Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
Circulation. 2004;109:3171-3175
Published online before print June 7, 2004, doi: 10.1161/01.CIR.0000130846.46168.03
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
109/25/3171    most recent
01.CIR.0000130846.46168.03v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Matetzky, S.
Right arrow Articles by Hod, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Matetzky, S.
Right arrow Articles by Hod, H.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*ACETYLSALICYLIC ACID
*EPINEPHRINE
Medline Plus Health Information
*Coronary Artery Disease
*Heart Attack
Related Collections
Right arrow Acute coronary syndromes
Right arrow Acute myocardial infarction
Right arrow Platelets

(Circulation. 2004;109:3171-3175.)
© 2004 American Heart Association, Inc.


Clinical Investigation and Reports

Clopidogrel Resistance Is Associated With Increased Risk of Recurrent Atherothrombotic Events in Patients With Acute Myocardial Infarction

Shlomi Matetzky, MD; Boris Shenkman, MD, PhD; Victor Guetta, MD; Michael Shechter, MD; Roy Bienart, MD; Ilan Goldenberg, MD; Ilya Novikov, PhD; Hanna Pres, MSc; Naphtali Savion, PhD; David Varon, MD; Hanoch Hod, MD

From the Heart Institute (S.M., V.G., M.S., R.B., I.G., I.N., H.P., H.H.), Institute of Thrombosis and Hemostasis (B.S., D.V.), and Goldschleger Eye Research Institute (N.S.), Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Israel.

Correspondence to Hanoch Hod, MD, Director, ICCU, Heart Institute, Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail hod{at}netvision.net.il

Received October 20, 2003; de novo received December 14, 2003; revision received February 24, 2004; accepted March 16, 2004.


*    Abstract
up arrowTop
*Abstract
down arrowIntroduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background— Although clopidogrel reduces the risk of cardiovascular episodes after coronary events and stenting, a substantial number of incidents continue to occur.

Methods and Results— The antiplatelet effect of clopidogrel was studied prospectively in 60 consecutive patients who underwent primary angioplasty (percutaneous coronary intervention [PCI]) with stenting for acute ST-segment–elevation myocardial infarction (STEMI) to determine whether variability in response to clopidogrel affects clinical outcomes. Patients were stratified into 4 quartiles according to the percentage reduction of ADP-induced platelet aggregation. Although patients in the first quartile were resistant to the effects of clopidogrel (ADP-induced platelet aggregation at day 6, 103±8% of baseline), ADP-induced aggregation was reduced to 69±3%, 58±7%, and 33±12% of baseline, respectively, in patients in quartiles 2 through 4 (P<0.01 for all). In addition, epinephrine-induced platelet aggregation and platelet aggregation under flow conditions, assessed by the cone-and-plate(let) analyzer method, were reduced significantly less in the first quartile than in quartiles 2 through 4. Whereas 40% of patients in the first quartile sustained a recurrent cardiovascular event during a 6-month follow-up, only 1 patient (6.7%) in the second quartile and none in the third and fourth quartiles suffered a cardiovascular event (P=0.007).

Conclusions— Up to 25% of STEMI patients undergoing primary PCI with stenting are resistant to clopidogrel and therefore may be at increased risk for recurrent cardiovascular events.


Key Words: platelets • myocardial infarction • clopidogrel


*    Introduction
up arrowTop
up arrowAbstract
*Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
The ADP-receptor blocker clopidogrel reduces the incidence of recurrent ischemic events in patients with acute coronary syndrome (ACS)1 and after coronary stenting.2 Nevertheless, a significant number of cardiovascular events continue to occur.1,2

See p 3064

The antiplatelet effect of clopidogrel has been studied in normal volunteers3 and in patients with stable coronary disease4–6 but not in patients with ACS, which is associated with platelet activation.7 In the present study, the antiplatelet effect of clopidogrel was studied prospectively in 60 consecutive patients with ST-segment–elevation acute myocardial infarction (STEMI) to determine whether there is significant individual variability in platelet response to clopidogrel and whether it might account for recurrent cardiovascular events.


*    Methods
up arrowTop
up arrowAbstract
up arrowIntroduction
*Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Study Population
The study comprised 60 consecutive STEMI patients who were admitted within 6 hours of symptom onset. All patients underwent primary PCI with stenting, which was the standard reperfusion therapy during the study period. Ten additional consecutive patients, who underwent primary angioplasty without stenting during the study period and were not treated with clopidogrel, were also investigated. All patients were enrolled and studied prospectively. The institutional review board approved the protocol, and patients gave written informed consent. All patients received 300 mg of chewable aspirin on admission and 200 mg/d thereafter throughout the study period. Heparin was administered during the procedure but was discouraged after the procedure. Eptifibatide was administered for a mean of 14±2 hours. Clopidogrel was administered as a loading dose of 300 mg on completion of the PCI, followed by doses of 75 mg/d for 3 months.

Blood samples for testing platelet activity were drawn in the catheterization laboratory before administration of eptifibatide at an average of 80±10 minutes after administration of chewable aspirin (baseline) and daily for 5 days thereafter.

Platelet Function Tests
Turbidimetric Platelet Aggregation
Platelet-rich plasma was prepared by centrifugation of citrated blood, and response to ADP (5 µmol/L) and epinephrine (10 µmol/L) was recorded by use of routine aggregometer (Helena Laboratory; PACKS-4).

Cone-and-Platelet Analyzer
This technology has been described elsewhere.8 Briefly, 200 µL of citrated blood was placed in a polystyrene well and subjected to a shear rate of 1800 s–1 using a rotating conical disk for 2 minutes. The well was washed and stained by May-Gruenwald stain. Platelet adhesion was evaluated as the percentage of total area covered with platelets designated as surface coverage (%) and aggregation as the mean size of the surface-bound aggregates designated as average size (µm2) by use of an image analysis system (Galai).

Clinical Follow-Up
All patients were followed up via outpatient clinic visits 3 and 6 months after hospital discharge. Drug therapy compliance was assessed by telephone calls 1 month after discharge and at the first outpatient clinic visit. All medical documents were reviewed in patients who sustained recurrent cardiovascular events or underwent coronary angiography. The treating physician and the investigators who evaluated the clinical end points were blinded to the results of the platelet function activity.

Statistical Analysis
Platelet activity was expressed as a percentage of baseline value. Each patient served as his or her own control, and changes in platelet activity were evaluated with paired t test.

Patients were stratified into 4 quartiles based on the percentage reduction of ADP-induced platelet aggregation at day 6 compared with the baseline ADP-induced platelet aggregation (determined before clopidogrel loading). Categorical variables were presented as percentages in the 4 quartiles and tested for linear trend with Mantel-Haenszel {chi}2 analysis. A 2-tailed Fisher’s exact test was used to compare patients in the first quartile with patients in the second through fourth quartiles. Continuous variables were presented as mean±SD. The linear trends of the variables in the 4 quartiles were compared by use of Pearson correlation. The Wilcoxon rank-sum test was used to compare patients in the first versus the second through fourth quartiles.


*    Results
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Of the 60 patients enrolled, 48 (80%) were male, mean age was 58±13 years, and mean time from symptom onset to admission was 2.8±2 hours.

Antiplatelet Effect of Clopidogrel
At day 2 (18±2 hours after clopidogrel loading and 4±0.5 hours after termination of eptifibatide), both mean ADP-induced platelet aggregation and mean epinephrine-induced platelet aggregation were inhibited to 40% of baseline (P<0.01) and at day 3 to 66% (P<0.01) and 78% (P<0.01) of baseline, respectively, with no further significant changes at days 4 through 6 (Figure 1a). The final ADP aggregation (day 6) correlated negatively with the percentage inhibition of baseline ADP-induced platelet aggregation (r2=0.94, P<0.01).



View larger version (18K):
[in this window]
[in a new window]
 
Figure 1. Changes in ADP-induced platelet aggregation (a) and aggregate size (b) after clopidogrel administration, expressed as percentage of baseline activity (*P<0.01 for changes from baseline). Changes in ADP-induced aggregation in patients receiving aspirin (ASA) (n=10) vs patients receiving clopidogrel and aspirin (n=60, §P<0.01 for comparison) (c).

The aggregate size, assessed by cone-and-platelet analysis, which reflects platelet aggregation under flow conditions, was significantly decreased to 60% of baseline value at day 2 and to {approx}70% at day 6 (Figure 1b). Although the surface coverage was decreased significantly, by {approx}50% (P<0.01), at day 2 when an eptifibatide effect could still be expected, clopidogrel had no significant effect on surface coverage on day 3 and thereafter ({approx}90% of baseline at days 3 through 6, P=0.16).

In patients who underwent angioplasty without stenting and therefore were treated with aspirin alone, no significant inhibition of ADP- and epinephrine-induced platelet aggregation at days 3 through 6 was noted compared with baseline activity, which had already been determined after aspirin loading. At each of these time points, platelet reactivity was significantly higher than in patients treated with both aspirin and clopidogrel (P<0.01, Figure 1c).

Variability in Platelet Response to Clopidogrel
When patients were stratified into 4 quartiles according to percentage reduction of ADP-induced platelet aggregation at day 6 compared with the baseline activity of each patient, significant variability was noted. Whereas patients in the first quartile were resistant to the effect of clopidogrel (ADP-induced platelet aggregation at day 6, 103±8% of baseline), ADP-induced platelet aggregation was reduced significantly in patients in the second through fourth quartiles, to 69±3%, 58±7%, and 33±12% of the respective baselines (P<0.01 for all, Figure 2a). Inhibition in platelet aggregation increased significantly in the first through fourth quartiles (P for trend <0.01). Patients in the first through fourth quartiles also exhibited increasing reduction in epinephrine-induced platelet aggregation (P for trend <0.001) and in aggregate size, reflecting aggregation under flow conditions (Figure 2b).



View larger version (25K):
[in this window]
[in a new window]
 
Figure 2. Study patients (pts) were stratified into quartiles according to degree of platelet activity inhibition in response to clopidogrel treatment. Patients in 4 quartiles were compared with regard to (a) changes in ADP-induced platelet aggregation expressed as percentage of baseline activity; (b) percentage reduction in aggregate size at day 6 compared with baseline values; and (c) incidence of recurrent major adverse cardiovascular events during a 6-month follow-up.

Clinical Outcomes
There was a gradual and significant increase in the number of cigarette smokers in the first through fourth quartiles (Table), but otherwise there were no significant differences in the other baseline demographic and clinical characteristics, platelet counts on admission and at day 6, indices of infarct size, and angiographic findings (Table). Similarly, there were no significant differences in the medications assigned to patients during hospitalization and at hospital discharge in all 4 quartiles (Table). Postinterventional heparin was discontinued in all patients, and none of the patients received anticoagulant therapy throughout the follow-up period.


View this table:
[in this window]
[in a new window]
 
Baseline Demographic and Clinical Characteristics of Patients

None of the 60 patients enrolled in the study were lost to the 6-month follow-up. During this period, 2 patients developed recurrent STEMI, one of whom had 2 recurrent MIs because of stent thrombosis; 3 had recurrent ACS; and a sixth suffered an acute peripheral arterial occlusion, necessitating urgent surgery. One patient died of ischemic stroke. Thus, 7 patients had 8 recurrent cardiovascular events, 6 of which occurred during treatment with clopidogrel. Seven of the 8 events (88%) occurred in patients resistant to clopidogrel (first quartile) and 1 event (12%) in a patient from the second quartile. Accordingly, whereas 40% of patients in the first quartile (clopidogrel resistant) sustained a recurrent cardiovascular event, only 1 patient (6.7%) in the second quartile and none in the third and fourth quartiles developed an event (P for trend=0.007, Figure 2c). In contrast, major bleeding occurred in 2 patients, both of whom were in the fourth quartile.

Patients with recurrent cardiovascular events were older (P=0.008), had higher Killip class on admission (P=0.004), and had a lower percentage reduction of ADP-induced platelet aggregation as early as day 3 (91±21% versus 62±21% percent of baseline, P<0.001), which persisted through day 6 (90±16% versus 64±27%, P<0.001, Figure 3).



View larger version (25K):
[in this window]
[in a new window]
 
Figure 3. Individual variability in reduction of ADP-induced platelet aggregation at day 6 compared with baseline activity (day 1) in patients who sustained recurrent cardiovascular (CVS) events (n=7) and those who did not (n=53).


*    Discussion
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
Although clopidogrel has been proved effective as an antithrombotic drug, to the best of our knowledge, this is the first study to report on its antiplatelet effect in STEMI patients and also the first to demonstrate an association between clopidogrel resistance and cardiovascular risk.

Clopidogrel Effects in AMI Patients
Clopidogrel yielded a 35% to 60% reduction in ex vivo platelet aggregation in normal volunteers and in patients with stable coronary disease.3–6 Clopidogrel did not confer significant inhibition of platelets, which are activated by the thrombin-related activating peptide (TRAP), suggesting that clopidogrel might be less effective in clinical situations characterized by high thrombin generation, as in ACS.5,6 Furthermore, previous studies have shown that there is a marked increase in platelet activity in patients with AMI undergoing PCI7 and that pretreatment platelet activity may negatively affect the antithrombotic effect of clopidogrel.9 These findings warrant investigation of the antiplatelet effect of clopidogrel in patients with AMI. In the present study, clopidogrel administration in STEMI patients undergoing primary PCI who were already receiving aspirin was followed by a significant inhibition of ADP-induced platelet aggregation of 35% and a significant reduction of 25% in aggregate size, indicating inhibition of aggregation under flow conditions. Clopidogrel also significantly inhibited epinephrine-induced platelet aggregation, probably by blocking the effect of secondarily released ADP.

Clopidogrel Resistance
Recently, laboratory documentation of aspirin resistance has been shown to predict an increased risk of cardiovascular events in patients with coronary artery disease.12 A few studies have revealed important individual heterogeneity in platelet response to clopidogrel in patients with stable coronary disease,9–11 but the clinical significance of this phenomenon has not yet been investigated. We expanded this finding by showing similar marked individual variability in response to clopidogrel in patients with STEMI, demonstrating that such heterogenicity may possess important clinical implications. In the present study, as many as 25% of patients with STEMI were resistant to clopidogrel and subsequently were at increased risk of recurrent cardiovascular events in a 6-month follow-up.

In the present study, smoking seemed to enhance the clopidogrel antiplatelet effect with a consistent gradual increase of the number of cigarette smokers from the first to the fourth quartile, opposing the possibility of this being a chance finding. Aside from smoking, no other baseline characteristic predicted the response to clopidogrel.

Clopidogrel is a prodrug, and the active metabolite formation is regulated primarily by cytochrome P450 isoenzymes 3A4 and 1A2, the latter of which is activated by the polycyclic aromatic hydrocarbons that exist in cigarette smoke.13 Furthermore, plasma nicotine levels similar to those reported in human smokers were shown to induce cytochrome 1A2 in rats.14 This possible explanation is in agreement with the findings of Lau et al,15 who showed that in normal volunteers and patients after coronary stenting, the individual platelet variability in response to clopidogrel correlates with cytochrome P450 metabolism activity. However, polymorphism in the ADP receptor or differences in the postreceptor signaling pathway cannot be excluded as an additional explanation for the variability in platelet responsiveness and clopidogrel resistance.

It should be mentioned that the present study is an observational one, comprising a relatively small sample size, and therefore does not allow for definitive conclusions. Nevertheless, clopidogrel resistance occurs in a significant percentage of STEMI patients and is associated with a higher risk of recurrent cardiovascular events. The question of whether increased doses of clopidogrel might overcome this resistance in nonresponsive patients warrants further investigation.


*    Acknowledgments
 
We thank Vivienne York for her editorial assistance.


*    Footnotes
 
Drs Savion and Varon are founders of the company developing the Cone and Plate(let) Analyser.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

  1. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. N Engl J Med. 2001; 345: 494–502.[Abstract/Free Full Text]
  2. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. JAMA. 2002; 288: 2411–2420.[Abstract/Free Full Text]
  3. Cadroy Y, Bossavy J-P, Thalamas C, et al. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation. 2000; 101: 2823–2828.[Abstract/Free Full Text]
  4. Moshfegh K, Redondo M, Julmy F, et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: enhanced inhibitory effects of combination therapy. J Am Coll Cardiol. 2000; 36: 699–705.[Abstract/Free Full Text]
  5. Müller I, Seyfarth M, Rüdiger, 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]
  6. Gaswaz M, Seyfarth M, Muller I, et al. Comparison of effects of clopidogrel versus ticlopidine on platelet function in patients undergoing coronary stent placement. Am J Cardiol. 2001; 87: 332–336.[CrossRef][Medline] [Order article via Infotrieve]
  7. Gawaz M, Neumann F-J, Ott I, et al. Platelet function in acute myocardial infarction treated with direct angioplasty. Circulation. 1996; 93: 229–237.[Abstract/Free Full Text]
  8. Varon D, Dardik R, Shenkman B, et al. A new method for quantitative analysis of whole blood platelet interaction with extracellular matrix under flow conditions. Thromb Res. 1997; 85: 283–294.[CrossRef][Medline] [Order article via Infotrieve]
  9. Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003; 107: 2908–2913.[Abstract/Free Full Text]
  10. Järemo P, Lindahl TL, Fransson SG, et al. Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med. 2002; 252: 233–238.[CrossRef][Medline] [Order article via Infotrieve]
  11. Gurbel PA, Bliden DP. Durability of platelet inhibition of clopidogrel. Am J Cardiol. 2003; 91: 1123–1125.[CrossRef][Medline] [Order article via Infotrieve]
  12. Gum PA, Kottke-Marchant K, Welsh PA, et al. 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]
  13. Zevin S, Benowitz NL. Drug interactions with tobacco smoking. Clin Pharmacokinet. 1999; 36: 425–438.[CrossRef][Medline] [Order article via Infotrieve]
  14. Iba MM, Fung J, Pak YW, et al. Dose-dependent up-regulation of rat pulmonary, renal, and hepatic cytochrome P-450 (CYP) 1A expression by nicotine feeding. Drug Metab Dispos. 1999; 27: 977–982.[Abstract/Free Full Text]
  15. 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]



This article has been cited by other articles:


Home page
Am J Health Syst PharmHome page
W. Alvarez Jr.
For better or for worse: The future of antiplatelet therapy
Am. J. Health Syst. Pharm., June 1, 2008; 65(11): 1017 - 1017.
[Full Text] [PDF]


Home page
J Am Coll Cardiol IntvHome page
C. S. Rihal
Drug-Eluting Stents for ST-Segment Elevation Myocardial Infarction: Treatment of Choice or Is Discretion the Better Part of Valor?
J. Am. Coll. Cardiol. Intv., June 1, 2008; 1(3): 233 - 235.
[Full Text] [PDF]


Home page
HeartHome page
T Geisler, M Kapp, K Gohring-Frischholz, K Daub, C Dosch, B Bigalke, H Langer, C Herdeg, and M Gawaz
Residual platelet activity is increased in clopidogrel- and ASA-treated patients with coronary stenting for acute coronary syndromes compared with stable coronary artery disease
Heart, June 1, 2008; 94(6): 743 - 747.
[Abstract] [Full Text] [PDF]


Home page
ANGIOLOGYHome page
D. Aradi, A. Konyi, L. Palinkas, T. Berki, T. Pinter, T. Tahin, I. Horvath, L. Papp, and A. Komocsi
Thienopyridine Therapy Influences Late Outcome After Coronary Stent Implantation
Angiology, May 1, 2008; 59(2): 172 - 178.
[Abstract] [PDF]


Home page
Eur Heart J SupplHome page
J.-P. Bassand
Unmet needs in antiplatelet therapy
Eur. Heart J. Suppl., May 1, 2008; 10(suppl_D): D3 - D11.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart J SupplHome page
J.J.J. van Giezen
Optimizing platelet inhibition
Eur. Heart J. Suppl., May 1, 2008; 10(suppl_D): D23 - D29.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart J SupplHome page
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]


Home page
J Am Coll CardiolHome page
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]


Home page
Eur Heart JHome page
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]


Home page
Eur Heart JHome page
D. R. Holmes Jr
Resistance to what, does it matter? How do we study it?
Eur. Heart J., April 2, 2008; 29(8): 957 - 958.
[Full Text] [PDF]


Home page
Am. J. Neuroradiol.Home page
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]


Home page
J Am Coll Cardiol IntvHome page
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]


Home page
Postgrad. Med. J.Home page
M Srinivasan and D Smith
Drug interaction with anti-mycobacterial treatment as a cause of clopidogrel resistance
Postgrad. Med. J., April 1, 2008; 84(990): 217 - 219.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
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]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
A. D. Michelson
P2Y12 Antagonism: Promises and Challenges
Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): s33 - s38.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Neuroradiol.Home page
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]


Home page
J Am Coll CardiolHome page
M. Gilard, B. Arnaud, J.-C. Cornily, G. Le Gal, K. Lacut, G. Le Calvez, J. Mansourati, D. Mottier, J.-F. Abgrall, and J. Boschat
Influence of Omeprazole on the Antiplatelet Action of Clopidogrel Associated With Aspirin: The Randomized, Double-Blind OCLA (Omeprazole CLopidogrel Aspirin) Study
J. Am. Coll. Cardiol., January 22, 2008; 51(3): 256 - 260.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart JHome page
L. Wallentin, C. Varenhorst, S. James, D. Erlinge, O. O Braun, J. A. Jakubowski, A. Sugidachi, K. J. Winters, and A. Siegbahn
Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease
Eur. Heart J., January 1, 2008; 29(1): 21 - 30.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart J SupplHome page
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]


Home page
Eur Heart J SupplHome page
C. Gachet and B. Aleil
Testing antiplatelet therapy
Eur. Heart J. Suppl., January 1, 2008; 10(suppl_A): A28 - A34.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
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]


Home page
NEJMHome page
S. D. Wiviott, E. Braunwald, C. H. McCabe, G. Montalescot, W. Ruzyllo, S. Gottlieb, F.-J. Neumann, D. Ardissino, S. De Servi, S. A. Murphy, et al.
Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes
N. Engl. J. Med., November 15, 2007; 357(20): 2001 - 2015.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
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]


Home page
J Am Coll CardiolHome page
C. P. Cannon, S. Husted, R. A. Harrington, B. M. Scirica, H. Emanuelsson, G. Peters, R. F. Storey, and for the DISPERSE-2 Investigators
Safety, Tolerability, and Initial Efficacy of AZD6140, the First Reversible Oral Adenosine Diphosphate Receptor Antagonist, Compared With Clopidogrel, in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome: Primary Results of the DISPERSE-2 Trial
J. Am. Coll. Cardiol., November 6, 2007; 50(19): 1844 - 1851.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
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]


Home page
J Am Coll CardiolHome page
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]


Home page
J Am Coll CardiolHome page
D. J. Angiolillo, E. Bernardo, M. Sabate, P. Jimenez-Quevedo, M. A. Costa, J. Palazuelos, R. Hernandez-Antolin, R. Moreno, J. Escaned, F. Alfonso, et al.
Impact of Platelet Reactivity on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease
J. Am. Coll. Cardiol., October 16, 2007; 50(16): 1541 - 1547.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
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]


Home page
J CARDIOVASC PHARMACOL THERHome page
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]


Home page
J Am Coll CardiolHome page
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]


Home page
J Am Coll CardiolHome page
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]


Home page
Eur Heart J