Author + information
- Received November 12, 2004
- Revision received December 20, 2004
- Accepted January 11, 2005
- Published online May 3, 2005.
- Paul A. Gurbel, MD, FACC⁎ (, )
- Kevin P. Bliden, BS,
- Kevin M. Hayes, DO,
- Jason A. Yoho, MD,
- William R. Herzog, MD, FACC and
- Udaya S. Tantry, PhD
- ↵⁎Reprint requests and correspondence:
Dr. Paul A. Gurbel, Sinai Center for Thrombosis Research, Hoffberger Building, Suite 56, 2401 W. Belvedere Avenue, Baltimore, Maryland 21215
Objectives We determined the effect of clopidogrel dosing on the incidence of nonresponsiveness (NR) and high post-treatment platelet aggregation (post-PA).
Background We have reported NR after a 300-mg loading dose. Limited information is available on the comparative effect of a 600-mg loading dose on the incidence of NR and high post-PA.
Methods Clopidogrel responsiveness and post-PA were measured in patients undergoing stenting (n = 190) randomly treated with either a 300-mg or a 600-mg clopidogrel load. Nonresponsiveness was defined as <10% absolute change in platelet aggregation, and high post-PA was defined as >75th percentile aggregation after 300 mg clopidogrel.
Results Nonresponsiveness was lower after 600 mg compared to the 300-mg dose (8% vs. 28% and 8% vs. 32% with 5 and 20 μM ADP, respectively, p < 0.001). Among the patients with high post-PA after 300 mg clopidogrel, 62% to 65% had NR, whereas after the 600-mg dose, all of the patients with high post-PA had NR.
Conclusions A 600-mg clopidogrel loading dose reduces the incidence of NR and high post-PA as compared to a 300-mg dose. Higher dosing strategies and methods to confirm platelet inhibition should be further investigated in order to optimally use clopidogrel in patients undergoing stenting.
We have reported response variability and nonresponsiveness (NR) after a 300-mg clopidogrel loading dose for coronary artery stenting (1). Since then other studies have confirmed that some patients do not achieve optimal platelet inhibition and exhibit NR after standard clopidogrel therapy (2–4). The mechanisms responsible for NR are incompletely defined; variability in intestinal absorption and the hepatic cytochrome P450 3A4 activity were reported as important factors (5–7).
Muller et al. (3) reported an 11% incidence of NR after a 600-mg loading dose versus the 31% incidence after a 300-mg loading dose reported in our previous study (1). In a small study (n = 10 per group), the same investigators also reported that a 600-mg clopidogrel loading dose provides superior early inhibition (8). Recently, a study of 50 patients also suggested that 600 mg clopidogrel was associated with a lower incidence of NR (9). Moreover, Kastrati et al. (10) found that patients on a 75-mg maintenance dose achieved additional platelet inhibition after treatment with a 600-mg load. These findings may be relevant to the occurrence of stent thrombosis in selected patients (11,12). We have recently observed higher post-treatment platelet aggregation (post-PA) in patients who developed stent thrombosis and six-month postprocedure ischemic complications as compared to patients without these events (13,14).
Based on the limited available data, we hypothesized that NR is directly related to the loading dose. We, therefore, conducted a prospective investigation of platelet aggregation and clopidogrel responsiveness after 300-mg and 600-mg loading doses in patients undergoing elective coronary stenting.
The Investigational Review Board of the Sinai Hospital of Baltimore approved the study. Patients undergoing elective coronary stenting (n = 190) were studied. The exclusion criteria included history of bleeding diathesis, acute myocardial infarction within 48 h, cerebrovascular event within 3 months, illicit drug or alcohol abuse, prothrombin time ≥1.5 times control, platelet count ≤100,000/mm3, hematocrit ≤30%, creatinine ≥4.0 mg/dl, and thienopyridine or glycoprotein (GP) IIb/IIIa inhibitor use before the procedure.
All patients received aspirin (81 to 325 mg) for at least seven days before the procedure and were given 325 mg of aspirin on the day of the procedure and daily thereafter. Patients were randomly administered a loading dose of 300 mg or 600 mg clopidogrel in the catheterization laboratory immediately after successful coronary stenting in a three-to-one distribution, followed by a maintenance dose of 75 mg daily. Heparin was administered to all patients (activated clotting time ≥300 s in patients treated without GP IIb/IIIa inhibitors and 200 to 250 s in patients treated with GP IIb/IIIa inhibitors).
Blood was collected as previously described in 3.8% trisodium citrate at baseline immediately before the procedure and before heparin and GP IIb/IIIa administration, and at 24 h after the procedure in those patients not receiving GP IIb/IIIa inhibitors, and at five days after the procedure in those treated with GP IIb/IIIa inhibitors (1). The rationale for the time of blood sampling was to avoid an antiplatelet effect from the GP IIb/IIIa inhibitor. Previous investigations have demonstrated a maximum antiplatelet effect after 300-mg and 600-mg clopidogrel loading doses at 24 h after the procedure and no effect on the level of inhibition at five days after the procedure (1,15).
The blood-citrate mixture was centrifuged at 120 gfor 5 min to recover platelet-rich plasma and at 850 gfor 5 min to recover platelet poor plasma (PPP). Platelets were stimulated with 5 and 20 μM adenosine diphosphate (ADP) (Chronolog, Haverton, Pennsylvania), and aggregation was assessed using a Chronolog Lumi-aggregometer (Model 490) as previously described (1). Platelet aggregation was expressed as the maximal percent change in light transmittance from baseline, using PPP as a reference.
High post-PA was defined as >75th percentile aggregation in response to 5 and 20 μM ADP in patients treated with a 300-mg loading dose, intermediate post-PA was defined as 50th to 75th percentile aggregation, and low post-PA was defined as <50th percentile aggregation. Clopidogrel responsiveness was determined by the absolute change in aggregation (ΔA), where ΔA is the baseline aggregation minus the post-treatment aggregation; NR was defined as a ΔA <10%, intermediate responsiveness as a ΔA = 10% to 30%, and responsiveness as a ΔA >30% (1,3). The distribution of responsiveness to clopidogrel in each group is represented by histograms as previously reported (1,16).
Comparisons were made between groups by using ttests, and p < 0.05 was considered significant. Curves were plotted of the best fit to a normal distribution by Statistica software (Tulsa, Oklahoma). Based on the normal distribution of data, the mean ± SD was used. Categorical variables are expressed as percentages.
Overall, the groups were well-matched except that hyperlipidemia, family history of coronary artery disease, and beta-blocker use were higher in the group treated with 600 mg clopidogrel (Table 1).The percentage of patients treated with GP IIb/IIIa inhibitors was 28% in the 300-mg group and 50% in the 600-mg group (p < 0.05).
Pretreatment platelet aggregation and post-PA
Pretreatment 5 μM and 20 μM ADP-induced aggregation in the 300-mg clopidogrel group did not differ from the 600-mg group (Tables 2and 3).A 600-mg loading dose produced lower 5 and 20 μM ADP-induced platelet aggregation (Tables 2and 3).
The 75th percentile post-PA cutpoint in the 300-mg clopidogrel group was 52% as induced by 5 μM ADP and 70% as induced by 20 μM ADP; post-PA followed a normal distribution that was narrower in the patients treated with 600 mg clopidogrel (Figs. 1Aand 1B). The distribution of post-PA shifted leftward for the group treated with 600 mg clopidogrel, indicative of a superior overall antiplatelet effect.
There were more responders in the 600 mg group (Tables 2and 3). There was also a normal distribution of clopidogrel responsiveness after both doses of clopidogrel (Figs. 2Aand 2B). The response curve is narrower and is shifted rightward for the 600-mg clopidogrel group, indicating its greater antiplatelet effect as compared to the 300-mg group; ΔA after 5 μM and 20 μM ADP was lower in the 300-mg group as compared to the 600-mg group (p < 0.001 for both agonist concentrations [Tables 2 and 3]). Figures 2A and 2B clearly demonstrate that the incidence of NR was significantly reduced by the higher loading dose.
Relation of high post-PA to clopidogrel NR
Figures 3and 4demonstrate that most patients with high post-PA had NR irrespective of the loading dose or the agonist concentration and that ∼35% of patients with high post-PA after a 300-mg loading dose of clopidogrel were responsive, whereas none of the patients with high post-PA after 600 mg were responsive. These data suggest that most patients responsive to clopidogrel can achieve low post-treatment reactivity by a high loading dose.
The present study demonstrated that a 600-mg clopidogrel loading strategy produces a superior antiplatelet effect in patients undergoing elective coronary stenting as compared with the standard 300-mg loading dose. This statement is based on findings of: 1) lower post-PA; 2) greater ΔA; and 3) a lower NR after 600 mg clopidogrel. The degree of post-PA is concordant with our earlier investigations that demonstrated ∼32% aggregation induced by 5 μM ADP, ∼57% aggregation induced by 20 μM ADP, and ∼31% incidence of NR at 24 h after loading with 300 mg clopidogrel (1,15).
Controversy exists in the interventional cardiology community regarding the optimal loading dose of clopidogrel. Currently, 300 mg is the most widely prescribed clopidogrel loading dose in the U.S. Based on information derived from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implimentation of the ACC/AHA Guidelines (CRUSADE) registry, in the first six months of 2004, 90% of patients presenting with a non-ST-segment elevation acute coronary syndrome received 300 mg clopidogrel (Dr. Eric Peterson, Duke University, Durham, North Carolina, personal communication, November 2004). Stent thrombosis remains a significant clinical problem (17). High post-PA and NR are possible risk factors for stent thrombosis and the late ischemic events. Recent studies have strongly supported this relation and suggest that a 300-mg load is not potent enough in some patients to overcome the thrombotic burden during and after percutaneous interventions (4,11–14). Low adverse event rates observed by Kastrati et al. (10) after pretreatment with 600 mg clopidogrel strongly support our findings of superior platelet inhibition with this dose.
Although clopidogrel responsiveness directly affects the incidence of high post-PA, it may overestimate the risk of stent thrombosis in nonresponders with low pretreatment aggregation. In the present study and in a previous investigation, we have demonstrated that some patients with low post-PA are clopidogrel nonresponsive, whereas some responders will continue to have high post-treatment aggregation (18). Therefore, we believe that post-PA is a better estimate of thrombotic risk rather than clopidogrel responsiveness. Recent studies from our center and others support the importance of high post-PA as an important risk factor (3,12–14).
Estimates of clopidogrel NR are clearly dose-dependent. A 600-mg loading dose is associated with lower post-PA, and, thus, 600 mg should be further investigated as the new standard therapy. Our data strongly support the importance of insufficient metabolite generation as the primary explanation for NR. In addition to higher dosing strategies, improved methods to confirm the level of platelet reactivity after treatment should be further studied in order to optimally use this drug.
This study was supported by the Sinai Center for Thrombosis Research, Baltimore, Maryland.
- Abbreviations and acronyms
- adenosine diphosphate
- intermediate responsiveness
- post-treatment platelet aggregation
- platelet poor plasma
- absolute change in platelet aggregation
- Received November 12, 2004.
- Revision received December 20, 2004.
- Accepted January 11, 2005.
- American College of Cardiology Foundation
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