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In a third study, Collet et al demonstrated that among 259 young survivors of a first myocardial infarction who were treated with chronic clopidogrel, death, MI, and urgent revascularization occurred more often in carriers  (*2 / *2 or *1 / *2) than in non-carriers (*1 / *1)(HR = 3.69 [95% CI 1.69-8.05], p=0.0005), as did stent thrombosis (HR = 6.02 [1.81-20.04], p=0.0009). <ref name="pmid19108880">{{cite journal |author=Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G |title=Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study |journal=Lancet |volume=373 |issue=9660 |pages=309–17 |year=2009 |month=January |pmid=19108880 |doi=10.1016/S0140-6736(08)61845-0 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(08)61845-0 |accessdate=2009-04-28}}</ref> These findings were true in a multivariate model of potential confounders.
In a third study, Collet et al demonstrated that among 259 young survivors of a first myocardial infarction who were treated with chronic clopidogrel, death, MI, and urgent revascularization occurred more often in carriers  (*2 / *2 or *1 / *2) than in non-carriers (*1 / *1)(HR = 3.69 [95% CI 1.69-8.05], p=0.0005), as did stent thrombosis (HR = 6.02 [1.81-20.04], p=0.0009). <ref name="pmid19108880">{{cite journal |author=Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G |title=Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study |journal=Lancet |volume=373 |issue=9660 |pages=309–17 |year=2009 |month=January |pmid=19108880 |doi=10.1016/S0140-6736(08)61845-0 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(08)61845-0 |accessdate=2009-04-28}}</ref> These findings were true in a multivariate model of potential confounders.


===Genetic variations===
  Although both [[prasugrel]] and [[clopidogrel]] require cytochrome P450 (CYP) enzymes for activation, a substudy of 1,466 patients enrolled in the TRITON-TIMI 38 study found that  CYP variations did not affect:
Unlike [[clopidogrel]], common genetic variations have not been shown to affect [[prasugrel]]'s efficacy. Although both [[prasugrel]] and [[clopidogrel]] require cytochrome P450 (CYP) enzymes for activation, a substudy of 1,466 patients enrolled in the TRITON-TIMI 38 study found that prasugrel did not appear to be affected by a common variant that has been linked to possible problems with [[clopidogrel]]. The researchers concluded CYP variations did not affect:


*active drug metabolite levels
*Levels of prasugrel's active metabolite


*inhibition of platelet aggregation, or
*Prasugrel's inhibition of platelet aggregation, or


*clinical cardiovascular event rates in persons treated with prasugrel <ref name="urlCytochrome P450 Genetic Polymorphisms and the Response to Prasugrel. Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes -- Mega et al., 10.1161/CIRCULATIONAHA.109.851949 -- Circulation">{{cite web|url=http://circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.109.851949v1 |title=Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel. Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes -- Mega et al., 10.1161/CIRCULATIONAHA.109.851949 -- Circulation |format= |work= |accessdate=}}</ref>
*Clinical cardiovascular event rates in persons treated with prasugrel <ref name="urlCytochrome P450 Genetic Polymorphisms and the Response to Prasugrel. Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes -- Mega et al., 10.1161/CIRCULATIONAHA.109.851949 -- Circulation">{{cite web|url=http://circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.109.851949v1 |title=Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel. Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes -- Mega et al., 10.1161/CIRCULATIONAHA.109.851949 -- Circulation |format= |work= |accessdate=}}</ref>


===Inhibition of Metabolism by Co-Ingestion of Other Drugs===
===Inhibition of Metabolism by Co-Ingestion of Other Drugs===

Revision as of 22:01, 5 May 2009

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Editors-in-Chief: Dominick Angiolillo, M.D. [1], C. Michael Gibson, M.S., M.D. [2], Gabriel Steg, M.D.[3], Tabassome Simon, M.D. [4] and Paul Gurbel, M.D. [5]

Associate Editors-in-Chief: Davide Capodanno, M.D. [6]

Assistant Editor-in-Chief: Leah Biller

Please Join in Editing This Page and Apply to be an Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [7] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.

Synonyms and related keywords: Clopidogrel non-responders, clopidogrel hyporesponders, clopidogrel non-responsiveness, clopidogrel hyporesponsiveness, clopidogrel failure

Overview

Administration of the same dose of a drug to all patients has the advantages of simplicity and ease of use. However, data regarding the variability in platelet inhibition across patients highlights the potential importance of tailoring the antiplatelet or dose of an antiplatelet to the pharmacodynamic response of the patient. Patients who do not achieve adequate inhibition in response to a dose of clopidogrel are variably termed “Clopidogrel non-responders” or “Clopidogrel hyporesponders”. A recent European Society of Cardiology working group has suggested the term "elevated platelet reactivity despite treatment".[1]

This chapter reviews the underlying etiology and clinical relevance of clopidogrel non-responsiveness.

Definitions of Clopidogrel Non Responsiveness

There are multiple definitions of clopidogrel non-responsiveness [2]

  1. Gurbel et al: Change in inhibition of platelet aggregation (IPA) of < 10% using light transmittance aggregometry (LTA)[3]
  2. Angiolillo et al: IPA < 40% by LTA [4]
  3. Lau et al: Platelet aggregation >= to 70% by LTA [5]

It should also be noted that the degree of non-responsiveness will also vary depending upon the timing following clopidogrel administration that responsiveness is tested. For instance, Gurbel et al have shown that using the same assay and the same definition, at 2 hours following clopidogrel administration, the rate of non-responsiveness was 60%; by one day the number was 33%, and by one month the number was 15%. Thus, non-responsiveness may vary depending upon the degree of activation of the platelets themselves. As the platelets become less activated following an acute coronary syndrome episode, the rate of non-responsiveness may be lower. This variability in platelet activation and variability in non-responsiveness raises important questions regarding the potential differences in the optimal acute dose and the optimal chronic dose of clopidogrel and other thienopyridines.

Incidence of Clopidogrel Resistance

The incidence of clopidogrel resistance varies significantly from 5% to 44%. The incidence varies depending upon

  1. The definition of clopidogrel resistance
  2. The timing of assessing clopidogrel resistance in relation to an acute coronary syndrome episode
  3. There may be circadian rhythm to platelet aggregation



Clopidogrel Resistance: World Experience
(Courtesy of Paul Gurbel MD)
Investigators n Patients Clopidogrel Dose (mg Load) Resistance
Jaremo et al. [6] 18 PCI 300 28%
Gurbel et al.[3] 92 PCI 300 31%
Muller et al. [7] 105 PCI 600 5-11%
Mobley et al.[8] 50 PCI 300 30%
Lepantalo et al.[9] 50 PCI 300 40%
Angiolillo et al.[4] 48 PCI 300 44%
Matetzky et al.[10] 60 PCI 300 25%
Dziewierz et al.[11] 31 Stable angina 300 23%
Gurbel et al.[12] 190 PCI 300/600 8-32%
Lev et al.[13] 150 PCI 300 24%
Total 794 5-44%



Association of Clopidogrel Non-Responsiveness with Adverse Clinical Outcomes

There are a large number of studies associating clopidogrel non-responsiveness with adverse outcomes:

Studies Linking Ex-Vivo Platelet Function to Clinical Events
(Courtesy of Paul Gurbel MD)
Study Results Clinical Relevance
Barragan et al. [14] ↑ P2Y12 reactivity ratio (VASP-P levels) Stent Thrombosis
Ajzenberg et al.[15] ↑ Shear- Induced platelet aggregation Stent Thrombosis
Gurbel et al.

(CREST study)[16]

↑ADP- induced aggregation

↑Stimulated GPIIb/IIIa expression

Stent Thrombosis
Matetzky et al.[10] ↑ ­ ADP-Induced platelet aggregation Recurrent Cardiac Events (4th quartile)
Gurbel et al.

(CLEAR PLATELETS[17] and CLEAR PLATELETS Ib[18])

↑ Periprocedural platelet aggregation Myonecrosis and Inflammation Marker Release
Bliden et al.[19] ↑ Platelet aggregation (pre-PCI) on chronic clopidogrel 1 yr Post-PCI Events
Cuisset et al.[20] ↑ Platelet aggregation 30-day Post-PCI events
Lev et al.[13] Clopidogrel/Aspirin resistant patients Post-PCI Myonecrosis
Cuisset et al.[21] ↑ Platelet aggregation 30-day Post-PCI events, 600mg - less events
Hochholzer et al.[22] ↑ Platelet aggregation (Upper quartile) 30 day MACE

Despite these associations of clopidogrel hyporesponsiveness with adverse outcomes, there is no large scale data suggesting that acting upon test results and modifying therapy based upon test results is associated with improved outcomes. It is important to ascertain if the patient has been compliant with the medication before declaring that the patient is a clopidogrel non-responder.

Is there a Threshold Effect to Efficacy or are Clinical Outcomes Improved with Higher and Higher Doses (a Continuous Relationship to Clinical Outcomes)

One unresolved question is whether there is a “threshold effect” whereby clinical outcomes are not further improved above a certain level of platelet inhibition, or alternatively whether clinical outcomes are further improved with higher and higher doses in which case there is a “continuous variable” relationship between platelet inhibition and clinical outcomes. Data supporting a potential threshold effect comes from Gurbel et al. [23] [24]When data regarding the relationship between stent thrombosis and clinical outcomes was plotted as a cumulative distribution function rather than a bell curve, it was noted that stent thrombosis was infrequent above 40-50% inhibition.

Mechanisms Underlying Clopidogrel Resistance

There are multpiple mechanisms underlying clopidogrel resistance: [25]

Clinical Factors

  • Poor patient compliance
  • Under-dosing: Some patients may alter the dosing to take the drug every other day
  • Poor absorption
  • The presence of an acute coronary syndrome and increased platelet activation
  • Co-morbidities such as diabetes mellitus that is known to be assoicated with heightened platelet activation [26]
  • Elevated body mass index
  • Elevated platelet count

Cellular Factors

  • Accelerated platelet turnover
  • Reduced CYP3A metabolic activity
  • Increased ADP exposure
  • Up-regulation of the P2Y12 pathway
  • Up-regulation of the P2Y1 pathway
  • Up-regulation of the P2Y–independent pathways (collagen, epinephrine, thomboxane A2, thrombin)

Genetic Basis

Clopidogrel is a pro-drug. When it appears in the bloodstream following absorption, it is not in the active form. This inactive metabolite or pro-drug must circulate to the liver to be metabolized and converted to the active metabolite (there appear to be 4 active isomers). Genetic polymorphisms that have been related to variability in clopidogrel metabolism include:

  • Polymorphisms of CYP
  • Polymorphisms of GPIa
  • Polymorphisms of P2Y12
  • Polymorphisms of GPIIIa

Variability in the function of the CYP 2C19 allele has been postulated to be related to the ability to metabolize clopidogrel. [27]

The three individual alleles and their relative ability to metabolize clopidogrel are as follows:

  • *17 hypermetabolizer allele
  • *1 normal metabolizer allele
  • *2 poor metabolizer allele, genetic functional variant 681 G>A

Based upon the combinations (pairs) of these three alleles, four types of metabolizers have been identified based upon the ability of the patients to generate active metabolite and pharmacodynamics:

  • Ultra-metabolizers (UM): (30% of patients)
*1 / *17 allele
*17 / *17 allele
  • Extensive metabolizers (EM): (36% of patients)
*1 / *1 allele
  • Intermediate metabolizers (IM): (29% of patients)
*1 / *2 allele
  • Poor metabolizers (PM): (5% of patients)
*2 / *2 allele

It should be noted that the active metabolites of clopidogrel and prasugrel are equally potent, [28] and that differences in pharmacodynamic and clinical outcomes are due to differences in the generation of active metabolite rather than potency of the active metabolite. Carriers of the allele (those patients with a least one copy of the *2 allele) had a higher 450 day event rate (12.1%) versus those patients with no copies of the allele (an 8.0% event rate, HR 1.53, p=0.014).

[29]

In a similar but slightly different finding, Simon et al have demonstrated that it was only those patients who carried two copies of the *2 allele (*2 / *2) and not just one copy (*1 / *2) who had a higher risk of adverse events (death, MI, stroke).[30]

In a third study, Collet et al demonstrated that among 259 young survivors of a first myocardial infarction who were treated with chronic clopidogrel, death, MI, and urgent revascularization occurred more often in carriers (*2 / *2 or *1 / *2) than in non-carriers (*1 / *1)(HR = 3.69 [95% CI 1.69-8.05], p=0.0005), as did stent thrombosis (HR = 6.02 [1.81-20.04], p=0.0009). [29] These findings were true in a multivariate model of potential confounders.

Although both prasugrel and clopidogrel require cytochrome P450 (CYP) enzymes for activation, a substudy of 1,466 patients enrolled in the TRITON-TIMI 38 study found that  CYP variations did not affect:
  • Levels of prasugrel's active metabolite
  • Prasugrel's inhibition of platelet aggregation, or
  • Clinical cardiovascular event rates in persons treated with prasugrel [31]

Inhibition of Metabolism by Co-Ingestion of Other Drugs

Statins

Statins have been found to interfere with the generation of clopidogrel’s active metabolite. [5] [32] [33] One statin that does not interfere with clopidogrel metabolism is pravastatin. Non-randomized data from clinical trials have not confirmed a higher risk of adverse outcomes among patients co-ingesting statins in addition to clopidogrel versus those treated with clopidogrel alone. It is possible that the higher loading dose of 600 mg used in current clinical pracitce overcomes this interference.

Omeprazole and Proton Pump Inhibitors

Omeprazole induces a conformational change in the CYP enzyme system and may alter the metabolism of clopidogrel. In a double-blind placebo-controlled trial, stented patients treated with clopidogrel were randomized to treatment with either omeprazole (20 mg/day) or placebo. Following 7 days of treatment, the residual platelet aggregation was significantly hgiher in the omeprazole group (p < 0.0001). [34] The clinical impact of this finding and whether this inhibition can be overcome with a higher dose of clopidogrel is not clear.

There have been non-randomized retrospective analyses of the clinical outcomes among patients treated with omeprazole vs no omeprazole. [35] [36] [37] However, these non-randomized analyses are very confounded by the fact that patients treated with omeprazole are more often diabetics, had undergone CABG, had a history of cerebrovascular disease and peripheral arterial disease, had previously been on clopidogrel, and more often had renal disease. [36] Indeed, it is notable that among patients not treated with clopidogrel, treatment with a proton pump inhibitor (PPI) was associated with a 1.6 fold higher event rate in CREDO despite multivariate adjustment for confounders [38] This points to the potential role of unidentified confounders in the association of PPIs with clinical outcomes.

Pantoprazole and esomeprazole are not associated with a phramcodynamic or clinical effect in non-randomized analyses [39]

Gold Standard Tests of Clopidogrel Responsiveness

Light transmittance aggregometry (LTA): This is a laboratory based study (not a bedside test) that evaluates the aggregation or clumping of platelets based upon the turbidity (how much light is transmitted through) a test tube. This test is capable of evaluating platelet aggregation in response to not only thienopyridines, but also aspirin and glycoprotein IIbIIIa inhibitors. [40]

Vasodilator-Stimulated Phosphoprotein (VASP)

Point of Care Devices

VerifyNow Rapid Platelet Function Assay: This is a bedside test that allows for monitoring of the efficacy of thienopyridines, aspirin, and glycoprotein IIbIIIa inhibitors

Platelet Function Analyzer (PFA-100): This is a bedside test that allows for monitoring of the efficacy of aspirin

Clinical Utility of Point of Care Testing Versus Genetic Testing

In so far as point of care testing results are more readily available, these may be a more suitable choice for use in clinical practice as compared to genetic testing. Furthermore, there may be mechanisms other than variability in metabolism that account for differences in response to clopidogrel which are assessed by point of care tests and not by genetic testing.

Strategies to Overcome Clopidogrel Non-Responsiveness

Due to the severity of its consequences, how to manage suboptimal clopidogrel response is a major clinical problem. The most important aspect is to guarantee patient compliance. The second aspect to evaluate is any potential drug-drug interactions. Studies are currently ongoing with the goal to better elucidate the interaction between clopidogrel and PPIs. The following strategies can be proposed to overcome inadequate clopidogrel responsiveness:

  1. increase clopidogrel dosing
  2. triple antiplatelet therapy
  3. using a different P2Y12 antiplatelet agent.

Increase clopidogrel dosing

Several studies have shown that a high clopidogrel loading dose regimen (≥ 600 mg) achieves more potent platelet inhibition when compared to a standard 300 mg loading dose[41][42][43][44]. This has also been associated with better clinical outcomes in patients undergoing PCI [45][46][21]. ]. A high maintenance dose (150 mg/day) dose regimen of clopidogrel has found to be associated with enhanced platelet inhibition compared to the currently recommended 75 mg/day [47][48][49], in particular in patients with high posttreatment platelet reactivity while on 75mg [47]. The OPTIMUS (Optimizing antiPlatelet Therapy In diabetes MellitUS) study selectively evaluated type 2 diabetes mellitus patients with high platelet reactivity while on 75mg clopidogrel and showed that 150 mg clopidogrel maintenance dose induced greater platelet inhibition compared with 75 mg dosing [48]. In a recently published observational study[50], Lemesle et al. showed better clinical outcomes in PCI patients treated with 600-mg loading dose followed by a high maintenance dose (150 mg/day) without a significant increase in bleeding events. The ongoing CURRENT/OASIS-7 (Clopidogrel optimal loading dose Usage to Reduce recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS; NCT00335452) will evaluate the efficacy of higher loading and maintenance doses of clopidogrel in ACS patients undergoing PCI. Several currently ongoing clinical trials are evaluating safety and/or efficacy of a tailored treatment with high clopidogrel maintenance dose in patients with inadequate response to clopidogrel. These include GRAVITAS (Gauging Responsiveness with a VerifyNow Assay: Impact on Thrombosis And Safety; NCT00645918), ARCTIC (Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and Interruption Versus Continuation of Double Antiplatelet Therapy; NCT00827411), and DANTE (Dual Antiplatelet Therapy Tailored on the Extent of Platelet Inhibition, NCT00774475).

Triple Antiplatelet Therapy

In the acute phase of therapy, adding a glycoprotein IIb/IIIa inhibitor may be considered as this leads to more potent platelet inhibition. Recently, Cuisset et al. showed that the rate of cardiovascular events at 1 month was significantly lower when abciximab was added compared to conventional dual antiplatelet therapy in clopidogrel nonresponders (n=149) referred for elective PCI [51]. The 3T/2R trial showed that better clinical outcomes in aspirin or clopidogrel non responders undergoing elective PCI treated with tirofiban[52]. In the maintenance phase of therapy, triple antiplatelet therapy achieved with the adjunctive use of cilostazol, a phosphodiesterase III inhibitor, is another option. The OPTIMUS-2 study showed that in a diabetic population cilostazol markedly enhances P2Y12 inhibition[53]This may explain the reduced stent thrombosis rates observed with this triple antiplatelet treatment regimen compared to standard dual antiplatelet therapy and reduced target lesion revascularization rates in patients treated with both bare-metal and drug-eluting stents with greater effects among diabetics[54][55][56][57][58]. All the above strategies have not been associated with increased bleeding.

Using a different P2Y12 receptor antagonists

Although clopidogrel has largely replace ticlopidine due to its better safety profile, it has been shown that ticlopidine may improve platelet inhibition among suboptimal responders[59]. However, the future likely resides with the use of newer agents. New [[P2Y12 receptor antagonist]]s are currently under different phases of clinical development (e.g. prasugrel, cangrelor, ticagrelor, elinogrel)[60][61][62]. These agents have more potent and less variable inhibitory effects than clopidogrel. Prasugrel, a third generation thienopyridine, has already completed its phase III investigation and received approval for clinical use in Europe [63]. If prasugrel yields better clinical outcomes without increasing bleeding hazards in clopidogrel non-responders is under investigation.

References

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  2. Barsky AA, Arora RR (2006). "Clopidogrel resistance: myth or reality?". J. Cardiovasc. Pharmacol. Ther. 11 (1): 47–53. PMID 16703219. Unknown parameter |month= ignored (help)
  3. 3.0 3.1 Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM (2003). "Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity". Circulation. 107 (23): 2908–13. doi:10.1161/01.CIR.0000072771.11429.83. PMID 12796140. Unknown parameter |month= ignored (help)
  4. 4.0 4.1 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E; et al. (2005). "Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting". Thromb. Res. 115 (1–2): 101–8. doi:10.1016/j.thromres.2004.07.007. PMID 15567460.
  5. 5.0 5.1 Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER (2003). "Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction". Circulation. 107 (1): 32–7. PMID 12515739. Retrieved 2009-04-28. Unknown parameter |month= ignored (help)
  6. Järemo P, Lindahl TL, Fransson SG, Richter A (2002). "Individual variations of platelet inhibition after loading doses of clopidogrel". J. Intern. Med. 252 (3): 233–8. PMID 12270003. Unknown parameter |month= ignored (help)
  7. Müller I, Besta F, Schulz C, Massberg S, Schönig A, Gawaz M (2003). "Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement". Thromb. Haemost. 89 (5): 783–7. doi:10.1267/THRO03050783. PMID 12719773. Unknown parameter |month= ignored (help)
  8. Mobley JE, Bresee SJ, Wortham DC, Craft RM, Snider CC, Carroll RC (2004). "Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization". Am. J. Cardiol. 93 (4): 456–8. doi:10.1016/j.amjcard.2003.10.042. PMID 14969622. Unknown parameter |month= ignored (help)
  9. Lepäntalo A, Virtanen KS, Heikkilä J, Wartiovaara U, Lassila R (2004). "Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions". Eur. Heart J. 25 (6): 476–83. doi:10.1016/j.ehj.2003.12.016. PMID 15039127. Unknown parameter |month= ignored (help)
  10. 10.0 10.1 Matetzky S, Shenkman B, Guetta V; et al. (2004). "Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction". Circulation. 109 (25): 3171–5. doi:10.1161/01.CIR.0000130846.46168.03. PMID 15184279. Unknown parameter |month= ignored (help)
  11. Dziewierz A, Dudek D, Heba G, Rakowski T, Mielecki W, Dubiel JS (2005). "Inter-individual variability in response to clopidogrel in patients with coronary artery disease". Kardiol Pol. 62 (2): 108–17, discussion 118. PMID 15815794. Unknown parameter |month= ignored (help)
  12. Gurbel PA, Bliden KP, Hayes KM, Yoho JA, Herzog WR, Tantry US (2005). "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. 45 (9): 1392–6. doi:10.1016/j.jacc.2005.01.030. PMID 15862408. Unknown parameter |month= ignored (help)
  13. 13.0 13.1 Lev EI, Patel RT, Maresh KJ; et al. (2006). "Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance". J. Am. Coll. Cardiol. 47 (1): 27–33. doi:10.1016/j.jacc.2005.08.058. PMID 16386660. Unknown parameter |month= ignored (help)
  14. Barragan P, Bouvier JL, Roquebert PO; et al. (2003). "Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation". Catheter Cardiovasc Interv. 59 (3): 295–302. doi:10.1002/ccd.10497. PMID 12822144. Unknown parameter |month= ignored (help)
  15. Ajzenberg N, Aubry P, Huisse MG; et al. (2005). "Enhanced shear-induced platelet aggregation in patients who experience subacute stent thrombosis: a case-control study". J. Am. Coll. Cardiol. 45 (11): 1753–6. doi:10.1016/j.jacc.2004.10.079. PMID 15936600. Unknown parameter |month= ignored (help)
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