Clopidogrel resistance

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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: Change in inhibition of platelet aggregation (IPA) of < 10% using light transmittance aggregometry (LTA)
  2. Angiolillio: IPA < 40% by LTA
  3. Serebrany: Platelet response to 5 micromolar ADP is 2 standard deviations below the mean of the normal distribution of the population
  4. Lau: Platelet aggregation >= to 70% by LTA

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.

Association of Clopidogrel Non-Responsiveness with Adverse Clinical Outcomes

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

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.


Studies Linking Ex-Vivo Platelet Function to Clinical Events
(Courtesy of Paul Gurbel MD)
Study Results Clinical Relevance
Barragan et al.

(Catheter Cardiovasc Interv. 2003;59(3):295-302)

↑ P2Y12 reactivity ratio (VASP-P levels) Stent Thrombosis
Ajzenberg et al.

(J Am Coll Cardiol. 2005;45(11):1753-1756)

↑ Shear- Induced platelet aggregation Stent Thrombosis
Gurbel et al.

(CREST study)
(J Am Coll Cardiol. 2005;46(10):1827-1832

↑ P2Y12 reactivity ratio

↑ADP- induced aggregation
↑Stimulated GPIIb/IIIa expression

Stent Thrombosis
Matzesky et al.

(Circulation. 2004;109(25):3171-1375)

↑ ­ ADP-Induced platelet aggregation Recurrent Cardiac Events (4th quartile)
Gurbel et al.

(CLEAR PLATELETS and CLEAR PLATELETS Ib)
(Circulation. 2005;111(9):1153-1159)
(J Am Coll Cardiol. 2006;48(11):2186-2191)

↑ Periprocedural platelet aggregation Myonecrosis and Inflammation Marker Release
Bliden et al.

(J Am Coll Cardiol. 2007;49(6):657-666)

↑ Platelet aggregation (pre-PCI) on chronic clopidogrel 1 yr Post-PCI Events
Cuisset et al.

(J Thromb Haemost. 2006;4(3):542-549)

↑ Platelet aggregation 30-day Post-PCI events
Lev et al.

(J Am Coll Cardiol. 2006;47(1):27-33)

Clopidogrel/Aspirin resistant patients Post-PCI Myonecrosis
Cuisset e al.

(J Am Coll Cardiol. 2006;48(7):1339-1345)

↑ Platelet aggregation 30-day Post-PCI events, 600mg - less events
Hochholzer et al.

(J Am Coll Cardiol 2006:48(9):1742-1750)

↑ Platelet aggregation (Upper quartile) 30 day MACE

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. 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 % inhibition.

Mechanisms Underlying Clopidogrel Resistance

There are multpiple mechanisms underlying clopidogrel resistance: [3]

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
  • Elevated body mass index

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)

The Genetic Basis for Clopidogrel Hyporesponsiveness

The cyp 2c19 allele has been postulated to be related to the ability to metabolize clopidogrel. Simon et al have demonstrated that those patients who carry either one or two alleles that reduce the ability to metabolize clopidogrel are at higher risk of adverse clinical outcomes compared to those patients in who tow alleles that code for normal clopidogrel metabolism.

Inhibition of Metabolism by Co-Ingestion of Other Drugs

Statins

Statins have been found to interfere with the generation of clopidogrel’s active metabolite. [4] [5] [6] 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

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.

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. [7]

VASP

Point of Care Devices

References

  1. Kuliczkowski W et al. Eur Heart J. 2009;30:426-435.
  2. Barsky AA et al. J Cardiovasc Pharmacol Therapeut. 2006;11:47–53.
  3. Angiolillio DJ et al. J Am Coll Cardiol. 2007;49:1505-1516
  4. 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)
  5. Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DG, Guyer KE, Tait AR, Bates ER (2004). "Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance". Circulation. 109 (2): 166–71. doi:10.1161/01.CIR.0000112378.09325.F9. PMID 14707025. Retrieved 2009-04-28. Unknown parameter |month= ignored (help)
  6. Lau WC, Carville DG, Bates ER (2004). "Clinical significance of the atorvastatin-clopidogrel drug-drug interaction". Circulation. 110 (6): e66–7, author reply e66–7. doi:10.1161/01.CIR.0000137956.92971.4A. PMID 15302813. Retrieved 2009-04-28. Unknown parameter |month= ignored (help)
  7. Wang T et al. Eur Heart J. 2006;27:647-654.

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