Clopidogrel resistance: Difference between revisions
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# Gurbel: Change in inhibition of platelet aggregation (IPA) of < 10% using light transmittance aggregometry (LTA)<ref name="pmid12796140">{{cite journal |author=Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM |title=Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity |journal=Circulation |volume=107 |issue=23 |pages=2908–13 |year=2003 |month=June |pmid=12796140 |doi=10.1161/01.CIR.0000072771.11429.83 |url=}}</ref> | # '''Gurbel et al:''' Change in inhibition of platelet aggregation (IPA) of < 10% using light transmittance aggregometry (LTA)<ref name="pmid12796140">{{cite journal |author=Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM |title=Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity |journal=Circulation |volume=107 |issue=23 |pages=2908–13 |year=2003 |month=June |pmid=12796140 |doi=10.1161/01.CIR.0000072771.11429.83 |url=}}</ref> | ||
# Angiolillio: IPA < 40% by LTA <ref name="pmid15567460">{{cite journal |author=Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, ''et al'' |title=Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting |journal=Thromb. Res. |volume=115 |issue=1-2 |pages=101–8 |year=2005 |pmid=15567460 |doi=10.1016/j.thromres.2004.07.007 |url=}}</ref> | # '''Angiolillio et al:''' IPA < 40% by LTA <ref name="pmid15567460">{{cite journal |author=Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, ''et al'' |title=Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting |journal=Thromb. Res. |volume=115 |issue=1-2 |pages=101–8 |year=2005 |pmid=15567460 |doi=10.1016/j.thromres.2004.07.007 |url=}}</ref> | ||
# Lau: Platelet aggregation >= to 70% by LTA <ref name="pmid12515739">{{cite journal |author=Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER |title=Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction |journal=Circulation |volume=107 |issue=1 |pages=32–7 |year=2003 |month=January |pmid=12515739 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12515739 |accessdate=2009-04-28}}</ref> | # '''Lau et al:''' Platelet aggregation >= to 70% by LTA <ref name="pmid12515739">{{cite journal |author=Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER |title=Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction |journal=Circulation |volume=107 |issue=1 |pages=32–7 |year=2003 |month=January |pmid=12515739 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12515739 |accessdate=2009-04-28}}</ref> | ||
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. | 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. |
Revision as of 17:52, 28 April 2009
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] and Paul Gurbel, M.D.
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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]
- Gurbel et al: Change in inhibition of platelet aggregation (IPA) of < 10% using light transmittance aggregometry (LTA)[3]
- Angiolillio et al: IPA < 40% by LTA [4]
- 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
- The definition of clopidogrel resistance
- The timing of assessing clopidogrel resistance in relation to an acute coronary syndrome episode
- There may be circadian rhythm to platelet aggregation
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:
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.
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. | ↑ 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 |
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: [23]
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
- 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
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. 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. [5] [24] [25] 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. [26]
VASP
Point of Care Devices
References
- ↑ Kuliczkowski W, Witkowski A, Polonski L; et al. (2009). "Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology". Eur. Heart J. 30 (4): 426–35. doi:10.1093/eurheartj/ehn562. PMID 19174428. Unknown parameter
|month=
ignored (help) - ↑ 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) - ↑ 3.0 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) - ↑ 4.0 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.
- ↑ 5.0 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 10.0 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) - ↑ 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) - ↑ 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) - ↑ 13.0 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) - ↑ 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) - ↑ 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) - ↑ Gurbel PA, Bliden KP, Samara W; et al. (2005). "Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study". J. Am. Coll. Cardiol. 46 (10): 1827–32. doi:10.1016/j.jacc.2005.07.056. PMID 16286166. Unknown parameter
|month=
ignored (help) - ↑ Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US (2005). "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. 111 (9): 1153–9. doi:10.1161/01.CIR.0000157138.02645.11. PMID 15738352. Unknown parameter
|month=
ignored (help) - ↑ Gurbel PA, Bliden KP, Tantry US (2006). "Effect of clopidogrel with and without eptifibatide on tumor necrosis factor-alpha and C-reactive protein release after elective stenting: results from the CLEAR PLATELETS 1b study". J. Am. Coll. Cardiol. 48 (11): 2186–91. doi:10.1016/j.jacc.2005.12.084. PMID 17161243. Unknown parameter
|month=
ignored (help) - ↑ Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA (2007). "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. 49 (6): 657–66. doi:10.1016/j.jacc.2006.10.050. PMID 17291930. Unknown parameter
|month=
ignored (help) - ↑ Cuisset T, Frere C, Quilici J; et al. (2006). "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. 4 (3): 542–9. doi:10.1111/j.1538-7836.2005.01751.x. PMID 16371119. Unknown parameter
|month=
ignored (help) - ↑ Cuisset T, Frere C, Quilici J; et al. (2006). "Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting". J. Am. Coll. Cardiol. 48 (7): 1339–45. doi:10.1016/j.jacc.2006.06.049. PMID 17010792. Unknown parameter
|month=
ignored (help) - ↑ Hochholzer W, Trenk D, Bestehorn HP; et al. (2006). "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. 48 (9): 1742–50. doi:10.1016/j.jacc.2006.06.065. PMID 17084243. Unknown parameter
|month=
ignored (help) - ↑ Angiolillio DJ et al. J Am Coll Cardiol. 2007;49:1505-1516
- ↑ 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) - ↑ 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) - ↑ Wang T et al. Eur Heart J. 2006;27:647-654.