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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Variability of response to antiplatelet therapy

Robert F. Storey*

Cardiovascular Research Unit, University of Sheffield, School of Medicine and Biomedical Sciences, Beech Hill Road, Sheffield S10 2RX, UK

* Corresponding author. Tel: +44 114 271 3964; fax: +44 114 271 1863.E-mail address: r.f.storey{at}sheffield.ac.uk


   Abstract
Top
 Abstract
Introduction
 Aspirin resistance
 Response to drugs that...
 Conclusion
 Funding
 References
 
The occurrence of ischaemic events despite aspirin therapy has been called ‘aspirin resistance’ but there is little evidence to support that concept. It has not been established that patients with low levels of response to aspirin treatment on platelet function tests are at increased risk for ischaemic events, and there is no evidence that changing therapy based on test results has any benefit. A subset of patients does appear to be resistant to clopidogrel, which apparently increases their risk for adverse cardiovascular outcomes. Increasing the dose of clopidogrel may improve outcomes. Resistance to newer antiplatelet agents such as prasugrel, cangrelor, and AZD6140 has not been described to date. Low response to glycoprotein (GP) IIb/IIIa inhibitors has been associated with increased incidence of myocardial infarction. Whether platelet function testing should be routinely performed in patients receiving these agents has not been fully assessed.

Key Words: Platelets • Drug resistance • Aspirin • Clopidogrel • Thienopyridines • GP IIb/IIIa inhibitors


   Introduction
Top
 Abstract
 Introduction
Aspirin resistance
 Response to drugs that...
 Conclusion
 Funding
 References
 
Antiplatelet agents are a mainstay of the treatment of patients with acute coronary syndromes (ACS) because they have been shown to reduce the risk of death, myocardial infarction (MI), and urgent revascularization. Some patients, however, experience adverse cardiac events despite treatment with single or dual antiplatelet therapy. Whether such patients are resistant to the effects of these agents or experience cardiac events for other reasons has been the subject of debate. The evidence for a clinical entity known as ‘aspirin resistance’ is weak, it has not been conclusively demonstrated to cause ischaemic events, and there is no known treatment for it. With other agents, by contrast, it is possible to identify a subset of patients with low response or non-response whose risk for ischaemic events is elevated and for whom dosage adjustment or other measures may be helpful.


   Aspirin resistance
Top
 Abstract
 Introduction
 Aspirin resistance
Response to drugs that...
 Conclusion
 Funding
 References
 
Aspirin inhibits platelet aggregation by acetylating cyclo-oxygenase-1 (COX-1), which blocks the production of thromboxane A2 (TxA2).1 Inhibition of COX-1 by aspirin is rapid and irreversible, persisting for the 7- to 10-day lifetime of the platelet.1

In high-risk patients with atherosclerosis, chronic antiplatelet therapy reduces the risk of an ischaemic event by ~25%; nevertheless, >10% of patients on aspirin therapy have a recurrent event.2 This phenomenon has been called ‘aspirin resistance,’ but the term is problematic. There is little evidence that aspirin does not act as expected in large numbers of people, and there is no evidence that changing therapy in response to a finding of ‘aspirin resistance’ changes clinical outcomes.

Definitions of aspirin resistance
Aspirin resistance has been defined in various ways. In addition to referring to the occurrence of ischaemic events despite aspirin therapy (‘clinical’ aspirin resistance), the term has been used to describe the failure of aspirin to prolong bleeding time, inhibit thromboxane biosynthesis, or produce a particular result on a platelet function test (‘biochemical’ or ‘laboratory’ aspirin resistance).3,4 To say that a patient has clinical aspirin resistance is to imply that, if the aspirin resistance were not present, the ischaemic event would not have occurred. Although aspirin reduces the production of TxA2, it may fail to inhibit platelet aggregation because platelets continue to respond strongly to other agonists; indeed, the role of TxA2 in the responses to numerous platelet agonists is limited when platelets are studied at physiological levels of divalent cations rather than in the setting of lowered divalent cation levels induced by citrate anticoagulation.5–9 The artefactual enhancement of TxA2 secretion by citrate anticoagulation, which has been used as the standard anticoagulant for platelet function tests, may have inappropriately raised expectations about the therapeutic potential of aspirin. TxA2-induced platelet aggregation is only one of many factors leading to thrombus formation, which is the most common, but not the only, mechanism leading to ischaemic events.10

Biochemical aspirin resistance can at least be identified before an ischaemic event occurs. However, there is no standard for diagnosing biochemical aspirin resistance, which has been reported in incidences ranging from ~1–60% depending on the specificity of the assay used, the definition of aspirin resistance, and the population studied.11–14 Also, it is not clear that the results of platelet function tests detecting aspirin resistance can be used to predict ischaemic events or guide therapy.1 However, since COX-1, and the consequent release of TxA2, is the target of aspirin, there is a growing body of opinion that specific measurement of platelet thromboxane release is the appropriate method for determining aspirin response in compliant subjects.12,15 Arachidonic acid (AA)-induced platelet aggregation assessed by light transmittance aggregometry (LTA) is a reasonable surrogate for thromboxane release.14

Evidence of aspirin resistance
There is some evidence that patients taking aspirin who have high levels of platelet aggregation as determined by platelet function tests are at increased risk of ischaemic events. Patients with intermittent claudication taking aspirin who had high levels of platelet aggregation were found to be at higher risk of reocclusion following balloon angioplasty.16 A case–control study found that urinary 11-dehydrothromboxane B2 levels in patients taking aspirin predicted the occurrence of MI, stroke, or cardiovascular death.17 Myonecrosis was more common in aspirin-treated patients undergoing elective percutaneous coronary intervention (PCI) who had high measures of platelet function than in those who did not.18 Patients with a history of stroke who had a recurrent event while taking aspirin showed less inhibition of platelet aggregation (IPA) than patients who did not have a recurrent event.19 Finally, 24% of stable cardiovascular patients with high levels of platelet activity despite aspirin treatment experienced death, MI, or cerebrovascular accident compared with 10% of similar patients with low levels of platelet activity (P = 0.03).20

All of these studies were small and each used a different assay to measure aspirin resistance. None of these methods has been established as standard, and in at least one study the aspirin dosage was lower than the minimum recommended by the assay's manufacturer.19,21 These trials did not evaluate whether changing therapy in response to measures of aspirin resistance changed clinical outcomes.

Causes of variability in response to aspirin
Non-compliance with drug therapy is a common problem. The prevalence and effects of non-compliance with an aspirin regimen were studied in patients with a history of MI who were tested with AA-stimulated LTA. Platelet aggregation was determined during usual care, after 7 days without aspirin, and 2 h after observed ingestion of aspirin. At the first time point, platelet aggregation was not inhibited in 17 of 190 patients; however, when patients were tested after a confirmed aspirin dose, only one of the patients still showed no inhibition of aggregation, and that patient admitted to having taken a non-steroidal anti-inflammatory drug 12 h before being tested.14

Aspirin formulations also affect the extent of IPA. In one study, platelet aggregation measured with optical aggregometry and serum thromboxane B2 showed that enteric-coated aspirin was less effective than plain aspirin, which was not associated with any cases of suboptimal response.22

Drug interactions, accelerated platelet turnover, single nucleotide polymorphisms, and platelet hyper-reactivity have also been proposed as explanations for the failure of aspirin to produce the desired clinical effects.21

If aspirin resistance exists, it appears to be rare. A study that included both healthy subjects and patients with occlusive coronary disease used AA-induced LTA and thrombelastography platelet mapping to identify aspirin resistance and found that only one of 223 individuals was aspirin resistant.13 Assessment with a serum thromboxane B2 assay and platelet aggregation tests of 96 healthy subjects who had received 100 mg/day of aspirin for 1 week also found only one subject who appeared to be aspirin resistant, although it was uncertain whether poor compliance played a role.12

Failure, not resistance
Given the problems surrounding the concept of ‘aspirin resistance,’ it is preferable to refer to the occurrence of ischaemic events despite aspirin therapy as ‘treatment failure’.23 Because there is no standard method of testing patients for hypo-responsiveness to aspirin and no evidence that changing therapy will overcome hypo-responsiveness, such testing is not recommended.24,25 Increasing the dosage of aspirin is unlikely to overcome treatment failure. There is some evidence that aspirin doses as low as 40 mg/day are as effective as higher doses at inhibiting platelet aggregation, and that doses of 75–150 mg/day may be more effective at preventing ischaemic events than doses up to 10 times as high.26 Thus, the appropriate response to aspirin treatment failure is unknown.


   Response to drugs that inhibit P2Y12 receptor activation
Top
 Abstract
 Introduction
 Aspirin resistance
 Response to drugs that...
Conclusion
 Funding
 References
 
Thienopyridines
Ticlopidine and clopidogrel (Figure 127–29) selectively inhibit adenosine diphosphate (ADP)-induced platelet aggregation but have no effect on AA metabolism (Figure 230). The effects of these agents depend on production of active metabolites in the liver.10 Both drugs induce irreversible alterations of the P2Y12 receptor.25 Use of ticlopidine has been associated with sometimes life-threatening neutropenia, and it has largely been replaced in clinical practice by clopidogrel.3,10,31 In contrast to aspirin resistance, there is evidence that clopidogrel resistance is verifiable and has predictable effects on clinical outcomes.


Figure 1
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  		Figure 1 Chemical structures of P2Y12 inhibitors. Used with permission from Siller-Matula et al.,27 Fugate and Cudd,28 and Tantry et al.29

 

Figure 2
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  		Figure 2 Overview of platelet activation mechanisms and site of action of antiplatelet drugs. Adapted with permission from Storey.30

 
Clopidogrel
Several hours after administration, plasma levels of the active clopidogrel metabolite vary widely among patients, as does the extent of ADP-induced platelet aggregation.10 High levels of platelet aggregation after clopidogrel administration correlate with low activity of hepatic cytochrome P450 CYP3A4, which contributes to production of the active metabolite.32 Low response or non-response to clopidogrel may occur in up to 50% of coronary patients32 and is more likely to be found among those with high pre-treatment platelet reactivity.33

Resistance to clopidogrel appears to be associated with increased risk of thrombotic events. In a trial of 105 patients undergoing PCI with stent placement, among poor responders (i.e. those who had <10% reduction in platelet aggregation despite chronic clopidogrel treatment), two of five patients experienced stent thrombosis within a week of stent placement.34 Similarly, in 60 patients with acute MI undergoing PCI with stenting, the percentage reduction of ADP-induced platelet aggregation after clopidogrel administration was determined. Within 6 months of stenting, 40% of patients with the lowest response to clopidogrel experienced recurrent cardiovascular events, whereas only one patient with intermediate response and none with good response did so.35

A retrospective study of 20 patients treated with clopidogrel who received stents and experienced stent thrombosis found 60% of patients with stent thrombosis had high platelet reactivity.36 In a prospective trial, platelet activity was analysed after clopidogrel administration in 106 patients with non-ST-segment elevation (NSTE)-ACS just before they underwent PCI with stenting. During 30-day follow-up, the recurrence of cardiovascular events was significantly associated with low response to clopidogrel.37

The cause of clopidogrel resistance is not known. Proposed mechanisms include reduced bioavailability resulting from poor absorption, low cytochrome P450 activity, drug interactions, non-compliance, and accelerated platelet turnover.38 Polymorphisms of the P2Y12 receptor have been proposed as a mechanism of clopidogrel resistance38; however, receptor polymorphism has been shown not to be a significant factor.39

The wide variability in platelet response to ADP that is seen among persons prior to taking clopidogrel explains some of the variability in the effects of this agent.33 It is reasonable to expect that individuals with high pre-treatment platelet reactivity would continue to have relatively higher reactivity after administration of the drug for any given level of receptor blockade, unless receptor blockade is high enough to counteract the enhanced reactivity.

Guidelines differ regarding platelet function testing in patients taking clopidogrel.3,40 Tests are available that provide reproducible results,38 but none has been established as the standard nor as suitable for guiding treatment decisions for individual patients.

Several clinical trials have compared various maintenance and loading doses of clopidogrel to determine whether higher doses can overcome resistance. In a study of maintenance dosing after PCI, 60 patients were randomized to receive clopidogrel 75 or 150 mg/day. At 30 days, platelet aggregation was significantly lower in the group treated with the higher dose.41 In studies of loading doses of clopidogrel in patients undergoing PCI, better results on platelet aggregation tests, fewer non-responders, and a faster onset of action were obtained with 600 mg than with 300 mg.42–44

It is unclear whether a 900-mg loading dose confers additional benefits over a 600-mg loading dose. One trial found no additional IPA with a 900-mg dose.45 In the ALBION trial, patients with NSTE-ACS were randomized to receive clopidogrel loading doses of 300, 600, or 900 mg. Both the 600- and 900-mg loading doses produced a more rapid onset of action, greater IPA, and a lower percentage of non-responders than the 300-mg loading dose. The 900-mg dose was superior to the 600-mg dose, but not significantly so.46

The clinical benefits of a higher loading dose of clopidogrel were investigated in the ARMYDA-2 trial. A total of 255 patients with stable angina pectoris or NSTE-ACS with an indication for coronary angiography were randomized to receive loading doses of 300 or 600 mg of clopidogrel and followed for 30 days. The primary endpoint of death, MI, or target vessel revascularization occurred in 4% of the high-dose group and 12% of the low-dose group (P = 0.041). The benefit for the high-dose group consisted entirely of a reduction in MI.47

From these studies, it appears that higher loading and maintenance doses of clopidogrel provide better IPA than standard doses, and that this may result in better clinical outcomes. Large, randomized clinical trials are needed to confirm these findings. Until they are conducted, clinicians must use their own judgement as to whether platelet aggregation testing should be performed for patients on clopidogrel therapy and whether higher doses should be prescribed.

Prasugrel
Prasugrel (formerly CS-747, Figure 127–29) is a new thienopyridine antiplatelet agent that, like ticlopidine and clopidogrel, is converted to an active metabolite in the liver and blocks the P2Y12 receptor (Figure 230).48 It is ~10 times more potent than clopidogrel,49 with a faster onset and a long duration of action.48

Prasugrel may produce less variability of response than clopidogrel. The two agents were compared in an open-label crossover study that randomized 68 healthy subjects to receive a single dose of prasugrel 60 mg or clopidogrel 300 mg. Platelet aggregation was measured before drug administration and over the subsequent 24 h. IPA was higher with prasugrel than with clopidogrel from 30 min through 24 h (P ≤ 0.01). The median time to achieve ≥20% IPA in response to 20 µmol/L ADP was 30 min with prasugrel and 90 min with clopidogrel (P < 0.001). The response to prasugrel was more consistent than the response to clopidogrel. At 24 h, the IPA measured by 20 µmol/L ADP was ≤20% in 27 of 64 subjects in response to clopidogrel but ≥20% in all subjects in response to prasugrel. In the 27 subjects with a poor response to clopidogrel, the response to prasugrel was similar to that seen in subjects who had a good response to clopidogrel.50

In another dose–response study, 99 patients with coronary artery disease were randomized to one of five treatment regimens, consisting of a single loading dose followed by a maintenance dose for 27 days: prasugrel 40/5 mg, prasugrel 40/7.5 mg, prasugrel 60/10 mg, prasugrel 60/15 mg, or clopidogrel 300/75 mg. At 4 h after administration, both prasugrel loading doses produced greater IPA than the clopidogrel loading dose. On days 7 and 28 during maintenance dosing, both the prasugrel 10- and 15-mg doses produced significantly greater IPA than the clopidogrel 75-mg dose. Fewer patients failed to respond to prasugrel. On day 1, 52% of patients taking clopidogrel and 3% of patients taking each of the prasugrel loading doses were classified as non-responders (P = 0.00002 for both). On day 28, 45% of patients taking clopidogrel and none of the patients taking 10 or 15 mg of prasugrel were classified as non-responders (P = 0.0007 for both).51

Non-thienopyridines
Cangrelor
Cangrelor (formerly AR-C69931MX, Figure 127–29) is a potent P2Y12 antagonist for intravenous administration (Figure 230). It has a rapid onset of action and reversible effects. It is a stable analogue of adenosine triphosphate, a natural antagonist at the P2Y12 receptor, and does not require conversion in the liver to an active metabolite.52 Cangrelor was administered to 33 patients with NSTE-ACS in a dose of 2 µg/kg/min for either 21 h or up to 69 h or in a dose of 4 µg/kg/min for up to 69 h. Mean IPA at 24 h was 96, 95, and 99% for the three dosages. All patients had >80% IPA; 100% IPA was achieved in 64%, 77%, and 86% of patients administered the three dosages. Recovery of platelet function occurred rapidly following cessation of cangrelor infusion, with 70% of patients recovering >60% of their baseline aggregation response after 1 h.53 The CHAMPION-PCI and CHAMPION-PLATFORM studies are currently assessing whether cangrelor is superior to clopidogrel or placebo, respectively, in patients undergoing PCI.

AZD6140
AZD6140 (Figure 127–29) is an oral reversible antagonist of P2Y12 receptors, the first of a new class of antiplatelet agents, the cyclopentyltriazolopyrimidines (Figure 230).54 In a study of patients with stable atherosclerotic disease, a dose of 100–400 mg/day produced greater mean IPA than clopidogrel 75 mg/day, with greater consistency of response, particularly at the higher doses.54 In the DISPERSE 2 trial of patients with NSTE-ACS, treatment with AZD6140 in a loading dose of 90–270 mg and a maintenance dose of 180–360 mg/day was associated with greater mean IPA and a trend towards lower rates of MI than treatment with clopidogrel.55,56 Administering AZD6140 to patients already treated with clopidogrel markedly suppressed platelet aggregation responses regardless of the effect of clopidogrel.57 The PLATO study is currently assessing whether this agent has clinical efficacy superior to clopidogrel in the management of ACS.

Glycoprotein IIb/IIIa inhibitors
The glycoprotein (GP) IIb/IIIa inhibitors abciximab, tirofiban, and eptifibatide are a diverse group of compounds for intravenous administration.3 The consistency of response to GP IIb/IIIa inhibitors and their effects on clinical outcomes were studied in a trial that included 485 patients undergoing PCI. Platelet function was measured before administration of one of the three agents and periodically over the following 24 h. A major adverse cardiac event occurred in 14.4% of patients in the lowest quartile of platelet inhibition at 10 min after drug administration but in only 6.4% of patients with higher levels of inhibition at that time (P = 0.006). The event rate was 25% in patients with <70% platelet inhibition at 8 h and 8.1% in those with ≥70% inhibition at that time (P = 0.009).58 This correlation between degree of platelet inhibition and adverse clinical outcomes suggests that platelet function testing may be useful for guiding the dosages of GP IIb/IIIa inhibitors in patients undergoing PCI, but further work is required to establish this.

Response to GP IIb/IIIa inhibitors appears to depend on the patient population studied. Abciximab has been shown to have greater effectiveness in patients with elevated troponin levels59 and not to be effective in patients with ACS not undergoing PCI.60

The causes of variability of response to GP IIb/IIIa inhibitors are unclear but may be related to their limited effect on micro-aggregation,61 lack of inhibition of platelet P-selectin expression and platelet leucocyte conjugate formation,62 or the possible pro-inflammatory effects of low concentrations of these agents.63


   Conclusion
Top
 Abstract
 Introduction
 Aspirin resistance
 Response to drugs that...
 Conclusion
Funding
 References
 
Many factors determine the response to antiplatelet agents, some related to the drug itself, some to the characteristics of individual patients. It has not been established that aspirin resistance is a common clinical occurrence, and the failure of aspirin to prevent ischaemic events is better termed ‘treatment failure’. By contrast, there is good evidence that patients vary considerably in their response to clopidogrel and GP IIb/IIIa inhibitors, and that patients with low response may be at increased risk for adverse cardiac events. It is not clear that platelet function testing should become part of therapy for patients treated with these drugs, nor which test is most reliable, but physicians should be aware that patients taking these agents may not benefit as hoped. Dosage adjustment and the use of newer antiplatelet agents with less variability in patient response may help overcome resistance to antiplatelet agents.


   Funding
Top
 Abstract
 Introduction
 Aspirin resistance
 Response to drugs that...
 Conclusion
 Funding
References
 
Sponsored by an educational grant from Daiichi Sankyo Europe GmbH and Eli Lilly and Company.


   Acknowledgments
 
Conflict of interest: Dr Storey has received research grants from the following companies: AstraZeneca, Eli Lilly, Daiichi Sankyo, Bristol-Myers Squibb, and Schering-Plough.

He has also worked as a consultant for AstraZeneca, Eli Lilly, The Medicines Company, and Shire.


   References
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 Abstract
 Introduction
 Aspirin resistance
 Response to drugs that...
 Conclusion
 Funding
 References
 

  1. Tran HA, Anand SS, Hankey GJ, Eikelboom JW. Aspirin resistance. Thromb Res (2007) 120:337–346.[CrossRef][Web of Science][Medline]
  2. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ (2002) 324:71–86.[Abstract/Free Full Text]
  3. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest (2004) 126(Suppl.):234–264.[CrossRef]
  4. Hankey GJ, Eikelboom JW. Aspirin resistance. BMJ (2004) 328:477–479.[Free Full Text]
  5. Storey RF, Sanderson HM, White AE, May JA, Cameron KE, Heptinstall S. The central role of the P2T receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol (2000) 110:925–934.[CrossRef][Web of Science][Medline]
  6. Mustard JF, Perry DW, Kinlough-Rathbone RL, Packham MA. Factors responsible for ADP-induced release reaction of human platelets. Am J Physiol (1975) 228:1757–1765.[Abstract/Free Full Text]
  7. Heptinstall S, Mulley GP. Adenosine diphosphate induced platelet aggregation and release reaction in heparinized platelet rich plasma and the influence of added citrate. Br J Haematol (1977) 36:565–571.[Web of Science][Medline]
  8. Lages B, Weiss HJ. Dependence of human platelet functional responses on divalent cations: aggregation and secretion in heparin- and hirudin-anticoagulated platelet-rich plasma and the effects of chelating agents. Thromb Haemost (1981) 45:173–179.[Web of Science][Medline]
  9. Packham MA, Bryant NL, Guccione MA, Kinlough-Rathbone RL, Mustard JF. Effect of the concentration of Ca2+ in the suspending medium on the responses of human and rabbit platelets to aggregating agents. Thromb Haemost (1989) 62:968–976.[Web of Science][Medline]
  10. 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]
  11. Sanderson S, Emery J, Baglin T, Kinmonth AL. Narrative review: aspirin resistance and its clinical implications. Ann Intern Med (2005) 142:370–380.[Abstract/Free Full Text]
  12. Fontana P, Nolli S, Reber G, de Moerloose P. Biological effects of aspirin and clopidogrel in a randomized cross-over study in 96 healthy volunteers. J Thromb Haemost (2006) 4:813–819.[CrossRef][Web of Science][Medline]
  13. Tantry US, Bliden KP, Gurbel PA. Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol (2005) 46:1705–1709.[Abstract/Free Full Text]
  14. Schwartz KA, Schwartz DE, Ghosheh K, Reeves MJ, Barber K, DeFranco A. Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction. Am J Cardiol (2005) 95:973–975.[CrossRef][Web of Science][Medline]
  15. Ohmori T, Yatomi Y, Nonaka T, Kobayashi Y, Madoiwa S, Mimuro J, Ozaki Y, Sakata Y. Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity: involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients. J Thromb Haemost (2006) 4:1271–1278.[CrossRef][Web of Science][Medline]
  16. Mueller MR, Salat A, Stangl P, Murabito M, Pulaki S, Boehm D, Koppensteiner R, Ergun E, Mittlboeck M, Schreiner W, Losert U, Wolner E. Variable platelet response to low-dose ASA and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty. Thromb Haemost (1997) 78:1003–1007.[Web of Science][Medline]
  17. Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation (2002) 105:1650–1655.[Abstract/Free Full Text]
  18. Chen WH, Lee PY, Ng W, Tse HF, Lau CP. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol (2004) 43:1122–1126.[Abstract/Free Full Text]
  19. Grundmann K, Jaschonek K, Kleine B, Dichgans J, Topka H. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks. J Neurol (2003) 250:63–66.[CrossRef][Web of Science][Medline]
  20. 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]
  21. Wiviott SD, Michelson AD, Berger PB, Lepor NE, Kereiakes DJ. Therapeutic goals for effective platelet inhibition: a consensus document. Rev Cardiovasc Med (2006) 7:214–225.[Web of Science][Medline]
  22. Cox D, Maree AO, Dooley M, Conroy R, Byrne MF, Fitzgerald DJ. Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Stroke (2006) 37:2153–2158.[Abstract/Free Full Text]
  23. Rocca B, Patrono C. Determinants of the interindividual variability in response to antiplatelet drugs. J Thromb Haemost (2005) 3:1597–1602.[CrossRef][Web of Science][Medline]
  24. Michelson AD, Cattaneo M, Eikelboom JW, Gurbel P, Kottke-Marchant K, Kunicki TJ, Pulcinelli FM, Cerletti C, Rao AK, on behalf of the Platelet Physiology Subcommittee of the Scientific Standardization Committee of the International Society on Thrombosis and Haemostasis. Aspirin resistance: position paper of the Working Group on Aspirin Resistance. J Thromb Haemost (2005) 3:1309–1311.[CrossRef][Web of Science][Medline]
  25. Patrono C, Bachmann F, Baigent C, Bode C, De Caterina R, Charbonnier B, Fitzgerald D, Hirsh J, Husted S, Kvasnicka J, Montalescot G, Garcia Rodriguez LA, Verheugt F, Vermylen J, Wallentin L. Expert consensus document on the use of antiplatelet agents: the task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European Society of Cardiology. Eur Heart J (2004) 25:166–181.[Free Full Text]
  26. Patrono C. Aspirin resistance: definition, mechanisms and clinical read-outs. J Thromb Haemost (2003) 1:1710–1713.[CrossRef][Web of Science][Medline]
  27. Siller-Matula J, Schror K, Wojta J, Huber K. Thienopyridines in cardiovascular disease: focus on clopidogrel resistance. Thromb Haemost (2007) 97:385–393.[Web of Science][Medline]
  28. Fugate SE, Cudd LA. Cangrelor for treatment of coronary thrombosis. Ann Pharmacother (2006) 40:925–930.[Abstract/Free Full Text]
  29. Tantry US, Bliden KP, Gurbel PA. AZD6140. Expert Opin Investig Drugs (2007) 16:225–229.[CrossRef][Web of Science][Medline]
  30. Storey RF. Biology and pharmacology of the platelet P2Y12 receptor. Curr Pharm Des (2006) 12:1255–1259.[CrossRef][Web of Science][Medline]
  31. Casella G, Ottani F, Pavesi PC, Sangiorgio P, Rubboli A, Galvani M, Fontanelli A, Bracchetti D. Safety and efficacy evaluation of clopidogrel compared to ticlopidine after stent implantation: an updated meta-analysis. Ital Heart J (2003) 4:677–684.[Medline]
  32. Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DGM, 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]
  33. 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]
  34. Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost (2003) 89:783–787.[Web of Science][Medline]
  35. 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]
  36. 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]
  37. 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][Web of Science][Medline]
  38. Michelson AD, Frelinger AL, Furman MI. Resistance to antiplatelet drugs. Eur Heart J (2006) 8(Suppl. G):G53–G58.[CrossRef]
  39. Smith SMG, Judge HM, Peters G, Armstrong M, Fontana P, Gaussem P, Daly ME, Storey RF. Common sequence variations in the P2Y12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy. Platelets (2006) 17:250–258.[CrossRef][Web of Science][Medline]
  40. 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, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK, 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). J Am Coll Cardiol (2006) 47:216–235.[Free Full Text]
  41. von Beckerath N, Kastrati A, Wieczorek A, Pogatsa-Murray G, Sibbing D, Graf I, Schomig 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]
  42. Gurbel PA, Bliden KP, Hayes KM, Yoho JA, Herzog WR, Tantry US. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol (2005) 45:1392–1396.[Abstract/Free Full Text]
  43. Hochholzer W, Trenk D, Frundi D, Blanke P, Fischer B, Andris K, Bestehorn HP, Buttner HJ, Neumann FJ. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation (2005) 111:2560–2564.[Abstract/Free Full Text]
  44. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation (2005) 111:1153–1159.[Abstract/Free Full Text]
  45. von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E, Kastrati A, Schomig 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]
  46. 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, for the 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]
  47. 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]
  48. 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][Web of Science][Medline]
  49. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M, Niitsu Y, Asai F. The greater in vivo antiplatelet effects of prasugrel compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to clopidogrel's active metabolite. J Thromb Haemost (2007) 5:1545–1551.[CrossRef][Web of Science][Medline]
  50. 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.e9–66.e16.
  51. 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]
  52. van Giezen JJJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost (2005) 31:195–204.[CrossRef][Web of Science][Medline]
  53. Storey RF, Oldroyd KG, Wilcox RG, on behalf of the Investigators. 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.[Web of Science][Medline]
  54. 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]
  55. Cannon CP, Harrington RA, Mahaffey KW, Husted S, Storey RF, Sanders N, Peters G, Emanuelsson H. Clinical outcomes with AZD6140, an oral reversible ADP receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes (ACS). Abstract 974–242. J Am Coll Cardiol (2007) 50:1844–1851.[Abstract/Free Full Text]
  56. Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Gurbel PA, Grande P, Sanders N, Peters G, Emanuelsson H, Cannon CP. AZD6140 yields greater inhibition of platelet aggregation than clopidogrel in patients with acute coronary syndromes without previous clopidogrel treatment. Abstract 821-3. J Am Coll Cardiol (2007) 50:1852–1856.[Abstract/Free Full Text]
  57. Storey RF, Harrington RA, Husted S, Heptinstall S, Wilcox RG, Gurbel PA, Grande P, Sanders N, Peters G, Emanuelsson H, Cannon CP. AZD6140 yields additional suppression of platelet aggregation in patients with acute coronary syndromes previously treated with clopidogrel. Abstract 821-4. J Am Coll Cardiol (2006) 47(Suppl.):204A.
  58. Steinhubl SR, Talley JD, Braden GA, Tcheng JE, Casterella PJ, Moliterno DJ, Navetta FI, Berger PB, Popma JJ, Dangas G, Gallo R, Sane DC, Saucedo JF, Jia G, Lincoff AM, Theroux P, Holmes DR, Teirstein PS, Kereiakes DJ. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study. Circulation (2001) 103:2572–2578.[Abstract/Free Full Text]
  59. Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H, Graf I, Ibrahim M, Pache J, Seyfarth M, Schuhlen H, Dirschinger J, Berger PB, Schomig A, for the Intracoronary Stenting Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA (2006) 295:1531–1538.[Abstract/Free Full Text]
  60. The GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet (2001) 357:1915–1924.[CrossRef][Web of Science][Medline]
  61. Storey RF, Wilcox RG, Heptinstall S. Differential effects of glycoprotein IIb/IIIa antagonists on platelet microaggregate and macroaggregate formation and effect of anticoagulant on antagonist potency. Implications for assay methodology and comparison of different antagonists. Circulation (1998) 98:1616–1621.[Abstract/Free Full Text]
  62. Zhao L, Bath PMW, May J, Losche W, Heptinstall S. P-selectin, tissue factor and CD40 ligand expression on platelet-leucocyte conjugates in the presence of a GPIIb/IIIa antagonist. Platelets (2003) 14:473–480.[CrossRef][Web of Science][Medline]
  63. Nannizzi-Alaimo L, Alves VL, Phillips DR. Inhibitory effects of glycoprotein IIb/IIIa antagonists and aspirin on the release of soluble CD40 ligand during platelet stimulation. Circulation (2003) 107:1123–1128.[Abstract/Free Full Text]

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