CLINICAL RESEARCH: ANTIPLATELET THERAPY
Incidence and Clinical Impact of Dual Nonresponsiveness to Aspirin and Clopidogrel in Patients With Drug-Eluting Stents
Anna Maria Gori, MD*,
Rossella Marcucci, MD*,
Angela Migliorini, MD ,
Renato Valenti, MD,
Guia Moschi, MD,
Rita Paniccia, MD*,
Piergiovanni Buonamici, MD,
Gian Franco Gensini, MD*,, ,
Ruben Vergara, MD,
Rosanna Abbate, MD* and
David Antoniucci, MD,*
* Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy
Department of Cardiology, Careggi Hospital, Florence, Italy
Center Santa Maria agli Ulivi, Don Carlo Gnocchi Foundation, Istituto di Ricovero e Cura a Carattere Scientifico, Impruneta, Florence, Italy.
Manuscript received February 4, 2008;
revised manuscript received May 5, 2008,
accepted May 6, 2008.
* Reprint requests and correspondence: Dr. David Antoniucci, Division of Cardiology, Careggi Hospital, Viale Pieraccini, I-50134, Florence, Italy. (Email: david.antoniucci{at}virgilio.it).
 |
Abstract
|
|---|
Objectives: This study sought to determine the incidence of aspirin nonresponsiveness in addition to clopidogrel nonresponsiveness and whether this association identifies patients at an increased risk of drug-eluting stent (DES) thrombosis.
Background: Nonresponsiveness to clopidogrel is a predictor of DES thrombosis. No prospective data exist about the possible association of dual nonresponsiveness to clopidogrel and aspirin with DES thrombosis.
Methods: Platelet function was assessed after a loading dose of 600 mg clopidogrel in 746 patients who had successful DES implantation followed by 6-month dual-antiplatelet therapy. Platelet reactivity was assessed by light transmittance aggregometry using adenosine 5'-diphosphate, arachidonic acid, and collagen. The primary end point was definite/probable DES thrombosis at 6 months. The secondary end point was the composite of cardiac mortality and DES thrombosis.
Results: The incidence of dual nonresponsiveness to aspirin and clopidogrel was 6%. Definite/probable DES thrombosis was significantly higher in dual aspirin and clopidogrel nonresponders (11.1%) than in clopidogrel and aspirin responders (2.1%, p < 0.001), isolated clopidogrel nonresponders (2.2%, p < 0.05), or aspirin nonresponders (2.3%, p < 0.05). The incidence of the secondary end point was 4.4% in isolated clopidogrel nonresponders, 2.3% in isolated aspirin nonresponders, and 13.3% in dual aspirin and clopidogrel nonresponders. Dual clopidogrel and aspirin nonresponsiveness was an independent predictor of DES thrombosis (hazard ratio: 3.18, 95% confidence interval: 1.14 to 8.83, p = 0.027) and the composite of cardiac mortality and DES thrombosis (hazard ratio: 2.94, 95% confidence interval: 1.16 to 7.41, p = 0.022).
Conclusions: Dual nonresponsiveness to aspirin and clopidogrel is a relatively infrequent condition that identifies patients at a very high risk of DES thrombosis or death.
Key Words: drug-eluting stent • stent thrombosis • nonresponsiveness • clopidogrel
|
Abbreviations and Acronyms
| | ADP = adenosine 5'-diphosphate | | CI = confidence interval | | DES = drug-eluting stent(s) | | GP = glycoprotein | | HR = hazard ratio |
|
Dual antiplatelet treatment with clopidogrel and aspirin is the standard treatment in patients treated with drug-eluting stents (DES) for coronary artery disease for the prevention of DES thrombosis (1–3). Early discontinuation of dual antiplatelet treatment is a strong predictor of DES thrombosis (4–7). However, DES thrombosis can occur also in patients who are compliant with dual antiplatelet treatment, and several retrospective studies and 2 prospective studies have shown that high residual platelet reactivity during antiplatelet treatment is related to the risk of thrombosis and other adverse events (8–14). The RECLOSE (Low Responsiveness to Clopidogrel and Sirolimus- or Paclitaxel-Eluting Stent Thrombosis) trial has shown that nonresponsiveness to a loading dose of 600 mg clopidogrel is independently related to the risk of DES thrombosis (14). No prospective data exist about the possible association of dual nonresponsiveness to clopidogrel and aspirin with thrombotic events in patients with DES. This study, based on the RECLOSE trial patient cohort, sought to determine the incidence of aspirin nonresponsiveness in addition to clopidogrel nonresponsiveness and whether this association identifies patients at increased risk of DES thrombosis compared with isolated nonresponsiveness to clopidogrel.
|
Methods
|
|---|
Patients.
The RECLOSE trial is a prospective study that included 804 consecutive patients who were treated with sirolimus-eluting (Cypher, Cordis Corporation, Miami Lakes, Florida) or paclitaxel-eluting (Taxus, Boston Scientific Corporation, Natick, Massachusetts) stents for coronary artery disease and who were compliant with 6-month dual antiplatelet treatment with aspirin (325 mg daily) and clopidogrel (75 mg daily). Patients with stable coronary artery disease as well as acute coronary syndromes and ST-segment elevation acute myocardial infarction were included irrespective of the coronary anatomy. The only exclusion criteria were: 1) in-hospital death not caused by DES thrombosis; 2) anticipated noncompliance with dual antiplatelet treatment for at least 6 months; and 3) premature discontinuation of clopidogrel or aspirin therapy. The study showed that nonresponsiveness to clopidogrel was associated with a 3-fold increase in DES thrombosis (hazard ratio [HR]: = 3.08, 95% confidence interval [CI]: 1.32 to 7.16, p = 0.009) compared with responsiveness. Details of the study have been published elsewhere (14).
Platelet reactivity assessment.
By light transmittance aggregometry, we evaluated platelet reactivity testing responsiveness to clopidogrel with adenosine 5'-diphosphate (ADP) and to aspirin with arachidonic acid. Furthermore, we evaluated platelet reactivity using collagen that is an aggregation stimulus not directly involved in the specific pathways of clopidogrel and aspirin. Blood samples anticoagulated with 0.129 mol/l sodium citrate (ratio 9:1) were obtained 12 to 18 h after 600-mg clopidogrel loading. For patients receiving both the loading dose of clopidogrel and a glycoprotein (GP) IIb/IIIa inhibitor in the catheterization laboratory, blood samples were obtained after 6 days, while patients were on the 75-mg maintenance dose of clopidogrel and 325 mg aspirin. Platelet-rich plasma, obtained by centrifuging whole blood for 10 min at 200 g, was stimulated with 10-µM ADP, 1-mM arachidonic acid, and 2-µg/ml collagen, and residual aggregation was assessed using a light transmittance aggregometer (APACT4, Helena Laboratories, Milan, Italy). The 100% line was set using platelet-poor plasma, and the 0 baseline was established with platelet-rich plasma (adjusted from 18 x 109/l up to 30 x 109/l). Platelet aggregation (according to the Born method) was evaluated considering the maximal percentage of platelet aggregation in response to stimulus. The coefficient of variation of ADP–, arachidonic acid–, and collagen–platelet aggregation were 6.8%, 5.8%, and 5.6%, respectively. Clopidogrel nonresponsiveness was defined as platelet aggregation by ADP  70% (14), and aspirin nonresponsiveness as platelet aggregation by arachidonic acid 20% (15). High residual platelet reactivity by collagen was defined as platelet aggregation above the 90th percentile of aggregation value distribution that resulted in 56%.
End points.
The primary end point of the study was definite or probable DES thrombosis during 6-month follow-up. Definite stent thrombosis was defined as acute coronary syndrome and either angiographic or pathological confirmation of thrombosis. Probable stent thrombosis was defined as sudden or otherwise explained death or nonfatal myocardial infarction in the territory supplied by a stented vessel without angiographic confirmation. The diagnosis of myocardial infarction was based on either the development of new Q waves on 2 or more electrocardiographic leads or an increase of creatine kinase-myocardial band isoenzyme or troponin T >3x the upper limit of normal. Event time was categorized as acute (within 24 h from stent implantation), subacute (from 1 to 30 days), and late (30 days to 6 months). The secondary end point was the composite of cardiac mortality and definite or probable stent thrombosis. All events were adjudicated by 3 observers (A.M., D.A., G.M.) who were blinded to patient responsiveness to clopidogrel and aspirin and were not involved in the follow-up process.
Follow-up.
All patients had scheduled clinical and electrocardiographic examinations at 1, 3, and 6 months. All other possible information derived from hospital readmission or by the referring physician, relatives, or municipality live registries was entered into the database.
Statistical analysis.
Discrete data are summarized as frequencies, whereas continuous data are summarized as mean ± SD. The chi-square test was used for comparison of categorical variables, and the 2-tailed Student t test was used to test differences among continuous variables.
Platelet reactivity test correlations were tested using the 2-tailed Spearman correlation coefficient entering responses to ADP, arachidonic acid, and collagen as continuous variables. The chi-square test was used for comparison among the 4 patient groups, including the post-hoc analysis. The multivariate analysis to evaluate the independent contribution of clinical, angiographic, procedural, and platelet reactivity variables to the primary and secondary end points was performed by a forward stepwise Cox proportional hazards model. Dichotomous platelet reactivity variables according to nonresponsiveness criteria were used (clopidogrel nonresponsiveness, aspirin nonresponsiveness, and the interaction term dual aspirin and clopidogrel nonresponsiveness). The other variables entered into the model were: age (years), male gender, family history of coronary artery disease, smoker, hypertension, hypercholesterolemia, diabetes mellitus, history of myocardial infarction, history of coronary surgery, acute coronary syndrome, acute ST-segment elevation myocardial infarction, left ventricular ejection fraction (%), multivessel disease, bifurcation lesion, thrombus-containing lesion, chronic total occlusion, and stent length (mm). Survival curves were generated using the Kaplan-Meier method, and the difference between the curves was assessed by a log-rank test. A value of p < 0.05 was considered significant. Analyses were performed using the software package SPSS version 8.0 (SPSS Inc., Chicago, Illinois).
|
Results
|
|---|
Of 804 patients enrolled in the study, complete platelet reactivity data were available for 746 (93%). Clinical and procedural characteristics of the patients investigated according to platelet reactivity are presented in Table 1.
The incidence of dual nonresponsiveness to aspirin and clopidogrel was 6%, whereas isolated nonresponsiveness to clopidogrel or to aspirin was 6% and 11.5%, respectively. The responses to the 3 stimuli were all correlated: correlation coefficient of ADP and arachidonic acid = 0.536 (p < 0.001), of ADP and collagen = 0.550 (p < 0.001), and of arachidonic acid and collagen = 0.617 (p < 0.001). The follow-up rate was 100%. Table 2
summarizes the clinical outcome at 6 months according to responsiveness to aspirin, clopidogrel, or both drugs.
Overall, definite or probable DES thrombosis occurred in 20 patients (2.7%). Patients with dual nonresponsiveness to clopidogrel and aspirin had the highest incidence of DES thrombosis (11.1%), whereas responsiveness to both drugs or isolated nonresponsiveness to clopidogrel or aspirin was associated with similar rates of DES thrombosis (2.1%, 2.2%, and 2.3%, respectively; p value among 4 groups = 0.005). Again, the secondary end point rate in patients with dual nonresponsiveness to aspirin and clopidogrel was 3- to 6-fold higher as compared with the other 3 groups: 13.3% in dual nonresponders, 2.6% in dual responders, 4.4% in isolated clopidogrel nonresponders, and 2.3% in isolated aspirin responders (p value among 4 groups = 0.002). Consistent with the results of a previous study (14), nonresponsiveness to clopidogrel with or without nonresponsiveness to aspirin (n = 90) was associated with an increased risk of DES thrombosis: in the 90 patients, the incidence of DES thrombosis was 6.7% (HR: 3.15, 95% CI: 1.21 to 8.20, p = 0.019). Nonresponsiveness to aspirin and dual nonresponsiveness were related to the primary end point (HR: 2.56, 95% CI: 1.02 to 6.40, p = 0.045; and HR: 5.31, 95% CI: 1.93 to 14.60, p = 0.001, respectively).
The Kaplan-Meier survival curves (Fig. 1) show that the overall risk of DES thrombosis and the composite of cardiac death and DES thrombosis were higher among dual nonresponders compared with the other 3 groups (primary end point: dual nonresponders vs. dual responders, p < 0.001; dual nonresponders vs. aspirin nonresponders, p = 0.036; dual nonresponders vs. clopidogrel nonresponders, p = 0.096; secondary end point: dual nonresponders vs. dual responders, p < 0.001; dual nonresponders vs. aspirin nonresponders, p = 0.011; dual nonresponders vs. clopidogrel nonresponders, p = 0.127).
View larger version (11K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 Kaplan-Meier Analysis
Kaplan-Meier analysis of drug-eluting stent thrombosis (A) and the composite of cardiac death and drug-eluting stent thrombosis (B) for dual responders, dual nonresponders, isolated aspirin nonresponders, and isolated clopidogrel nonresponders.
|
|
When platelet function was assessed by collagen, which explores receptors other than those involved in aspirin and clopidogrel pathways, more than one-half of dual nonresponder patients showed an abnormal platelet reactivity (24 of 45 dual nonresponders). In this subgroup of patients, the incidence of the primary end point was higher than in those without residual platelet reactivity (20.8% and 1.8%, respectively; p < 0.001). In the other 3 groups, the incidences of abnormal collagen test results were 15.6% (7 patients) in the isolated clopidogrel nonresponder group, 32.6% (28 patients) in the isolated aspirin nonresponder group, and 3.3% (19 patients) in the dual responder group.
At multivariable analysis (Table 3), dual nonresponsiveness to clopidogrel and aspirin was an independent predictor of both DES thrombosis (HR: 3.18, 95% CI: 1.14 to 8.83, p = 0.027) and the composite of cardiac mortality and DES thrombosis (HR: 2.94, 95% CI: 1.16 to 7.41, p = 0.022). The other variables related to the risk of DES thrombosis and the composite of cardiac death and DES thrombosis were age, total stent length, and left ventricular ejection fraction. If aspirin nonresponsiveness and clopidogrel nonresponsiveness were forced into the multivariable model, the HRs for the primary end point were 1.44 (95% CI: 0.54 to 3.82, p = 0.463) and 2.23 (95% CI: 0.85 to 5.82, p = 0.101), respectively.
|
Discussion
|
|---|
This study shows that a high residual platelet reactivity after a loading dose of 600 mg clopidogrel as revealed by 1 or more stimuli is relatively frequent and can be revealed in nearly one-fourth of patients treated with coronary DES. However, dual nonresponsiveness to aspirin and clopidogrel involves only 6% of patients. Patients with dual nonresponsiveness to clopidogrel and aspirin have a very high risk of DES thrombosis during a 6-month follow-up in comparison with dual responders or with isolated clopidogrel or aspirin nonresponders. The present novel findings are not inconsistent with those we previously obtained in the same patient cohort showing that a persistent platelet reactivity to ADP is a predictor of DES thrombosis, because in the previous study, the group of patients with residual platelet reactivity to ADP includes patients with associated residual platelet reactivity to arachidonic acid (14).
One-half of the patients with nonresponsiveness to clopidogrel have associated nonresponsiveness to aspirin. Again, among the dual nonresponders, more than one-half of patients have high residual platelet reactivity by collagen stimulus that explores different pathways other than cyclooxygenase-1 and P2Y12 for the antithrombotic effect of aspirin and clopidogrel. These associations can be explained, at least in part, by the fact that the different pathways involved in platelet reactivity can influence each other at different degrees. Arachidonic acid–induced platelet aggregation is mainly influenced by the inhibition of the thromboxane synthesis, and ADP-induced platelet aggregation is mainly sensitive to the inhibition of P2Y1 and P2Y12 receptors (16–18). However, evidence exists of the role of the P2Y12 receptor, the target of clopidogrel, as a functional regulator of thromboxane-A2 generation consequent to protein-activated receptor stimulation, whereas ADP-induced and collagen-induced platelet aggregation are affected to some extent by aspirin (19,20). Collagen acts on GP VI and directly activates the receptor function of GP IIb/IIIa to induce a maximal platelet aggregation response (21). Signaling by these receptors causes the secretion of ADP, which also participates in GP IIb/IIIa activation.
We did not use tests related to the specific pathways of thromboxane generation and ADP signaling in platelets, and as a consequence, the underlying mechanisms of aspirin, clopidogrel, or dual nonresponsiveness remain unclear. However, it seems likely that an abnormal response to 2 or 3 different platelet aggregation stimuli after a clopidogrel loading dose of 600 mg could define a primary abnormal platelet function as a main cause of thrombotic events, and that "aggressive blood" makes the patient a "vulnerable patient."
Clinically it seems relevant that a single platelet aggregation assessment after clopidogrel loading may provide a definite risk profile for DES thrombosis despite the lack of standardization in definition of clopidogrel and aspirin resistance (22), and the fact that in vitro platelet responsiveness may be quite variable because of the influence of several factors, such as inadequate generation of the active drug metabolite of clopidogrel or differences in the rate of intestinal absorption of antiplatelet drugs (18,21,23). Again, in this study the majority of patients had an acute coronary syndrome or ST-segment elevation acute myocardial infarction, which are conditions associated with higher baseline platelet reactivity compared with stable coronary artery disease (24,25), and it is surprising that a single platelet reactivity assessment in the acute phase of coronary artery disease maintains a high predictive value for subacute or late DES thrombosis when most patients are stable and the evidence of the acuity of coronary disease has disappeared.
Study limitations.
The deferred blood sample collection in patients who received GP IIb/IIIa inhibitors could have the potential for a confounding effect on the assessment of residual platelet reactivity to the collagen stimulus. However, this confounding effect is unlikely, considering the delay from the GP IIb/IIIa inhibitor administration and the assessment of platelet reactivity.
The analysis according to platelet responsiveness to both aspirin and clopidogrel decreases the statistical power of the sample size used in the RECLOSE trial, which was sufficiently powered for the responsiveness to clopidogrel with or without nonresponsiveness to aspirin. However, the concentration of DES thrombosis and mortality in the dual nonresponders patient group is impressive, whereas no other data from prospective studies on dual aspirin and clopidogrel nonresponsiveness in patients treated with DES are currently available. This limitation highlights the need for a large-scale confirmatory trial; meanwhile, the findings of this study should be considered as hypothesis generating rather than offering a definitive answer.
|
References
|
|---|
1. Metha SR, Yusuf S, Peters RJG, et al. Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study Lancet 2001;358:527-533.[CrossRef][Web of Science][Medline]2. Steinhubl SR, Berger PB, Mann III JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial JAMA 2002;288:2411-2420.[Abstract/Free Full Text] 3. Bhatt DL, Bertrand ME, Berger PB, et al. Meta-analysis of randomized and registry comparison of ticlopidine with clopidogrel after stenting J Am Coll Cardiol 2002;39:9-14.[Abstract/Free Full Text] 4. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy Lancet 2004;364:1519-1521.[CrossRef][Web of Science][Medline] 5. Kaiser C, Brunner-La Rocca HP, Buser PT, et al. Incremental cost-effectiveness of drug eluting stents compared with a third generation bare-metal stents in a real-world setting: randomised Basel Stent Kosten Effektivitats Trial (BASKET) Lancet 2005;366:921-929.[CrossRef][Web of Science][Medline] 6. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents JAMA 2005;293:2126-2130.[Abstract/Free Full Text] 7. Park D-W, Park S-W, Park K-H, et al. Frequency and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up Am J Cardiol 2006;98:352-356.[CrossRef][Web of Science][Medline] 8. 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] 9. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis J Am Coll Cardiol 2005;46:1827-1832.[Abstract/Free Full Text] 10. Gurbel PA, Bliden KP, Guyer BS, et al. Platelet reactivity in patients and recurrent events post-stenting J Am Coll Cardiol 2005;46:1820-1826.[Abstract/Free Full Text] 11. Ajzenberg G, Aubry P, Huisse MG, et al. Enhanced shear-induced platelet aggregation in patients who experienced stent thrombosis J Am Coll Cardiol 2005;45:1653-1656. 12. Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet reactivity identified low responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome J Thromb Haemost 2006;4:542-549.[CrossRef][Web of Science][Medline] 13. Hochholzer W, Trenk D, Bestehorn H-P, et al. 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 2006;48:1742-1750.[Abstract/Free Full Text] 14. Buonamici P, Marcucci R, Migliorini A, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis J Am Coll Cardiol 2007;49:2312-231724.[Abstract/Free Full Text] 15. Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. A prospective blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease J Am Coll Cardiol 2003;41:961-965.[Abstract/Free Full Text] 16. Reilly IA, Fitzgerald GA. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs Blood 1987;69:180-186.[Abstract/Free Full Text] 17. Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance Arterioscler Thromb Vasc Biol 2004;24:1980-1987.[Abstract/Free Full Text] 18. Maree AO, Fitzgerald DJ. Variable platelet response to aspirin and clopidogrel in atherothrombotic disease Circulation 2007;115:2196-2207.[Free Full Text] 19. Shankar H, Garcia A, Prabhakar J, Kunapuli SP. P2Y12 receptor-mediated potentiation of thrombin-induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation J Thromb Haemost 2006;4:638-647.[CrossRef][Web of Science][Medline] 20. André P, LaRocca T, Delaney SM, et al. Anticoagulants (thrombin inhibitors) and aspirin synergize with P2Y12 receptor antagonism in thrombosis Circulation 2003;108:2697-2703.[Abstract/Free Full Text] 21. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability Eur Heart J 2004;5:1903-1910. 22. Gurbel PA, Becker RC, Mann KG, Steinubl SR, Michelson AD. Platelet function monitoring in patients with coronary artery disease J Am Coll Cardiol 2007;50:1822-1834.[Abstract/Free Full Text] 23. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives J Am Coll Cardiol 2007;49:1505-1516.[Abstract/Free Full Text] 24. Patel PB, Pfau SE, Cleman MW, et al. Comparison of coronary artery specific leukocyte platelet conjugate formation in unstable versus stable angina pectoris Am J Cardiol 2004;93:410-413.[CrossRef][Web of Science][Medline] 25. Sibbing D, von Beckerath O, Schomig A, Kastrati A, von Beckerath N. Platelet function in clopidogrel-treated patients with acute coronary syndrome Blood Coagul Fibrinolysis 2007;18:335-339.[Web of Science][Medline]
Related Articles
-
Aspirin Resistance: An Underestimated Risk in Patients With Drug-Eluting Stents?
- Dietmar Trenk and Franz-Josef Neumann
J. Am. Coll. Cardiol. 2008 52: 740-742.
[Full Text]
[PDF]
-
Inside This Issue of JACC
J. Am. Coll. Cardiol. 2008 52: A27-A28.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
F. Marin, R. Gonzalez-Conejero, P. Capranzano, T. A. Bass, V. Roldan, and D. J. Angiolillo
Pharmacogenetics in cardiovascular antithrombotic therapy.
J. Am. Coll. Cardiol.,
September 15, 2009;
54(12):
1041 - 1057.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. Dixon, C. L. Grines, and W. W. O'Neill
The year in interventional cardiology.
J. Am. Coll. Cardiol.,
June 2, 2009;
53(22):
2080 - 2097.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
A. N. DeMaria, O. Ben-Yehuda, J. J. Bax, G. K. Feld, B. H. Greenberg, W. Y.W. Lew, J. A.C. Lima, A. S. Maisel, S. M. Narayan, D. J. Sahn, et al.
Highlights of the Year in JACC 2008.
J. Am. Coll. Cardiol.,
January 27, 2009;
53(4):
373 - 398.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Marcucci, A. M. Gori, R. Paniccia, B. Giusti, S. Valente, C. Giglioli, P. Buonamici, D. Antoniucci, R. Abbate, and G. F. Gensini
Cardiovascular Death and Nonfatal Myocardial Infarction in Acute Coronary Syndrome Patients Receiving Coronary Stenting Are Predicted by Residual Platelet Reactivity to ADP Detected by a Point-of-Care Assay: A 12-Month Follow-Up
Circulation,
January 20, 2009;
119(2):
237 - 242.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Nonresponsiveness to Aspirin and Clopidogrel After Drug-Eluting Stent Placement
Journal Watch (General),
September 30, 2008;
2008(930):
2 - 2.
[Full Text]
|
|
|
|
|
|
|
D. Trenk and F.-J. Neumann
Aspirin Resistance: An Underestimated Risk in Patients With Drug-Eluting Stents?
J. Am. Coll. Cardiol.,
August 26, 2008;
52(9):
740 - 742.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods