Donate Help Contact The AHA Sign In Home
American Heart Association
Arteriosclerosis, Thrombosis, and Vascular Biology
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:s33-s38
Published online before print January 3, 2008, doi: 10.1161/ATVBAHA.107.160689
Free Article
This Article
Free upon publication Free Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
28/3/s33    most recent
ATVBAHA.107.160689v1
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
Google Scholar
Right arrow Articles by Michelson, A. D.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Michelson, A. D.
(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:s33.)
© 2008 American Heart Association, Inc.

Translational Therapeutics at the Platelet Vascular Interface: A CME-Certified Activity

P2Y12 Antagonism

Promises and Challenges

Alan D. Michelson

From the Center for Platelet Function Studies, Departments of Pediatrics, Medicine, and Pathology, University of Massachusetts Medical School, Worcester.

Correspondence to Alan D. Michelson, MD, Director, Center for Platelet Function Studies, University of Massachusetts Medical School, Room S5-846, 55 Lake Avenue North, Worcester, MA 01655. E-mail michelson{at}platelets.org

Abstract

The P2Y12 antagonist clopidogrel has a well-established role as an antithrombotic agent in the settings of percutaneous coronary intervention and acute coronary syndromes. However, several challenges remain, including the relatively slow onset of action of clopidogrel and the phenomenon of clopidogrel response variability or "resistance". Novel P2Y12 antagonists, including prasugrel, AZD6140, and cangrelor, have a faster onset of action, as well as more potent, and less variable, inhibition of platelet function ex vivo. Whether this promise will be translated into clinical benefit for patients will be determined by the results of ongoing phase 3 clinical trials.


Key Words: platelets • clopidogrel • prasugrel • AZD6140 • cangrelor

This article is part of a multi-part CME-certified activity titled Translational Therapeutics at the Platelet Vascular Interface. In order to achieve all of the activity’s learning objectives, please read all of the components of the activity listed in the Table of Contents and follow the "Instructions for Participation and Obtaining CME Credit" outlined prior to the Introduction.

Platelets normally circulate in a resting form. In response to a vascular injury, eg, rupture of an atherosclerotic plaque in a coronary artery, platelets adhere to the damaged vessel wall, become activated, and aggregate with one another, resulting in a platelet-dependent thrombus. The goal of antiplatelet therapy is to prevent or treat this platelet-dependent thrombus. This article reviews a clinically important category of antiplatelet drugs: the P2Y12 antagonists (Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1. P2Y12 Antagonists

Adenosine diphosphate (ADP), an important platelet agonist in vivo, has 2 types of receptors in the platelet plasma membrane: P2Y1 and P2Y12.1 P2Y1 is a 7-transmembrane receptor linked to a Gq protein (Figure 1A). The end result of ADP signaling through its P2Y1 receptor is calcium mobilization, platelet shape change, and rapidly reversible platelet aggregation. P2Y12 is also a 7-transmembrane domain receptor, but it is linked to a G inhibitory protein (Figure 1A). The end result of ADP signaling through its P2Y12 receptor is amplification of stable platelet aggregation and secretion.


Figure 1
View larger version (27K):
[in this window]
[in a new window]

  		Figure 1. A, Mechanism of action of P2Y12 antagonists. The 2 currently FDA-approved P2Y12 antagonists, ticlopidine and clopidogrel, are thienopyridines which are metabolized through cytochrome P450 in the liver. The thienopyridine metabolites, not the parent ticlopidine or clopidogrel molecules, irreversibly antagonize the P2Y12 receptor. B, Vasodilator-stimulated phosphoprotein (VASP) assay for the measurement of P2Y12 antagonism. PGE1 binds to its IP receptor on the platelet surface and signals through a G stimulatory (Gs) protein and adenylyl cyclase (AC) to convert ATP to cAMP, and then through protein kinase A (PKA) to convert VASP to phosphorylated VASP (VASP-P). ADP binds to its P2Y12 receptor on the platelet surface and signals through a G inhibitory (Gi) protein to inhibit PGE1-induced signaling through AC. P2Y12 antagonists, eg, the active metabolite of clopidogrel, inhibit this ADP-induced effect. Therefore, in the presence of both PGE1 and ADP, VASP-P is directly proportional to the degree of P2Y12 antagonism. VASP-P is measured by whole blood flow cytometry, using permeabilization and a monoclonal antibody specific for the phosphorylated form of VASP. Modified with permission from Cattaneo.1

Currently-Approved P2Y12 Antagonists

The 2 currently FDA-approved P2Y12 antagonists, ticlopidine and clopidogrel, are thienopyridines (Table 1) that are metabolized through cytochrome P450 in the liver. The thienopyridine metabolites (Figure 2A), not the parent ticlopidine or clopidogrel molecules, irreversibly antagonize the P2Y12 receptor (Figure 1A, Table 1). Ticlopidine, the first FDA-approved P2Y12 antagonist, is given orally twice a day. However, in the United States and most other countries, ticlopidine has been largely replaced in clinical practice by clopidogrel, given orally in a more convenient daily dose, because of the better side-effect profile of clopidogrel—for example, less neutropenia and a lower incidence of the rare but dangerous thrombotic thrombocytopenic purpura.2


Figure 2
View larger version (25K):
[in this window]
[in a new window]

  		Figure 2. A, Thienopyridines and their active metabolites. B, ATP and its analogs. Reproduced with permission from Cattaneo.2

Clopidogrel is well established as an antiplatelet therapy.2 Large multicenter randomized controlled trials have demonstrated its benefit. The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial was performed in 12 562 patients with acute coronary syndrome, unstable angina, or non-ST elevation myocardial infarction.3 These patients were randomized to either a clopidogrel loading dose of 300 mg or placebo followed by clopidogrel 75 mg daily plus aspirin 75 to 325 mg daily or placebo plus aspirin 75 to 325 mg daily. Patients were followed for 12 months, with a primary end point of myocardial infarction, stroke, and cardiovascular death, and there was a relative risk reduction (RRR) of 20% in the clopidogrel-treated group (P<0.001). The PCI-CURE (Percutaneous Coronary Intervention CURE) study was a continuation of the CURE study.4 Those 2658 patients who went on to PCI received open-label thienopyridine and 30 days post-PCI were randomized to either clopidogrel plus aspirin or placebo plus aspirin and then followed for 12 months. Based on a composite end point of cardiovascular death or myocardial infarction from randomization to the end of follow-up in PCI-CURE, patients treated with clopidogrel had a 31% RRR compared with patients treated with placebo (P=0.002). The CREDO (Clopidogrel for the Reduction of Events During Observation) trial confirmed the beneficial effect of clopidogrel in post-PCI patients.5 Subsequently, the COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) and CLARITY-TIMI 28 (CLopidogrel as Adjunctive ReperfusIon TherapY-Thrombolysis In Myocardial Infarction 28) trials demonstrated the benefit of clopidogrel and aspirin in patients with ST-elevation myocardial infarction.6,7 However, in patients with stable cardiovascular disease or asymptomatic patients with multiple cardiovascular risk factors, the 15 603-patient CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial reported that the combination of clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes.8 Furthermore, the risk of moderate-to-severe bleeding was increased.8 In a retrospective analysis of the CHARISMA trial, dual antiplatelet therapy with clopidogrel and aspirin in the primary prevention subgroup of patients was associated with an increase in cardiovascular death.9 The cause of this apparent harm has not been elucidated.9

Clopidogrel Response Variability

P2Y12 antagonist therapy can be monitored in patients by a number of methods (Table 210). Arguably the most specific method currently available for the monitoring of P2Y12 antagonist therapy in patients is the flow cytometric measurement of the phosphorylation of vasodilator stimulated phosphoprotein (VASP, BioCytex). Under the conditions of this assay, which uses a combination of ADP and prostaglandin (PG) E1 (Figure 1B), the phosphorylation of VASP (identified by a monoclonal antibody specific for the phosphorylated form of VASP) is directly proportional to the degree of inhibition of the P2Y12 receptor.11 The major advantage of the VASP assay is its direct dependence on the target of clopidogrel, P2Y12 (Figure 1B).


View this table:
[in this window]
[in a new window]

  		Table 2. Platelet Function Tests for Measuring Response to Clopidogrel

Alternatively, P2Y12 antagonist therapy can be monitored by ex vivo stimulation of the platelets with ADP and then reading out one of a number of end points including platelet aggregation (Table 2). Comparison of the VASP assay with ADP-induced turbidometric platelet aggregation demonstrated that the measured level of thienopyridine-induced inhibition is higher in the VASP assay, presumably because platelet aggregation can still occur via ADP stimulation of P2Y1 in the presence of a thienopyridine.12 The VerifyNow P2Y12 Assay (Accumetrics) has a number of advantages, including (1) like the VASP phosphorylation assay, it uses a combination of ADP and PGE1 and (2) it is a point-of-care device that can produce a rapid readout at the patient’s bedside.

Monitoring of clopidogrel by each of the assays listed in Table 2 reveals interpatient response variability.10,12–14 Furthermore, there is evidence that a poor response in such in vitro assays (ie, clopidogrel hyporesponsiveness or "resistance") predict a poor clinical response to clopidogrel—as evidenced by major adverse clinical events (MACE).10 Thus, clopidogrel hyporesponsiveness, defined by ADP-induced turbidometric platelet aggregation,15–20 VASP phosphorylation,16,21 or the TEG PlateletMapping System,19 has been reported to be associated with post-PCI MACE. However, it is important to emphasize that the number of adverse clinical events was low in all these studies.15–21

The possible mechanisms of clopidogrel response variability or "resistance" are shown in Table 3. Noncompliance is an important issue. If a patient is not taking clopidogrel or only taking it intermittently, the patient will appear by platelet function testing to be hyporesponsive or "resistant" to clopidogrel. In addition to clopidogrel, many other drugs are metabolized through cytochrome P450 in the liver—and therefore may interfere with the effectiveness of clopidogrel. One reported example of this phenomenon is atorvastatin,22 but large clinical studies have not confirmed that this is a clinically-relevant interaction.23,24 Single nucleotide polymorphisms (SNPs), eg, the IVS10+12G>A SNP of the CYP3A4 gene, may modulate platelet activation in patients treated with clopidogrel and therefore contribute to clopidogrel response variability.25 Alternatively, is clopidogrel response variability or "resistance" really (1) treatment failure unrelated to a lack of clopidogrel effectiveness (because arterial thrombosis is multifactorial and not solely dependent on P2Y12-dependent signaling) or (2) platelet response variability? With regard to the latter possibility, there is evidence in both normal subjects and patients that preclopidogrel response to ADP predicts postclopidogrel response to ADP, as determined by a number of different platelet function assays (turbidometric platelet aggregation, platelet surface P-selectin, platelet surface activated integrin {alpha}IIbβ3, monocyte-platelet aggregates, neutrophil-platelet aggregates).26–30 These data suggest that the variability lies, at least in part, within the platelet response to ADP rather than the platelet response to clopidogrel.


View this table:
[in this window]
[in a new window]

  		Table 3. Possible Mechanisms of Clopidogrel Response Variability or "Resistance"

How Should a Patient With Clopidogrel Hyporesponsiveness or "Resistance" be Managed?

Noncompliance is certainly an important consideration to be addressed. Interference by other drugs metabolized via cytochrome P450 may be a consideration,22 but the evidence for a clinically-important effect is not strong.23,24 Because no published studies address the clinical effectiveness of altering therapy based on a laboratory finding of clopidogrel resistance, the correct treatment, if any, of clopidogrel hyporesponsiveness or "resistance" remains unknown.10 Nevertheless, the current American College of Cardiology/American Heart Association PCI guidelines have a Class IIb recommendation based on level C evidence that, in patients in whom subacute stent thrombosis may be catastrophic or lethal, platelet aggregation studies may be considered and the maintenance dose of clopidogrel increased from 75 mg to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated.31 Although there are as yet no published clinical outcomes studies to support this approach, a 150 mg daily maintenance dose of clopidogrel has recently been shown to provide more effective platelet inhibition (as determined by ADP-induced turbidometric platelet aggregation, the VerifyNow P2Y12 Assay, and VASP phosphorylation) than the current standard maintenance dose of 75 mg daily.32,33 However, even at the higher maintenance dose of 150 mg daily there is still a large variability in the degree of platelet inhibition,32,33 and the possible increased hemorrhagic risks of this approach have not been studied. In the PCI setting, a loading dose of 600 mg of clopidogrel, rather than the previous standard loading dose of 300 mg, has been widely adopted based on small studies showing more rapid and profound inhibition of ADP-induced turbidometric platelet aggregation, reduced myonecrosis markers, and reduced MACE at 30 days.34–36 An increase in the clopidogrel loading dose from 600 mg to 900 mg may36 or may not35 result in an additional significant increase in inhibition of platelet function. However, even at these higher clopidogrel loading doses of 600 mg and 900 mg, there is still large variability in the degree of platelet inhibition.34–37 The ongoing CURRENT/OASIS 7 (Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS 7) trial (www.clinicaltrials.gov/ct/show/NCT00335452) may help clarify the optimal loading and maintenance doses of clopidogrel.

Novel P2Y12 Antagonists

Continuing interrelated challenges with regard to clopidogrel treatment include (1) the still significant incidence of stent thrombosis in patients treated with clopidogrel and aspirin,38 (2) the phenomenon of clopidogrel hyporesponsiveness or "resistance",10 and (3) the relatively slow onset of action of clopidogrel,2 with little antithrombotic benefit from a 300-mg loading dose given less than 12 hours before PCI.39 A number of novel P2Y12 antagonists (Table 1) are therefore under investigation to determine whether they can result in better or more rapid antithrombotic effects than clopidogrel, without an unacceptable increase in hemorrhagic (or other) side effects.

Prasugrel (Eli Lilly & Co./Daiichi Sankyo) is an investigational orally-administered thienopyridine prodrug that, like clopidogrel, is metabolized via cytochrome P450 in the liver (Figure 2A).40,41 The active metabolite of prasugrel irreversibly inhibits the platelet P2Y12 receptor to a similar extent to the active metabolite of clopidogrel.42 However, there is much more efficient in vivo generation of the active metabolite of prasugrel than of the active metabolite of clopidogrel.41 As a result, a prasugrel 60 mg loading dose results in a much more rapid, potent, and consistent inhibition of platelet function than the standard clopidogrel loading dose of 300 mg43,44 and the more recently adopted clopidogrel loading dose of 600 mg.37 Furthermore, a maintenance dose of prasugrel 10 mg daily results in a more potent and consistent inhibition of platelet function than the standard clopidogrel maintenance dose of 75 mg daily.37 Animal studies have shown that prasugrel has a much more potent antithrombotic effect than clopidogrel,42 and phase 2 studies of prasugrel in humans showed no significant increase in bleeding compared with clopidogrel.45

The 13 608-patient phase 3 trial, TRITON-TIMI 38 (TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel), was recently completed.46 This trial demonstrated that in patients with acute coronary syndromes with scheduled PCI, prasugrel (60 mg loading dose and a 10 mg daily maintenance dose), as compared with approved doses of clopidogrel (300 mg loading dose and a 75 mg daily maintenance dose), was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel versus clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). There were also significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel versus 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% versus 2.5%; P<0.001), and stent thrombosis (2.4% versus 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P=0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% versus 0.9%; P=0.01), including nonfatal bleeding (1.1% versus 0.9%; hazard ratio, 1.25; P=0.23) and fatal bleeding (0.4% versus 0.1%; P=0.002). A posthoc subgroup exploratory analysis of the data identified 3 subgroups of interest that had less clinical efficacy and greater absolute levels of bleeding than the overall cohort, resulting in less net clinical benefit or in clinical harm. These subgroups were: patients with a history of stroke or transient ischemic attack, age ≥75 years, and body weight <60 kg.46

The PRINCIPLE-TIMI 44 trial demonstrated that, among patients undergoing cardiac catheterization with planned PCI, a 60 mg prasugrel loading dose resulted in greater platelet inhibition than the now widely used higher clopidogrel loading dose of 600 mg.47 Maintenance therapy with prasugrel 10 mg daily resulted in a greater antiplatelet effect than the high clopidogrel maintenance dose of 150 mg daily. This trial was not powered for clinical outcomes.47

AZD6140 (AstraZeneca) is another investigational P2Y12 antagonist (Table 1). To increase oral bioavailability, the structure of AZD6140 was modified from AR-C109318XX (Figure 2B).48 Unlike ticlopidine, clopidogrel, and prasugrel, AZD6140 is (1) not a thienopyridine but an ATP analog (Figure 2B), (2) a direct P2Y12 antagonist (ie, no metabolism of a prodrug is required), and (3) a reversible P2Y12 antagonist.48 Like prasugrel, AZD6140: (1) results in a more rapid onset of action and greater degree of platelet inhibition than clopidogrel, (2) maintenance therapy results in more potent inhibition of platelet function than the standard clopidogrel maintenance dose of 75 mg daily, (3) showed no significant increase in bleeding compared with clopidogrel in phase 2 studies.48–50 In these phase 2 studies, dyspnea was greater, in an apparently dose-dependent manner, in patients on AZD6140 compared with patients on clopidogrel. AZD6140 is given orally twice a day and is currently in a phase 3 trial: PLATO (PLATelet inhibition and patient Outcomes).

Cangrelor (The Medicines Company) is an investigational, direct-acting, reversible P2Y12 antagonist (Table 1, Figure 2B). Unlike the above-described orally-administered P2Y12 antagonists (ticlopidine, clopidogrel, prasugrel, and AZD6140), cangrelor is administered intravenously—which, together with the rapid reversal of its effects after the end of the infusion, may be potentially advantageous in the PCI setting. Like prasugrel and AZD6140, cangrelor results in a more rapid onset of action and greater degree of platelet inhibition than clopidogrel, and showed no significant increase in bleeding compared with clopidogrel in phase 2 studies.51,52 Cangrelor is currently in phase 3 trials: CHAMPION-PCI and CHAMPION-PLATFORM.

PRT060128 (Portola) is an investigational, direct-acting, reversible P2Y12 antagonist with a novel structure.53 PRT060128, which can potentially be administered orally or intravenously, has completed phase 1 clinical studies.

Conclusions

The P2Y12 antagonist clopidogrel has a well-established role as an antithrombotic agent in the settings of PCI and acute coronary syndromes. However, several challenges remain, including the relatively slow onset of action of clopidogrel and the phenomenon of clopidogrel response variability or "resistance". Novel P2Y12 antagonists, including prasugrel, AZD6140, and cangrelor have a faster onset of action, as well as more potent, and less variable, inhibition of platelet function ex vivo. Whether this promise will be translated into clinical benefit for patients will be determined by the results of phase 3 clinical trials.

Acknowledgments

Disclosures

Dr. Michelson has received research funding from Accumetrics, Arena Pharmaceuticals, Dade Behring, GL Synthesis, Lilly/Daiichi Sankyo, McNeil Consumer Healthcare, and Sanofi-Aventis/Bristol-Myers Squibb, and has received consulting fees from or served on paid advisory boards for Lilly/Daiichi Sankyo, McNeil Consumer Healthcare, and Sanofi-Aventis/Bristol Myers Squibb.

Footnotes

Original received December 5, 2007; final version accepted December 21, 2007.

References

  1. Cattaneo M. The platelet P2 receptors. In: Michelson AD, ed. Platelets. 2nd ed. San Diego: Elsevier/Academic Press 2007; 201–213.
  2. Cattaneo M. ADP receptor antagonists. In: Michelson AD, ed. Platelets. 2nd ed. San Diego: Elsevier/Academic Press 2007; 1127–1144.
  3. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345: 494–502.[Abstract/Free Full Text]
  4. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK; Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE) Investigators. Effects of pretreatment 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][Medline] [Order article via Infotrieve]
  5. Steinhubl SR, Berger PB, Mann JT III, Fry ET, DeLago A, Wilmer C, Topol EJ; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002; 288: 2411–2420.[Abstract/Free Full Text]
  6. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005; 366: 1607–1621.[CrossRef][Medline] [Order article via Infotrieve]
  7. Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E; CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005; 352: 1179–1189.[Abstract/Free Full Text]
  8. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006; 354: 1706–1717.[Abstract/Free Full Text]
  9. Wang TH, Bhatt DL, Fox KA, Steinhubl SR, Brennan DM, Hacke W, Mak KH, Pearson TA, Boden WE, Steg PG, Flather MD, Montalescot G, Topol EJ; CHARISMA Investigators. An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial. Eur Heart J. In press.
  10. Michelson AD, Frelinger AL, Furman MI. Resistance to antiplatelet drugs. Eur Heart J Suppl. 2006; 8 (suppl G): G53–G58.[Abstract/Free Full Text]
  11. Schwarz UR, Geiger J, Walter U, Eigenthaler M. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets–definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost. 1999; 82: 1145–1152.[Medline] [Order article via Infotrieve]
  12. Aleil B, Ravanat C, Cazenave JP, Rochoux G, Heitz A, Gachet C. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost. 2005; 3: 85–92.[CrossRef][Medline] [Order article via Infotrieve]
  13. Michelson AD. Platelet function testing in cardiovascular diseases. Circulation. 2004; 110: e489–e493.[Free Full Text]
  14. 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]
  15. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. 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]
  16. Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ, Tantry US. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol. 2005; 46: 1827–1832.[Abstract/Free Full Text]
  17. Cuisset T, Frere C, Quilici J, Barbou F, Morange PE, Hovasse T, Bonnet JL, Alessi MC. 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][Medline] [Order article via Infotrieve]
  18. Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM, Ferenc M, Gick M, Caputo A, Büttner HJ, Neumann FJ. 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]
  19. Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA. 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. 2007; 49: 657–666.[Abstract/Free Full Text]
  20. Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R, Moschi G, Gori AM, Abbate R, Antoniucci D. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol. 2007; 49: 2312–2317.[Abstract/Free Full Text]
  21. Bonello L, Paganelli F, Arpin-Bornet M, Auquier P, Sampol J, Dignat-George F, Barragan P, Camoin-Jau L. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost. 2007; 5: 1630–1636.[CrossRef][Medline] [Order article via Infotrieve]
  22. Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DG, Guyer KE, Tait AR, Bates ER. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation. 2004; 109: 166–171.[Abstract/Free Full Text]
  23. Saw J, Steinhubl SR, Berger PB, Kereiakes DJ, Serebruany VL, Brennan D, Topol EJ; Clopidogrel for the Reduction of Events During Observation Investigators. Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation. 2003; 108: 921–924.[Abstract/Free Full Text]
  24. Saw J, Brennan DM, Steinhubl SR, Bhatt DL, Mak KH, Fox K, Topol EJ; CHARISMA Investigators. Lack of evidence of a clopidogrel-statin interaction in the CHARISMA trial. J Am Coll Cardiol. 2007; 50: 291–295.[Abstract/Free Full Text]
  25. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramírez C, Cavallari U, Trabetti E, Sabaté M, Hernández R, Moreno R, Escaned J, Alfonso F, Bañuelos C, Costa MA, Bass TA, Pignatti PF, Macaya C. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol. 2006; 26: 1895–1900.[CrossRef][Medline] [Order article via Infotrieve]
  26. Michelson AD, Linden MD, Furman MI, Li Y, Barnard MR, Fox ML, Lau WC, McLaughlin TJ, Frelinger AL. Evidence that pre-existent variability in platelet response to ADP accounts for ‘clopidogrel resistance’. J Thromb Haemost. 2007; 5: 75–81.[CrossRef][Medline] [Order article via Infotrieve]
  27. Angiolillo DJ, Fernández-Ortiz A, Bernardo E, Ramírez C, Barrera-Ramirez C, Sabaté M, Hernández R, Moreno R, Escaned J, Alfonso F, Bañuelos C, Costa MA, Bass TA, Macaya C. Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thromb Res. 2005; 115: 101–108.[CrossRef][Medline] [Order article via Infotrieve]
  28. Angiolillo DJ, Fernández-Ortiz A, Bernardo E, Ramírez C, Sabaté M, Bañuelos C, Hernández-Antolín R, Escaned J, Moreno R, Alfonso F, Macaya C. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J. 2004; 25: 1903–1910.[Abstract/Free Full Text]
  29. Samara WM, Bliden KP, Tantry US, Gurbel PA. The difference between clopidogrel responsiveness and posttreatment platelet reactivity. Thromb Res. 2005; 115: 89–94.[CrossRef][Medline] [Order article via Infotrieve]
  30. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003; 107: 2908–2913.[Abstract/Free Full Text]
  31. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kern MJ, King SB III, Morrison DA, O’Neill WW, Schaff HV, Whitlow PL, Williams DO, Antman EM, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention–summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). Circulation. 2006; 113: 156–175.[Free Full Text]
  32. von Beckerath N, Kastrati A, Wieczorek A, Pogatsa-Murray G, Sibbing D, Graf I, Schömig A. 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. 2007; 28: 1814–1819.[Abstract/Free Full Text]
  33. Angiolillo DJ, Shoemaker SB, Desai B, Yuan H, Charlton RK, Bernardo E, Zenni MM, Guzman LA, Bass TA, Costa MA. 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. 2007; 115: 708–716.[Abstract/Free Full Text]
  34. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation. 2005; 111: 2099–2106.[Abstract/Free Full Text]
  35. von Beckerath N, Taubert D, Pogatsa-Murray G, Schömig E, Kastrati A, Schömig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation. 2005; 112: 2946–2950.[Abstract/Free Full Text]
  36. Montalescot G, Sideris G, Meuleman C, Bal-dit-Sollier C, Lellouche N, Steg PG, Slama M, Milleron O, Collet JP, Henry P, Beygui F, Drouet L; ALBION Trial Investigators. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol. 2006; 48: 931–938.[Abstract/Free Full Text]
  37. Payne CD, Li YG, Small DS, Ernest CS, Farid NA, Jakubowski JA, Brandt JT, Salazar D, Winters KJ. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol. In press.
  38. Holmes DR Jr, Kereiakes DJ, Laskey WK, Colombo A, Ellis SG, Henry TD, Popma JJ, Serruys PW, Kimura T, Williams DO, Windecker S, Krucoff MW. Thrombosis and drug-eluting stents: an objective appraisal. J Am Coll Cardiol. 2007; 50: 109–118.[Abstract/Free Full Text]
  39. Steinhubl SR, Berger PB, Brennan DM, Topol EJ; CREDO Investigators. Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol. 2006; 47: 939–943.[Abstract/Free Full Text]
  40. Asai F, Jakubowski JA, Naganuma H, Brandt JT, Matsushima N, Hirota T, Freestone S, Winters KJ. Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: a single ascending dose study in healthy humans. Platelets. 2006; 17: 209–217.[CrossRef][Medline] [Order article via Infotrieve]
  41. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M, Niitsu Y, Asai F. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite. J Thromb Haemost. 2007; 5: 1545–1551.[CrossRef][Medline] [Order article via Infotrieve]
  42. Niitsu Y, Jakubowski JA, Sugidachi A, Asai F. Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb Hemost. 2005; 31: 184–194.[CrossRef][Medline] [Order article via Infotrieve]
  43. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, Jakubowski JA, Naganuma H, Winters KJ. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. 2007; 153: 66.
  44. Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, Naganuma H, Siegbahn A, Wallentin L. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J. 2006; 27: 1166–1173.[Abstract/Free Full Text]
  45. Wiviott SD, Antman EM, Winters KJ, Weerakkody G, Murphy SA, Behounek BD, Carney RJ, Lazzam C, McKay RG, McCabe CH, Braunwald E; JUMBO-TIMI 26 Investigators. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation. 2005; 111: 3366–3373.[Abstract/Free Full Text]
  46. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann F-J, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007; 357: 2001–2015.[Abstract/Free Full Text]
  47. Wiviott SD, Trenk D, Frelinger AL, O’Donaghue M, Neumann F-J, Michelson AD, Angiolillo DJ, Hod H, Montalescot G, Miller DL, Jakubowski JA, Cairns R, Murphy SA, McCabe CH, Antman EM, Braunwald E. 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. 2007; 116: 2923–2932.[Abstract/Free Full Text]
  48. van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost. 2005; 31: 195–204.[CrossRef][Medline] [Order article via Infotrieve]
  49. Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006; 27: 1038–1047.[Abstract/Free Full Text]
  50. Cannon CP, Husted S, Storey RF, Harrington RA, Watkins C, Hill S. The DISPERSE2 trial: safety, tolerability and preliminary efficacy of AZD6140, the first oral reversible ADP receptor antagonist compared with clopidogrel in patients with non-ST elevation acute coronary syndrome. Presented at: 78th American Heart Association Scientific Sessions; November 13–16, 2005; Dallas, TX. Abstract 2906.
  51. Greenbaum AB, Grines CL, Bittl JA, Becker RC, Kereiakes DJ, Gilchrist IC, Clegg J, Stankowski JE, Grogan DR, Harrington RA, Emanuelsson H, Weaver WD. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J. 2006; 151: 689.[Medline] [Order article via Infotrieve]
  52. Storey RF, Oldroyd KG, Wilcox RG. Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes. Thromb Haemost. 2001; 85: 401–407.[Medline] [Order article via Infotrieve]
  53. Gretler DD, Conley PB, Andre P, Jurek M, Pandey A, Ronanko K, Leese PT, Hutchaleelaha A, Phillips DR. "First in human" experience with PRT060128, a new direct-acting, reversible, P2Y12 inhibitor for IV and oral use. J Am Coll Cardiol. 2007; 49 [9 (suppl 2)]: 326A.




This Article
Free upon publication Free Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
28/3/s33    most recent
ATVBAHA.107.160689v1
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
Google Scholar
Right arrow Articles by Michelson, A. D.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Michelson, A. D.

ATVB Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2008 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.