD 600 mg may reduce hard events within the first months of PCI, suggesting also that poor response to clopidogrel was a modifiable risk factor.6 The ongoing Clopidogrel Optimal Dose Usage to Reduce Recurrent Events (CURRENT-OASIS 7) trial, which is evaluating the effects of a clopidogrel 600-mg LD versus the standard regimen of 300 mg in patients with acute coronary syndromes undergoing an early invasive strategy with intent for PCI within 24 hours of randomization, should provide a more definite answer. In our clopidogrel-treated patients in the RELOAD study, we found that a single administration of a 900-mg LD was the only independent correlate of optimal response and that this regimen was associated with a dramatic reduction in poor response, regardless of the definition, within 4 hours of administration. The RELOAD study provides rationale for the clinical use of a high clopidogrel LD (900 mg) in patients undergoing PCI regardless of the presence or absence of prior long-term therapy. However, evidence also exists that even higher levels of platelet inhibition can be reached either by doses of clopidogrel >900 mg or by more potent thienopyridines with recent demonstration of better clinical outcome in patients undergoing PCI.9,22,23 For example, a 1620±480-mg LD of clopidogrel has been described as the average LD necessary to sensitize all patients according to the vasodilator-stimulated phosphoprotein index, allowing a reduction of PCI-related ischemic events compared with the standard 600-mg LD of clopidogrel.9 In the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) biological investigation, a LD of 60 mg prasugrel doubled the level of IPA compared with 600 mg clopidogrel without any poor responders 6 hours after loading (versus 27% with clopidogrel).23 In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) trial, the higher potency of prasugrel (60-mg LD/10-mg maintenance dose) compared with clopidogrel (300-mg LD/75-mg maintenance dose) led to improved clinical outcomes, including a significant reduction in stent thrombosis in high-risk PCI patients.22
The great variability in platelet response to a maintenance dose of 75 mg clopidogrel is another rising issue highlighted by the RELOAD study. Whether point-of-care monitoring of IPA can help identify suboptimal response, leading to dose adjustment and improvement in prognosis, remains to be shown. Indeed, a higher level of platelet inhibition can be easily obtained by the use of a higher maintenance dose of clopidogrel (150 mg in resistant patients) or by more potent thienopyridine such as prasugrel (10 mg).12,23 Such a strategy of individualized therapy could help reduce ischemic events in poor responders to clopidogrel without exposing unnecessarily good responders to higher doses with the risk of excess bleeding.9,22,24 Finally, the RELOAD study shows that identifying suboptimal response in the maintenance dose phase is not an easy task. LTA and the point-of-care VerifyNow P2Y12 correlated very well, which was expected given previous work and the fact that both tests measure the same phenomena and the correlations use dependent variables.18,25,26 The poor concordance suggests that when a cutoff value is used to define a suboptimal response with the different tests, fewer patients are simultaneously categorized as having a suboptimal response with the 2 approaches. Our data are in agreement with recent publications highlighting that the point-of-care VerifyNow P2Y12 has limitations compared with LTA when IPA (by LTA) fell to <
20% and >70%.26 The relation is not linear but more sigmoidal. As a consequence, the issue of the best method to identify suboptimal response is critical and so far unresolved with the great concern of late ischemic events such as stent thrombosis in patients implanted with a drug-eluting stent.
Study Limitations
The nonrandomized nature of the RELOAD study is acknowledged. However, patients were consecutively enrolled and allocated successively to the 3 groups according to the order of inclusion in the study. This is reflected by the similar baseline characteristics in the 3 groups. More important, the study was carefully designed to keep investigators and laboratory technicians blinded to treatment assignments. In particular, study investigators were always different from the treating physicians who were responsible for the clopidogrel treatment delivery. This particular design has probably overcome the limitation of open-label administration of clopidogrel. LTA is a nonstandardized methodology that has several technical limitations responsible for a substantial rate of nonevaluable subjects, which raises concern over the utility of LTA for routine clinical monitoring. However, LTA remains the reference method, and our results were reproduced by the VerifyNow point-of-care assay. The safety profile of a high LD is reassuring in our study, but we acknowledge that the study is not sized for clinical end points.
Conclusions
Our findings suggest that the level of platelet inhibition can be increased in patients treated long term with a maintenance dose of 75 mg, providing support for the use of a high clopidogrel LD of 900 mg in patients undergoing PCI regardless of the presence or absence of prior long-term therapy. Slow response and/or poor response to clopidogrel also were reduced with this regimen.
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Acknowledgments |
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Source of Funding
This study was funded by an unrestricted research grant from Bristol-Myers Squibb/Sanofi-Aventis.
Disclosures
Dr Montalescot received research grants from Bristol Myers Squibb, Sanofi-Aventis Group, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, and Fédération Française de Cardiologie; consulting fees from Sanofi-Aventis Group, Eli Lilly, Bristol-Myers Squibb, Merck Sharpe & Dohme, GlaxoSmithKline, The Medicines Company, and Schering-Plough; and lecture fees from Sanofi-Aventis, Eli Lilly, Bristol-Myers Squibb, Merck Sharpe & Dohme, Cordis, GlaxoSmithKline, and Schering-Plough. Dr Collet received research grants from Bristol Myers Squibb, Sanofi-Aventis Group, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, and Fédération Française de Cardiologie; consulting fees from Sanofi-Aventis Group, Eli Lilly, and Bristol-Myers Squibb; and lecture fees from Sanofi-Aventis, Eli Lilly, Bristol-Myers Squibb, Merck Sharpe & Dohme, Cordis, GlaxoSmithKline, and Endotis. The other authors report no conflicts.
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Circulation 2008 118: 1217-1218.
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