CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
The Relation of Dosing to Clopidogrel Responsiveness and the Incidence of High Post-Treatment Platelet Aggregation in Patients Undergoing Coronary Stenting
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
Sinai Center for Thrombosis Research, Baltimore, Maryland
Manuscript received November 12, 2004;
revised manuscript received December 20, 2004,
accepted January 11, 2005.
* Reprint requests and correspondence: Dr. Paul A. Gurbel, Sinai Center for Thrombosis Research, Hoffberger Building, Suite 56, 2401 W. Belvedere Avenue, Baltimore, Maryland 21215 (Email: pgurbel{at}lifebridgehealth.org).
 |
Abstract
|
|---|
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.
|
Abbreviations and Acronyms
| | ADP = adenosine diphosphate | | GP = glycoprotein | | IR = intermediate responsiveness | | NR = nonresponsiveness | | post-PA = post-treatment platelet aggregation | | PPP = platelet poor plasma |  A = absolute change in platelet aggregation |
|
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.
|
Methods
|
|---|
Patients.
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 samples.
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).
Platelet aggregation.
The blood-citrate mixture was centrifuged at 120 g for 5 min to recover platelet-rich plasma and at 850 g for 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.
Definitions.
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 (A), where A is the baseline aggregation minus the post-treatment aggregation; NR was defined as a A <10%, intermediate responsiveness as a A = 10% to 30%, and responsiveness as a A >30% (1,3). The distribution of responsiveness to clopidogrel in each group is represented by histograms as previously reported (1,16).
Statistical analysis.
Comparisons were made between groups by using t tests, 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.
|
Results
|
|---|
Demographics.
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 2 and 3). A 600-mg loading dose produced lower 5 and 20 µM ADP-induced platelet aggregation (Tables 2 and 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. 1A and 1B). The distribution of post-PA shifted leftward for the group treated with 600 mg clopidogrel, indicative of a superior overall antiplatelet effect.
View larger version (32K):
[in this window]
[in a new window]
|
Figure 1 (A) Distribution of post-treatment platelet aggregation as measured by 5 µM adenosine diphosphate (ADP)-induced aggregation. Distribution is shifted leftward for the 600-mg group, indicating lower reactivity to ADP. (B) Distribution of post-treatment platelet aggregation as measured by 20 µM ADP-induced aggregation. Distribution is shifted leftward for the 600-mg group, indicating lower reactivity to ADP.
|
|
Clopidogrel responsiveness.
There were more responders in the 600 mg group (Tables 2 and 3). There was also a normal distribution of clopidogrel responsiveness after both doses of clopidogrel (Figs. 2A and 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; A 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 3 and 4 demonstrate 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.
View larger version (18K):
[in this window]
[in a new window]
|
Figure 3 Relation of post-treatment platelet aggregation (Post-PA) to nonresponsiveness in 300- and 600-mg groups as measured by 5 µM adenosine-diphosphate-induced aggregation.
|
|
View larger version (18K):
[in this window]
[in a new window]
|
Figure 4 Relation of post-treatment platelet aggregation (Post-PA) to nonresponsiveness in 300- and 600-mg groups as measured by 20 µM adenosine-diphosphate-induced aggregation.
|
|
|
Discussion
|
|---|
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 A; 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).
Conclusions.
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.
|
Footnotes
|
|---|
This study was supported by the Sinai Center for Thrombosis Research, Baltimore, Maryland.
|
References
|
|---|
1. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stentingresponse variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908-2913.[Abstract/Free Full Text]
2. 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]
3. Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement Thromb Haemost 2003;89:783-787.[Web of Science][Medline]
4. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction Circulation 2004;109:3171-3175.[Abstract/Free Full Text]
5. Gurbel PA. Clopidogrel response variability and resistance Haematologica 2004;89(Suppl 7):9-11.[Free Full Text]
6. Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance Circulation 2004;109:166-171.[Abstract/Free Full Text]
7. Taubert D, Kastrati A, Harlfinger S, et al. Pharmacokinetics of clopidogrel after administration of a high loading dose Thromb Haemost 2004;92:311-316.[Web of Science][Medline]
8. Muller 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]
9. Angiolillo DJ, Fernandeez-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]
10. Kastrati A, von Beckerath N, Joost A, Pogatsa-Murray G, Gorchakova O, Schomig A. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy Circulation 2004;110:1916-1919.[Abstract/Free Full Text]
11. Gurbel PA, Samara WM, Bliden KP. Failure of clopidogrel to reduce platelet reactivity and activation following standard dosing in elective stentingimplications for thrombotic events and restenosis. Platelets 2004;15:95-99.[CrossRef][Web of Science][Medline]
12. Barragan P, Bouvier JL, Roquebert PO, et al. Resistance to thienopyridinesclinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003;59:295-302.[CrossRef][Web of Science][Medline]
13. Bliden KP, Tantry U, Zaman K, et al. High platelet reactivity is a risk factor for post-discharge ischemic complications following elective coronary stenting(abstr) J Am Coll Cardiol 2005;45(Suppl A):33A.
14. Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes KM, Tantry U. The Clopidogrel Resistance and Stent Thrombosis (CREST) study(abstr) J Am Coll Cardiol 2005;45(Suppl A):34A.
15. Gurbel PA, Bliden KP, Hiatt BL. The early antiplatelet effects of clopidogrel loading for coronary stenting and the long-term stability of inhibition J Thromb Haemost 2003;1:1319-1321.[CrossRef][Web of Science][Medline]
16. Gurbel PA, Bliden KP. A new method of representing drug-induced platelet inhibitionbetter description of time course, response variability, non-response, and heightened activity. Platelets 2003;14:481-483.[CrossRef][Web of Science][Medline]
17. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern eraa pooled analysis of multicenter coronary stent clinical trials. Circulation 2001;103:1967-1971.[Abstract/Free Full Text]
18. Samara WM, Bliden KP, Tantry US, Gurbel PA. The difference between clopidogrel responsiveness and post-treatment platelet reactivity Thromb Res 2005;115:89-94.[CrossRef][Web of Science][Medline]
This article has been cited by other articles:
|
|
|
|
 
H. Ge, Y. Zhou, X. Liu, X. Nie, Z. Wang, Y. Guo, W. Chen, and Q. Yang
Relationship Between Plasma Inflammatory Markers and Platelet Aggregation in Patients With Clopidogrel Resistance After Angioplasty
Angiology,
January 1, 2012;
63(1):
62 - 66.
[Abstract]
[PDF]
|
|
|
|
|
|
|
W. McAuliffe, V. Wycoco, H. Rice, C. Phatouros, T. J. Singh, and J. Wenderoth
Immediate and Midterm Results following Treatment of Unruptured Intracranial Aneurysms with the Pipeline Embolization Device
AJNR Am. J. Neuroradiol.,
January 1, 2012;
33(1):
164 - 170.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Patti, G. Barczi, D. Orlic, F. Mangiacapra, G. Colonna, V. Pasceri, E. Barbato, B. Merkely, I. Edes, M. Ostojic, et al.
Outcome Comparison of 600- and 300-mg Loading Doses of Clopidogrel in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction: Results From the ARMYDA-6 MI (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Myocardial Infarction) Randomized Study
J. Am. Coll. Cardiol.,
October 4, 2011;
58(15):
1592 - 1599.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Trenk, W. Hochholzer, M. F. Fromm, O. Zolk, C. M. Valina, C. Stratz, and F.-J. Neumann
Paraoxonase-1 Q192R Polymorphism and Antiplatelet Effects of Clopidogrel in Patients Undergoing Elective Coronary Stent Placement
Circ Cardiovasc Genet,
August 1, 2011;
4(4):
429 - 436.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. S. Wright, J. L. Anderson, C. D. Adams, C. R. Bridges, D. E. Casey Jr, S. M. Ettinger, F. M. Fesmire, T. G. Ganiats, H. Jneid, A. M. Lincoff, et al.
2011 ACCF/AHA Focused Update Incorporated Into the 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 Foundation/American Heart Association Task Force on Practice Guidelines
J. Am. Coll. Cardiol.,
May 10, 2011;
57(19):
e215 - e367.
[Full Text]
[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.
2011 ACCF/AHA Focused Update Incorporated Into the 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 Foundation/American Heart Association Task Force on Practice Guidelines
Circulation,
May 10, 2011;
123(18):
e426 - e579.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. G. Aragam and D. L. Bhatt
Review: Antiplatelet Therapy in Acute Coronary Syndromes
Journal of Cardiovascular Pharmacology and Therapeutics,
March 1, 2011;
16(1):
24 - 42.
[Abstract]
[PDF]
|
|
|
|
|
|
|
R. Hall and C. D. Mazer
Review Article: Antiplatelet Drugs: A Review of Their Pharmacology and Management in the Perioperative Period
Anesth. Analg.,
February 1, 2011;
112(2):
292 - 318.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. R. Holmes Jr, D. J. Kereiakes, S. Garg, P. W. Serruys, G. J. Dehmer, S. G. Ellis, D. O. Williams, T. Kimura, and D. J. Moliterno
Stent Thrombosis
J. Am. Coll. Cardiol.,
October 19, 2010;
56(17):
1357 - 1365.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Bonello, U. S. Tantry, R. Marcucci, R. Blindt, D. J. Angiolillo, R. Becker, D. L. Bhatt, M. Cattaneo, J. P. Collet, T. Cuisset, et al.
Consensus and Future Directions on the Definition of High On-Treatment Platelet Reactivity to Adenosine Diphosphate
J. Am. Coll. Cardiol.,
September 14, 2010;
56(12):
919 - 933.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Spinler
Oral antiplatelet therapy after acute coronary syndrome and percutaneous coronary intervention: Balancing efficacy and bleeding risk
Am. J. Health Syst. Pharm.,
August 1, 2010;
67(15_Supplement_7):
S7 - S17.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Roffman
Considerations in patients receiving oral antiplatelet therapy after acute coronary syndrome and percutaneous coronary intervention
Am. J. Health Syst. Pharm.,
August 1, 2010;
67(15_Supplement_7):
S18 - S24.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Gurbel, K. P. Bliden, K. Butler, M. J. Antonino, C. Wei, R. Teng, L. Rasmussen, R. F. Storey, T. Nielsen, J. W. Eikelboom, et al.
Response to Ticagrelor in Clopidogrel Nonresponders and Responders and Effect of Switching Therapies: The RESPOND Study
Circulation,
March 16, 2010;
121(10):
1188 - 1199.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Fiorella
Anti-thrombotic medications for the neurointerventionist: aspirin and clopidogrel.
JNIS,
March 1, 2010;
2(1):
44 - 49.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Gurbel and U. S. Tantry
Combination Antithrombotic Therapies
Circulation,
February 2, 2010;
121(4):
569 - 583.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Hobson and N. Curzen
Chapter 22 Current status of oral antiplatelet therapies
Oxford Textbook of Interventional Cardiology,
January 1, 2010;
1(1):
med-9780199569083-chapter - med-9780199569083-chapter.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
D. I. Simon and S. A. Parikh
Hunting for the "Sweet Spot" in P2Y12 Receptor Blockade
J. Am. Coll. Cardiol.,
October 6, 2009;
54(15):
1447 - 1449.
[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]
|
|
|
|
|
|
|
L Bonello, A De Labriolle, M Scheinowitz, G Lemesle, P Roy, D H Steinberg, T L Pinto Slottow, R Pakala, A D Pichard, P Barragan, et al.
Emergence of the concept of platelet reactivity monitoring of response to thienopyridines
Heart,
August 1, 2009;
95(15):
1214 - 1219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Paniccia, E. Antonucci, N. Maggini, E. Romano, A. M. Gori, R. Marcucci, D. Prisco, and R. Abbate
Assessment of Platelet Function on Whole Blood by Multiple Electrode Aggregometry in High-Risk Patients With Coronary Artery Disease Receiving Antiplatelet Therapy
Am J Clin Pathol,
June 1, 2009;
131(6):
834 - 842.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Veverka and J. M. Hammer
Prasugrel: A New Thienopyridine Inhibitor
Journal of Pharmacy Practice,
April 1, 2009;
22(2):
158 - 165.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. S. SABATINE
Novel antiplatelet strategies in acute coronary syndromes
Cleveland Clinic Journal of Medicine,
April 1, 2009;
76(Suppl_1):
S8 - S15.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Gurbel, K. P. Bliden, J. F. Saucedo, T. A. Suarez, J. DiChiara, M. J. Antonino, E. Mahla, A. Singla, W. R. Herzog, A. K. Bassi, et al.
Bivalirudin and Clopidogrel With and Without Eptifibatide for Elective Stenting: Effects on Platelet Function, Thrombelastographic Indexes, and Their Relation to Periprocedural Infarction: Results of the CLEAR PLATELETS-2 (Clopidogrel With Eptifibatide to Arrest the Reactivity of Platelets) Study
J. Am. Coll. Cardiol.,
February 24, 2009;
53(8):
648 - 657.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Kuliczkowski, A. Witkowski, L. Polonski, C. Watala, K. Filipiak, A. Budaj, J. Golanski, D. Sitkiewicz, J. Pregowski, J. Gorski, et al.
Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology
Eur. Heart J.,
February 2, 2009;
30(4):
426 - 435.
[Abstract]
[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]
|
|
|
|
|
|
|
D.H. Lee, A. Arat, H. Morsi, H. Shaltoni, J.R. Harris, and M.E. Mawad
Dual Antiplatelet Therapy Monitoring for Neurointerventional Procedures Using a Point-of-Care Platelet Function Test: A Single-Center Experience
AJNR Am. J. Neuroradiol.,
August 1, 2008;
29(7):
1389 - 1394.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. T. Newsome, M. A. Kutcher, and R. L. Royster
Coronary Artery Stents: Part I. Evolution of Percutaneous Coronary Intervention
Anesth. Analg.,
August 1, 2008;
107(2):
552 - 569.
[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. Wallentin
Dual antiplatelet therapy in the drug-eluting stent era
Eur. Heart J. Suppl.,
May 1, 2008;
10(suppl_D):
D38 - D44.
[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]
|
|
|
|
|
|
|
M. J. Price, S. Endemann, R. R. Gollapudi, R. Valencia, C. T. Stinis, J. P. Levisay, A. Ernst, N. S. Sawhney, R. A. Schatz, and P. S. Teirstein
Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation
Eur. Heart J.,
April 2, 2008;
29(8):
992 - 1000.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Muller-Schunk, J. Linn, N. Peters, M. Spannagl, M. Deisenberg, H. Bruckmann, and T.E. Mayer
Monitoring of Clopidogrel-Related Platelet Inhibition: Correlation of Nonresponse with Clinical Outcome in Supra-Aortic Stenting
AJNR Am. J. Neuroradiol.,
April 1, 2008;
29(4):
786 - 791.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
S. Prabhakaran, K.R Wells, V.H. Lee, C.A. Flaherty, and D.K. Lopes
Prevalence and Risk Factors for Aspirin and Clopidogrel Resistance in Cerebrovascular Stenting
AJNR Am. J. Neuroradiol.,
February 1, 2008;
29(2):
281 - 285.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
P. A. Gurbel, R. C. Becker, K. G. Mann, S. R. Steinhubl, and A. D. Michelson
Platelet Function Monitoring in Patients With Coronary Artery Disease
J. Am. Coll. Cardiol.,
November 6, 2007;
50(19):
1822 - 1834.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. F. Storey, S. Husted, R. A. Harrington, S. Heptinstall, R. G. Wilcox, G. Peters, M. Wickens, H. Emanuelsson, P. Gurbel, P. Grande, et al.
Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y12 Receptor Antagonist, Compared With Clopidogrel in Patients With Acute Coronary Syndromes
J. Am. Coll. Cardiol.,
November 6, 2007;
50(19):
1852 - 1856.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. I. Simon and A. H. Schmaier
Sweet and Sticky: Diabetic Platelets, Enhanced Reactivity, and Cardiovascular Risk
J. Am. Coll. Cardiol.,
October 16, 2007;
50(16):
1548 - 1550.
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Campo, M. Valgimigli, D. Gemmati, G. Percoco, L. Catozzi, A. Frangione, F. Federici, F. Ferrari, M. Tebaldi, S. Luccarelli, et al.
Poor Responsiveness to Clopidogrel: Drug-Specific or Class-Effect Mechanism?: Evidence From a Clopidogrel-to-Ticlopidine Crossover Study
J. Am. Coll. Cardiol.,
September 18, 2007;
50(12):
1132 - 1137.
[Abstract]
[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]
|
|
|
|
|
|
|
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 Executive Summary: 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):
652 - 726.
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. von Beckerath, A. Kastrati, A. Wieczorek, G. Pogatsa-Murray, D. Sibbing, I. Graf, and A. Schomig
A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days
Eur. Heart J.,
August 1, 2007;
28(15):
1814 - 1819.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Buonamici, R. Marcucci, A. Migliorini, G. F. Gensini, A. Santini, R. Paniccia, G. Moschi, A. M. Gori, R. Abbate, and D. Antoniucci
Impact of Platelet Reactivity After Clopidogrel Administration on Drug-Eluting Stent Thrombosis
J. Am. Coll. Cardiol.,
June 19, 2007;
49(24):
2312 - 2317.
[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]
|
|
|
|
|
|
|
K. P. Bliden, J. DiChiara, U. S. Tantry, A. K. Bassi, S. K. Chaganti, and P. A. Gurbel
Increased Risk in Patients With High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing Percutaneous Coronary Intervention: Is the Current Antiplatelet Therapy Adequate?
J. Am. Coll. Cardiol.,
February 13, 2007;
49(6):
657 - 666.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Angiolillo, S. B. Shoemaker, B. Desai, H. Yuan, R. K. Charlton, E. Bernardo, M. M. Zenni, L. A. Guzman, T. A. Bass, and M. A. Costa
Randomized Comparison of a High Clopidogrel Maintenance Dose in Patients With Diabetes Mellitus and Coronary Artery Disease: Results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) Study
Circulation,
February 13, 2007;
115(6):
708 - 716.
[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]
|
|
|
|
|
|
|
F. Alfonso and D. J. Angiolillo
Platelet Function Assessment to Predict Outcomes After Coronary Interventions: Hype or Hope?
J. Am. Coll. Cardiol.,
November 7, 2006;
48(9):
1751 - 1754.
[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]
|
|
|
|
|
|
|
T. Cuisset, C. Frere, J. Quilici, P.-E. Morange, L. Nait-Saidi, J. Carvajal, A. Lehmann, M. Lambert, J.-L. Bonnet, and M.-C. Alessi
Benefit of a 600-mg Loading Dose of Clopidogrel on Platelet Reactivity and Clinical Outcomes in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome Undergoing Coronary Stenting
J. Am. Coll. Cardiol.,
October 3, 2006;
48(7):
1339 - 1345.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-P. Collet and G. Montalescot
Premature withdrawal and alternative therapies to dual oral antiplatelet therapy
Eur. Heart J. Suppl.,
October 1, 2006;
8(suppl_G):
G46 - G52.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Michelson, A. L. Frelinger, and M. I. Furman
Resistance to antiplatelet drugs
Eur. Heart J. Suppl.,
October 1, 2006;
8(suppl_G):
G53 - G58.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Kereiakes and E. M. Antman
Clinical Guidelines and Practice: In Search of the Truth
J. Am. Coll. Cardiol.,
September 19, 2006;
48(6):
1129 - 1135.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Angiolillo, A. Fernandez-Ortiz, E. Bernardo, C. Ramirez, U. Cavallari, E. Trabetti, M. Sabate, R. Hernandez, R. Moreno, J. Escaned, et al.
Contribution of Gene Sequence Variations of the Hepatic Cytochrome P450 3A4 Enzyme to Variability in Individual Responsiveness to Clopidogrel
Arterioscler Thromb Vasc Biol,
August 1, 2006;
26(8):
1895 - 1900.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. Dixon, C. L. Grines, and W. W. O'Neill
The Year in Interventional Cardiology
J. Am. Coll. Cardiol.,
April 18, 2006;
47(8):
1689 - 1706.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. T. Ivandic, P. Schlick, P. Staritz, K. Kurz, H. A. Katus, and E. Giannitsis
Determination of Clopidogrel Resistance by Whole Blood Platelet Aggregometry and Inhibitors of the P2Y12 Receptor
Clin. Chem.,
March 1, 2006;
52(3):
383 - 388.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. I. Lev, R. T. Patel, K. J. Maresh, S. Guthikonda, J. Granada, T. DeLao, P. F. Bray, and N. S. Kleiman
Aspirin and Clopidogrel Drug Response in Patients Undergoing Percutaneous Coronary Intervention: The Role of Dual Drug Resistance
J. Am. Coll. Cardiol.,
January 3, 2006;
47(1):
27 - 33.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. I. Lev, R. T. Patel, K. J. Maresh, S. Guthikonda, J. Granada, T. DeLao, P. F. Bray, and N. S. Kleiman
Aspirin and Clopidogrel Drug Response in Patients Undergoing Percutaneous Coronary Intervention: The Role of Dual Drug Resistance
J. Am. Coll. Cardiol.,
December 13, 2005;
(2005)
j.jacc.2005.08.058v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Herrmann
Peri-procedural myocardial injury: 2005 update
Eur. Heart J.,
December 1, 2005;
26(23):
2493 - 2519.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Gurbel, K. P. Bliden, W. Samara, J. A. Yoho, K. Hayes, M. Z. Fissha, and U. S. Tantry
Clopidogrel Effect on Platelet REactivity in Patients With Stent Thrombosis: Results of the CREST Study
J. Am. Coll. Cardiol.,
November 15, 2005;
46(10):
1827 - 1832.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. S. Tantry, K. P. Bliden, and P. A. Gurbel
Overestimation of Platelet Aspirin Resistance Detection by Thrombelastograph Platelet Mapping and Validation by Conventional Aggregometry Using Arachidonic Acid Stimulation
J. Am. Coll. Cardiol.,
November 1, 2005;
46(9):
1705 - 1709.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. P. Giugliano and E. Braunwald
The Year in Non--ST-Segment Elevation Acute Coronary Syndromes
J. Am. Coll. Cardiol.,
September 6, 2005;
46(5):
906 - 919.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods