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'''Editors-in-Chief:''' [[C. Michael Gibson]], M.S., M.D. [mailto:mgibson@perfuse.org] and Paul Gurbel, M.D.
'''Editors-in-Chief:''' [[C. Michael Gibson]], M.S., M.D. [mailto:mgibson@perfuse.org] and Paul Gurbel, M.D. [mailto:pgurbel@lifebridgehealth.org]


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Revision as of 13:17, 29 April 2009

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Editors-in-Chief: C. Michael Gibson, M.S., M.D. [1] and Paul Gurbel, M.D. [2]

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Synonyms: Clopidogrel non-responders, clopidogrel hyporesponders, clopidogrel non-responsiveness, clopidogrel hyporesponsiveness

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. Angiolillio 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.

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] [31] [32] 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). [33] 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. [34] [35] [36] 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. [35] 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 [37] 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 [38]

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. [39]

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

Administration of a higher 600 mg dose clopidogrel results in greater levels of IPA than 300 mg. However, a 900 mg loading dose may not further increase IPA. [40] The OASIS 7 study is testing the efficacy and safety of a higher loading dose of clopidogrel (600 mg vs 300 mg) and a higher maintenance dose of clopidogrel for one week (150 mg vs 75 mg).

References

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