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Gurbel clop resistance
Gurbel clop resistance
Gurbel clop resistance
Gurbel clop resistance
Gurbel clop resistance
Gurbel clop resistance
Gurbel clop resistance
Gurbel clop resistance
Gurbel clop resistance
Gurbel clop resistance
Gurbel clop resistance
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Gurbel clop resistance

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  • 1. Thrombosis Research (2007) 120, 311–321 intl.elsevierhealth.com/journals/threREVIEW ARTICLEClopidogrel resistance?Paul A. Gurbel ⁎, Udaya S. TantrySinai Center for Thrombosis Research, Baltimore, Maryland, USAReceived 5 July 2006; received in revised form 31 July 2006; accepted 10 August 2006Available online 14 November 2006 KEYWORDS Abstract Clopidogrel is an effective inhibitor of platelet activation and aggregation Clopidogrel; due to its selective and irreversible blockade of the P2Y12 receptor. Combination Responsiveness; antiplatelet therapy with clopidogrel and aspirin is an important strategy for patients Resistance; with acute coronary syndromes and those undergoing percutaneous interventions. Platelet aggregation; Despite significant benefits demonstrated with combination antiplatelet treatment P2Y12 receptor in large clinical trials, the occurrence of adverse ischemic events, including stent thrombosis, remains a serious clinical problem. Recent studies have demonstrated distinct response variability and nonresponsiveness to clopidogrel therapy based on ex vivo platelet function measurements. Small scale investigations have suggested that nonresponsiveness may be associated with a heightened risk for adverse clinical events. The above findings have stimulated a close examination of clopidogrel metabolism. © 2006 Elsevier Ltd. All rights reserved.Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 Mechanism of action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Clopidogrel resistance — definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Laboratory evaluation of clopidogrel responsiveness. . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Clopidogrel responsiveness and time of treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 Clopidogrel responsiveness and effect of dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 Relation of clopidogrel nonresponsiveness to adverse clinical events . . . . . . . . . . . . . . . . . 315 Mechanism of clopidogrel resistance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 Management of clopidogrel resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 Higher doses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 New P2Y12 receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 ⁎ Corresponding author. Sinai Center for Thrombosis Research, Hoffberger Building, Suite 56, 2401 W. Belvedere Ave, Baltimore, MD21215, Maryland, USA. Tel.: +1 410 601 9600; fax: +1 410 601 9601. E-mail address: PGURBEL@LIFEBRIDGEHEALTH.ORG (P.A. Gurbel).0049-3848/$ - see front matter © 2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.thromres.2006.08.012
  • 2. 312 P.A. Gurbel, U.S. Tantry Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319Introduction antiplatelet treatment in large clinical trials, the occurrence of adverse ischemic events, includingClopidogrel effectively inhibits ADP-induced plate- stent thrombosis, remains a serious clinical prob-let activation and aggregation by selectively and lem. Moreover, in the recent CHARISMA trial, theirreversibly blocking the P2Y12 receptor [1]. The addition of clopidogrel to aspirin as a long termCAPRIE study demonstrated the significant benefit treatment strategy was found to be beneficial onlyof clopidogrel treatment in selected patients as in high risk patients with clinically evident athero-compared to aspirin therapy alone [2]. Since thrombosis. In CHARISMA the effect of clopidogrel asclopidogrel and aspirin inhibit platelet aggregation a primary prevention strategy in addition to aspirinthrough different pathways, combined antiplatelet was associated with an increased risk of bleedingtherapy provides complementary and additive with no extra clinical benefits over aspirin therapybenefits compared to either agent alone. Clopido- alone [7]. The recent ACTIVE W trial indicated thatgrel treatment along with aspirin is considered the oral anticoagulation therapy was clearly superior to“gold standard” for attenuation of platelet activa- dual antiplatelet therapy with clopidogrel andtion and aggregation during acute coronary syn- aspirin for the prevention of vascular events indromes and in patients undergoing stenting [3–5]. In patients with atrial fibrillation at high risk of strokethe United States, between 1998 and 2004, clopi- [8]. The latter trials highlight the importance ofdogrel use has increased seven times whereas use of understanding the pathophysiology of the diseaseclopidogrel with aspirin has increased 16 times [6]. state and targeting dual antiplatelet therapy toDespite significant benefits reported with combined patients at high risk for arterial thrombotic events.Figure 1 Mechanism of action of clopidogrel and laboratory evaluation of clopidogrel nonresponsiveness. Abbreviations; ADP —adenosine diphosphate, CYP3A4; hepatic cytochrome 3A4, TxA2 — thromboxane A2, LS-MS/MS — liquid chromatography-massspectrometry, LTA — light transmittance aggregometry, PRP — platelet rich plasma, TEG — thrombelastography, VASP-P — vasodilator-stimulated phosphoprotein-phosphorylated, PLA — platelet–leukocyte aggregation, PFA-100 — platelet function analyzer.
  • 3. Clopidogrel resistance? 313B:1 Box 1 egy directed against a specific receptor cannot overcome all thrombotic complications. With this in mind, it is our opinion that the optimal definition of resistance or nonresponsiveness to an antiplatelet agent is the failure of the antiplatelet agent to inhibit the target of its action. The identification of resistance would therefore utilize a laboratory technique that detects residual activity of the target. Therefore, clopidogrel resistance is best demonstrated by evidence of residual post-treat- ment P2Y12 activity by measuring ADP-induced platelet aggregation before and after treatment. Since thrombosis involves multiple signaling path- ways, treatment failure is not synonymous with drug In addition, the previous clinical trials focussed on resistance (BOX-1). the reduction of clinical events following antiplate- let therapy without laboratory evaluation of plate- Laboratory evaluation of clopidogrel let function. However, subsequent demonstrations responsiveness of distinct response variability and nonresponsive- ness to clopidogrel therapy, based on the laboratory A standardized laboratory method that simulates evaluation of platelet response and the association the in vivo platelet response to antiplatelet therapy of nonresponsiveness to adverse clinical events, is still lacking. Since clopidogrel specifically inhibits demand a closer look at the effectiveness of one of two ADP receptors, ex-vivo measurement of clopidogrel treatment [9–12]. ADP-induced maximum platelet aggregation by light transmittance aggregometry (LTA) has been the Mechanism of action most commonly used laboratory method to evaluate clopidogrel responsiveness and is considered the Clopidogrel inhibits ADP-induced platelet aggrega- gold standard [9]. Recently, it was suggested that tion. Clopidogrel also inhibits collagen-, and throm- since antiplatelet drugs (especially clopidogrel), bin-induced aggregation; however, the inhibitory induce platelet disaggregation, the response to effect on collagen- and thrombin-induced aggrega- clopidogrel would be better demonstrated by tion can be overcome by increased concentrations measuring late platelet aggregation at 6 min after of these agonists. These findings suggest that stimulation with ADP rather than maximum aggre- clopidogrel indirectly inhibits the effect of these gation [20]. However, unpublished data from our agonists via the attenuation of ADP-mediated laboratory, based on the evaluation of both maxi- amplification of the platelet response [13]. mum and final aggregation from 100 consecutive Clopidogrel is rapidly absorbed from the intestine patients undergoing stenting and treated with and extensively converted by hepatic cytochrome clopidogrel, indicated that both measurements P450 isoenzymes (CYP3A4, CYP3A5, 2C19) to an were equivalent in determining the prevalence of active thiol metabolite [14,15]. This short lived clopidogrel nonresponsiveness. Flow cytometric active metabolite binds to the P2Y12 receptor via a measurements of the expression of activated GP disulfide bridge between the reactive thiol group IIb/IIIa receptor and p-selectin expression after ADP and two cysteine residues (cys17 and cys270) stimulation can also identify clopidogrel nonrespon- present in the extracellular domains of the P2Y12 siveness and correlated with measurements of receptor. Thus, the binding of ADP to the P2Y12 maximum aggregation stimulated by ADP [9,21]. In receptor is permanently inhibited [1](Fig. 1). addition, measurements of ADP-induced platelet- Clopidogrel has also been reported to attenuate fibrin clot strength by whole blood thrombelasto- platelet–leukocyte aggregate formation, and the graphy and the VerifyNow P2Y12 receptor assay using levels of CRP, p-selectin and CD 40L; and the rate of ADP as the agonist can also be used to measure thrombin formation [16–20]. clopidogrel responsiveness as point-of-care assays [22,23]. The PFA-100 method using collagen-ADP Clopidogrel resistance — definition based cartridges and whole blood aggregometry are associated with inconsistent estimates of platelet No single receptor signaling pathway mediating reactivity to ADP. The phosphorylation state of platelet activation is responsible for all thrombotic vasodilator-stimulated phosphoprotein is a specific complications. Therefore, a single treatment strat- intracellular marker of residual P2Y12 receptor
  • 4. 314 P.A. Gurbel, U.S. Tantry Clopidogrel responsiveness and time of treatment Similar to other drugs, response variability and nonresponsiveness to clopidogrel have been dem- onstrated in patients following coronary stenting [9,25]. In an early investigation from our center, 96 patients undergoing elective stenting were treated with a 300 mg clopidogrel loading dose in the catheterization laboratory followed by a 75 mgFigure 2 Relationship between frequency of patients and maintenance dose. ADP-induced platelet aggrega-absolute change in aggregation (Δ Aggregation [%]) in tion and activation dependent platelet surfaceresponse to 5 uM ADP at 2 h (A), 24 h (B), days (C), and30 days (D) after stenting. Δ Aggregation (%) is defined marker expression (p-selectin and activated GPIIb/baseline aggregation (%) minus post-treatment aggregation IIIa) were assessed at baseline and serially for(%). Resistance, as defined therein, is Δ Aggregation ≤ 10%. 30 days following stenting. Response variability toResistance is present in those patients subtended by double- clopidogrel was demonstrated as measured by allheaded arrow. Curves represent normal distribution of data. markers and a certain percentage of patients were(Adapted from, Gurbel et al. Circulation 2003;107:2908–13). found to have no demonstrable antiplatelet effect [9]. In the latter patients, the difference between pre- and post-treatment ADP-induced plateletreactivity in patients treated with clopidogrel and aggregation was ≤10%. We defined these patientscan be measured by flow cytometry. This technique as clopidogrel “resistant” or “nonresponsive” tois perhaps the most specific indicator of residual clopidogrel therapy. A subgroup of resistant patientsP2Y12 activity in patients treated with a P2Y12 exhibited platelet aggregation that was greaterinhibitor. However, the methodology is labor inten- after stent implantation than at baseline despitesive and requires permeation of the platelet clopidogrel therapy. These patients were defined asmembrane and use of monoclonal antibodies spe- having heightened platelet reactivity to ADP.cific for phosphorylated vasodilator-stimulated In the latter study, 53–63% of patients werephosphoprotein [21,24] (Fig. 2). resistant to clopidogrel treatment at 2 h post- Table 1 Clopidogrel resistance studies Investigators n Patients Clopidogrel dose Definition of clopidogrel resistance Time Incidence (mg, load/qd) Gurbel et al [9] 92 PCI 300/75 5 and 20 uM ADP-induced aggregation 24 h 31–35% b10% absolute change Jaremo et al [27] 18 PCI 300/75 ADP-induced fibrinogen binding b40% of 24 h 28% baseline Muller et al [28] 119 PCI 600/75 5 and 50 uM ADP-induced aggregation 4h 5–11% b10% relative change Mobely et al [29] 50 PCI 300/75 1 uM ADP-induced aggregation, TEG and Pre and 30% Ichor PW; b10% absolute inhibition post Lepantalo et al [30] 50 PCI 300/75 2 or 5 uM AD-induced aggregation and 2.5 h 40% PFA-100 10% inhibition and 170s Angiolillo et al [31] 48 PCI 300/75 6 uM ADP-induced aggregation b40% 10 min, 4 44% inhibition and 24 h Matetzky et al [32] 60 STEMI 300/75 5 uM ADP-induced aggregation and CPA Daily for 25% b10% inhibition 5 days Dziewierz A et al 31 CAD 300 20 uM ADP-induced aggregation b 10% 24 h 23% [33] absolute change Lev EI et al [34] 150 PCI 300 5 uM ADP-induced aggregation b10% 20–24 h 24% absolute change Angiolillo et al [35] 52 Diabetics and 300 b10% relative inhibition 24 h 38% diabetics 8% non-diabetics non-diabetics Gurbel et al [25] 190 PCI 300 or 600/75 5 and 20 uM ADP-induced aggregation 24 h 28–32% with b10% absolute inhibition 300 mg 8% with 600 mg Abbreviations— PCI = percutaneous coronary interventions; ADP= adenosine diphosphate; CAD = Coronary artery disease TEG = throm- belastography; PW= Plateletworks; PFA-100= Platelet function analyzer-100; CPA= Cone and platelet analyzer.
  • 5. Clopidogrel resistance? 315stenting; ∼ 30% were resistant at day 1 and day 5 pendent on dose. In the largest pharmacodynamicpost-stenting; and 13%–21% were resistant at day 30 study comparing 300 mg and 600 mg clopidogrelpost-stenting [9] (Fig. 2). Therefore, clopidogrel loading doses, treatment with a 600 mg loading dose“resistance” in this study appeared to be time during elective PCI reduced clopidogrel nonrespon-dependent. Based on the results we hypothesized siveness to 8% compared to 28–32% after a 300 mgthat the occurrence of clopidogrel resistance might loading dose (Fig. 3). Moreover, the study demon-be related to the inadequacy of a 300 mg loading strated a narrower response profile followingdose to provide sufficient active metabolite gener- treatment with 600 mg compared to 300 mgation to arrest platelet reactivity in selected clopidogrel [25]. Muller et al also observed a timepatients, and that these resistant patients may be and dose dependent effect of clopidogrel in patientsat particular risk for thrombotic complications undergoing stenting [28]. A similar increased re-including periprocedural infarction and stent sponsiveness was also observed in the ISAR-CHOICEthrombosis [9,22,26]. study, where a ceiling effect of platelet inhibition Since this initial description, multiple investiga- was observed with a 600 mg clopidogrel loading dosetors have confirmed the phenomenon of clopidogrel whereas a nonsignificant increase in platelet inhi-resistance [27–35]. The prevalence of clopidogrel bition was observed with a 900 mg loading dose [36].nonresponsiveness has been reported at 5–44%. Thiswide variation in prevalence is primarily due to Relation of clopidogrel nonresponsiveness todosing and is less related to various definitions, adverse clinical eventslaboratory methods, and the time at which bloodsamples were evaluated for responsiveness [27–35] Limited data are available to link clopidogrel(Table 1). As demonstrated in Table 1, the data are nonresponsiveness to the occurrence of thromboticmarkedly concordant. The higher resistance esti- events. Matetzky et al studied clopidogrel respon-mates are present following the 300 mg loading dose siveness in patients undergoing stenting for acuteand the lower estimates occur after the 600 mg ST-elevation myocardial infarction and found thatloading dose [25,28]. Diabetic patients who were on patients who exhibited the highest quartile of ADP-long term dual antiplatelet therapy had a higher induced aggregation had a 40% probability for anumber of clopidogrel nonresponders compared to recurrent cardiovascular event within 6 monthsnondiabetic patients in a recent study [35]. [32]. In the PREPARE POST-STENTING (Platelet REactivity in Patients And Recurrent Events POST-Clopidogrel responsiveness and effect of STENTING) Study, patients suffering a recurrentdose ischemic event within 6 months of elective stenting had high post-stent platelet reactivity to ADPSubsequent investigations have unequivocally dem- compared to patients without ischemic eventsonstrated that clopidogrel nonresponsiveness is de- despite dual antiplatelet therapy [22]. In the CLEAR PLATELETS (Clopidogrel Loading with Eptifi- batide to Arrest PLATELET reactivity) and CLEAR PLATELETS Ib Studies, a 600 mg clopidogrel loading dose used to treat patients undergoing elective stenting was associated with superior early platelet inhibition compared to a 300 mg loading dose and this inhibition was accompanied by a decrease in release of myocardial necrosis and inflammation markers [37,38]. Cuisset et al demonstrated that patients with high post-treatment platelet reactiv- ity had an increased risk of cardiovascular events. More importantly, these patients were resistant to both clopidogrel and aspirin treatment [39]. Simi-Figure 3 Distribution of the absolute change in 5 uM ADP- larly Lev et al demonstrated that occurrence ofinduced aggregation (Δ aggregation) and incidence of clopido- creatinine kinase-myocardial band after stentinggrel resistance in patients treated with 300 mg and 600 mg was more frequent in patients exhibiting aspirin andclopidogrel loading dose. All of the patients under double-headed arrow meet the definition of clopidogrel resistance. clopidogrel resistance [34]. Finally, significantlyThe distribution is shifted rightward and narrower in the higher recurrent ischemic events within 6 months600 mg group indicating greater inhibition (responsiveness to of the procedure were observed in patients whoclopidogrel) and lower incidence of resistance. (Adapted from were on chronic clopidogrel therapy undergoingGurbel et al. J Am Coll Cardiol 2005;45:1392–1396). elective coronary stenting and had higher pre-
  • 6. 316 P.A. Gurbel, U.S. Tantryprocedure ADP-induced platelet aggregation [40] grel-induced P2Y12 receptor inhibition, nonrespon-(Table 2). All these findings strongly suggest that a siveness to clopidogrel treatment has beenhigh platelet reactivity despite currently recom- suggested as a risk factor for the occurrence ofmended antiplatelet therapy is a risk factor for stent thrombosis [21,41]. In the recent CRESTischemia in patients undergoing PCI. (Clopidogrel effect on platelet REactivity in Based on the analysis of flow cytometric mea- patients with Stent Thrombosis) Study, elevatedsurements of intracellular VASP phosphorylation levels of ADP-induced platelet aggregation, ADP-levels, a specific intracellular marker of clopido- stimulated expression of active GPIIb/IIIa expres- sion and the P2Y12 reactivity ratio measured by VASP phosphorylation were observed in patients with stent thrombosis compared to patients without Table 2 Clinical relevance of clopidogrel stent thrombosis, indicating inadequate inhibition nonresponsiveness of P2Y12 receptor [21]. Other investigators have Study n Results Clinical reported that high ex vivo shear-induced platelet relevance aggregation despite dual antiplatelet therapy may Post-stent ischemic events and periprocedural infarction be a risk factor for stent thrombosis [42] (Table 2). 1. Matetzky et al. [32] 60 ↑ ADP-induced Recurrent platelet cardiac aggregation events Mechanism of clopidogrel resistance (4th quartile) 2. Gurbel et al. [22] 192 ↑ Periprocedural Post-PCI The mechanisms responsible for clopidogrel re- (PREPARE Post- platelet ischemic sponse variability and resistance are incompletely Stenting Study) aggregation events defined. Differences in intestinal absorption, he- (6 months) patic conversion to the active metabolite through 3. Gurbel et al. 120 ↑ Periprocedural Myonecrosis [37,38] (CLEAR platelet and cytochrome 3A4 (CYP3A4) activity, and platelet PLATELETS and aggregation inflammation receptor polymorphisms have been suggested CLEAR PLATELETS marker [14,43–46]. Ib) release Only up to 30–50% inhibition of ex vivo ADP- 4. Bliden et al. [40] 100 ↑ Periprocedural Post-PCI induced platelet aggregation was demonstrated platelet ischemic aggregation in events following a repeated daily dose of 75 mg in normal patients on (6 months) volunteers or loading doses of 300 or 600 mg in chronic patients undergoing PCI [13,37,38]. This level of clopidogrel inhibition indicated an incomplete P2Y12 receptor 5. Cuisset et al. [39] 106 ↑ Platelet Recurrent blockade and suboptimal inhibition of ADP-induced aggregation events 6. Lev et al. [34] 120 ↑ Clopidogrel/ Post-PCI platelet aggregation. The repeated demonstrations aspirin resistant myonecrosis that a high loading dose of 600 mg clopidogrel is patients associated with increased inhibition of ex vivo ADP- induced platelet aggregation in patients undergoing Stent thrombosis PCI and a decreased prevalence of nonresponders 7. Barragen et al. [41] 36 ↑ P2Y12 reactivity Stent ratio (VASP-levels) thrombosis support insufficient active metabolite generation as 8. Gurbel et al. [21] 120 ↑ P2Y12 reactivity Stent a major factor in clopidogrel resistance [25,28,36, (CREST Study) ratio thrombosis 43,47]. ↑ platelet Recent studies involving the measurement of aggregation hepatic cytochrome (CYP) P450 activity suggest that ↑ stimulated GPIIb/IIIa individual variations in the activity of this enzyme expression play a major role [14,48–50]. In a landmark 9. Ajzenberg et al. [42] 49 ↑ Shear-induced Stent investigation, Lau et al demonstrated that pharma- platelet thrombosis cologic stimulation of CYP3A4 activity by rifampin aggregation enhances the inhibitory effect of clopidogrel, ADP=adenosine diphosphate; CLEAR PLATELETS Study =clopido- whereas agents that compete with clopidogrel for grel loading with eptifibatide to arrest the reactivity of platelets: CYP 3A4 activity (e.g. erythromycin) attenuate the results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets study; CREST Study=clopidogrel effect on antiplatelet effect of clopidogrel [14,48]. Addition- platelet reactivity in patients with stent thrombosis; GP=glyco- al information supporting the pivotal role of CYP protein; PCI=percutaneous coronary intervention; PREPARE P450 in generating the active metabolite of clopi- POST-Stenting Study=platelet reactivity in patients and recur- dogrel was demonstrated in a small study involving rent events post-stenting study; VASP=vasodilator-stimulated human volunteers where the effects of the CYP3A4 phosphoprotein. inhibitor, ketoconazole, on the pharmacokinetics
  • 7. Clopidogrel resistance? 317 Figure 4 Clopidogrel metabolism and factors affecting clopidogrel responsiveness.and the ex vivo platelet inhibitory effects of CYP3A4 gene may be an important contributor toprasugrel and clopidogrel were investigated. Prasu- clopidogrel response variability [53] (Fig. 4).grel is also a thienopyridine that requires conversion Suboptimal platelet response to clopidogrel mayto an active metabolite by a hepatic cytochrome. In be due to an increased number of platelet P2Y12this study, ketoconazole co-administration did not receptors, or polymorphism of platelet receptors.have any effect on prasugrel active metabolite Genetic polymorphisms of platelet GPIIb/IIIa, GPIa/generation or prasugrel-induced platelet inhibition, IIa, or P2Y12 receptors have been reported to affectwhereas clopidogrel-induced platelet inhibition was platelet function and may influence clopidogrelreduced following a loading dose as well as after a response variability [54–56]. Recently, it wasmaintenance dose [49]. The latter effect on reported that an increased percentage of patientsclopidogrel-induced platelet inhibition was accom- with peripheral arterial disease have the P2Y12panied by lesser active metabolite generation. receptor H2 haplotype [55]. However, in anotherSimilarly, in another study, prasugrel treatment study, the relation of this haplotype to clopidogrelwas associated with superior active metabolite responsiveness could not be demonstrated [56]. Sincegeneration and platelet inhibition together with a the relation of genetic polymorphisms to clopidogrellower incidence of nonresponsiveness compared to responsiveness is inconclusive, further studies areclopidogrel treatment [50]. required to establish a correlation between receptor In recent studies, the influence of CYP3A5 and polymorphisms and clopidogrel nonresponsiveness.CYP2C19 isoenzymes on clopidogrel metabolic It has been shown that patients with diabetesactivation and responsiveness has been demonstrat- exhibit platelet activation and increased reactivityed [51,52]. Suh J et al demonstrated higher to agonists. The heightened platelet reactivity mayclopidogrel responsiveness among subjects with be related to the increased prevalence of nonre-the CYP3A5 expressor genotype than subjects with sponders and occurrence of ischemic eventsthe non-expressor genotype. Moreover, worse out- reported in patients with diabetes [57,58]. It hascomes were seen in patients undergoing stent also been reported that patients with a high bodyimplantation with the non-expressor genotype mass index (BMI) exhibited a suboptimal plateletfollowing treatment with clopidogrel than in response with the standard 300 mg loading dosepatients with the CYP3A5 expressor genotype [51]. [59].Similarly, Hulto J et al and Brandt et al indepen- All of the above data strongly support thedently demonstrated the influence of the CYP2C19 importance phenomenon of insufficient metabolitegenotype on clopidogrel responsiveness in healthy generation secondary to limitations in the intestinalvolunteers [52]. Finally, Angiolillo DJ et al demon- absorption, drug–drug interaction at CYP 3A4 orstrated that the IVS10 + 12G N A polymorphism of the genetic polymorphisms of CYP isoenzymes as the
  • 8. 318 P.A. Gurbel, U.S. Tantryprimary explanations for resistance rather than data to support the cutpoint of 50% inhibition [21,37].genetic polymorphisms of platelet receptors or In the CLEAR PLATELETS Study we observed peripro-intracellular signaling mechanisms. The latter cedural myocardial infarction only in those patientsmechanisms may be relevant in those patients who with 5 μM ADP-induced aggregation N 50% [37]. In theremain resistant and with high platelet reactivity to CREST Study the cutpoint for stent thrombosis wasADP even after high dosing strategies. 20 μM ADP-induced aggregation N40% [21].Management of clopidogrel resistance New P2Y12 receptor antagonistsHigher doses New P2Y12 receptor antagonists are currently under- going investigation. AZD 6140 (Astra-Zeneca) andIn recent clinical studies of patients undergoing cangrelor (Medicines Company) are reversible, directstenting, a 600 mg clopidogrel loading dose was and potent inhibitors of the P2Y12 receptor [64,65].associated with a higher level of platelet inhibition, AZD 6140 is an oral inhibitor whereas cangrelor islower mean post-treatment reactivity to ADP, and a administered parenterally. Both of these agentslower incidence of nonresponsiveness when com- exhibit more consistent and greater platelet inhibitionpared to a 300 mg dose [25,28,37,60]. Moreover, a compared to clopidogrel. The short onset and offset of600 mg clopidogrel loading dose was associated with action make these agents appealing adjunctive anti-a narrower response profile [25]. Kastrati et al found platelet agents during PCI when maximum and rapidthat patients achieved additional platelet inhibition platelet inhibition of ADP-induced aggregation iswhen a 75 mg/day clopidogrel maintenance dose desired [64,65]. Prasugrel is an irreversible inhibitorwas followed by an additional 600 mg loading dose of P2Y12 and, similar to clopidogrel, is a prodrug that[61]. In the CLEAR PLATELETS Study a 600 mg loading requires metabolic activation. In the JUMBO-TIMI-26dose was associated with a superior pharmacody- trial, prasugrel treatment was associated with anamic antiplatelet profile compared to a 300 mg similar primary endpoint of significant bleedingclopidogrel loading dose [37,38]. In the recent ISAR- compared to standard clopidogrel regimen (1.7 vs.CHOICE (Intracoronary Stenting and Antithrombotic 1.2) and the bleeding events were the same for allRegimen: Choice Between 3 High Oral doses for doses of prasugrel [66]. The pharmacodynamic profileImmediate Clopidogrel Effect) Study, there was a of prasugrel is superior to clopidogrel and is associatedceiling effect in unchanged clopidogrel and clopido- with lesser incidences of nonresponsiveness [67]. Allgrel metabolite levels and platelet inhibition with three of the above agents will undergo study in phase 3the 600 mg loading dose, and no significant clinical trials. Prasugrel is currently being compared toadditional effect was seen with the 900 mg loading clopidogrel in an ACS trial in patients undergoing PCI.dose. Based on the pharmacokinetic profile of thefree drug and metabolites the investigators con- Conclusioncluded that intestinal absorption was the majorfactor explaining response variability [62]. Clopidogrel use has increased over the last few Thus, higher loading doses may be considered for years following its effectiveness together withselected patients exhibiting high platelet reactivity to aspirin in significantly reducing adverse events inADP However, the superiority of a high dose regimen . large-scale clinical trials. At the same time, basedin reducing ischemic events and the associated risk on the laboratory evaluation of platelet response,profile compared to a standard dose has yet to be wide response variability and nonresponsiveness inestablished in large scale clinical trials. Despite these selected patients are also present. In the recentlimitations, the current ACC/AHA guidelines for PCI small studies, heightened platelet reactivity orprovide a Class IIa recommendation that “a regimen clopidogrel nonresponsiveness in patients whoof greater than 300 mg is reasonable to achieve higher were on clopidogrel treatment was associatedlevels of antiplatelet activity more rapidly”. Finally, with adverse thrombotic events including stentthe ACC/AHA Guidelines provide a Class IIb recom- thrombosis. The primary reason has been attributedmendation that “in patients in whom subacute to the suboptimal generation of active metabolitethrombosis may be catastrophic or lethal… platelet secondary to potential limitation in intestinalaggregation studies may be considered and the dose absorption, drug–drug interaction at CYP3A4 andof clopidogrel increased to 150 mg per day if less than genetic polymorphism of hepatic cytochrome P45050% inhibition of platelet aggregation is demonstrat- isoenzymes. Use of higher loading or maintenanceed” [63]. The latter guidelines however, do not doses of clopidogrel or new and more potent P2Y12specify the methodology that should be used to assess receptor blockers is a potential alternative strategy.inhibition. Moreover, there are very limited clinical In addition, treatment with combined antiplatelet
  • 9. Clopidogrel resistance? 319therapies may be confined to the pharmacologic [7] Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE,management of patients at high risk for arterial et al. CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.thrombotic events but not as a primary prevention N Engl J Med 2006;354:1706–17.strategy or as an alternative to anticoagulants. [8] ACTIVE Writing Group on behalf of the ACTIVE Investiga- tors, Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S,Acknowledgements et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular EventsDr. Gurbel has a research grant from Schering and (ACTIVE W): a randomised controlled trial. Lancet 2006;Millenium in the last 2 years studying antiplatelet 367:1903–12.effects of clopidogrel and eptifibatide in elective [9] Gurbel PA, Bliden KP, Hiatt BL, OConnor CM. Clopidogrel forstenting. Dr. Gurbel has a research grant from Astra coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. CirculationZeneca in the last 2 years studying antiplatelet 2003;107:2908–13.effects of clopidogrel in relation to stent thrombosis. [10] Cattaneo M. Aspirin and clopidogrel: efficacy, safety, andDr. Gurbel has a research grant from Bayer in the last the issue of drug resistance. Arterioscler Thromb Vasc Biol2 years studying antiplatelet effects of aspirin in 2004;24:1980–7.outpatients. Dr. Gurbel has a research grant from [11] Rocca B, Patrono C. Determinants of the interindividual variability in response to antiplatelet drugs. J ThrombAstra Zeneca in the last 2 years studying antiplatelet Haemost 2005;3:1597–602.effects of AZD6140 in elective stenting. Dr. Gurbel has [12] Tantry US, Bliden KP, Gurbel PA. Resistance to antiplateleta research grant from Haemoscope and NIH in the last drugs: current status and future research. Expert Opin2 years studying physical properties of clot formation Pharmacother 2005;6:2027–45 [Review].and recurrent ischemic events post-elective stenting. [13] Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, ef-Dr. Gurbel has been a co-investigator in the last 2 years fectiveness, and side effects: the Seventh ACCP Confe-for Medtronic and Boston Scientific studying new drug- rence on Antithrombotic and Thrombolytic Therapy. Chesteluting stents in elective stenting. Dr. Gurbel was a 2004;126(3 Suppl):234S–64S.scientific officer for a start-up company — Throm- [14] Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carvilleboscience that is no longer in existence. Dr. Gurbel DG, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrelserves as consultant for Astra Zeneca, Lilly, Sanofi, resistance. Circulation 2004;109:166–71.Bayer, and the Medicines Company. There is no con- [15] Savi P, Combalbert J, Gaich C, Rouchon MC, Maffrand JP,flict of interest for other authors. Berger Y, et al. The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A. Thromb Haemost 1994;72:313–7.References [16] Xiao Z, Theroux P. Clopidogrel inhibits platelet–leukocyte interactions and thrombin receptor agonist peptide-in- [1] Ding Z, Kim S, Dorsam RT, Jin J, Kunapuli SP. 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  • 10. 320 P.A. Gurbel, U.S. Tantry[23] von Beckerath N, Pogatsa-Murray G, Wieczorek A, Sibbing D, With Eptifibatide to Arrest the Reactivity of Platelets Schomig A, Kastrati A. Correlation of a new point-of-care (CLEAR PLATELETS) study. Circulation 2005;111:1153–9. test with conventional optical aggregometry for the [38] Gurbel PA, Bliden KP Tantry US. The effect of clopidogrel with , assessment of clopidogrel responsiveness. Thromb Haemost and without eptifibatide on tumor necrosis factor-alpha and 2006;95:910–1. C-reactive protein release after elective stenting: Results of[24] Aleil B, Ravanat C, Cazenave JP, Rochoux G, Heitz A, Gachet the CLEAR PLATELETS-Ib study. J Am Coll Cardiol in press. C. Flow cytometric analysis of intraplatelet VASP phosphor- [39] Cuisset T, Frere C, Quilici J, Barbou F, Morange PE, Hovasse ylation for the detection of clopidogrel resistance in T, et al. High post-treatment platelet reactivity identified patients with ischemic cardiovascular diseases. J Thromb low-responders to dual antiplatelet therapy at increased Haemost 2005;3:85–92. risk of recurrent cardiovascular events after stenting for[25] Gurbel PA, Bliden KP, Hayes KM, Yoho JA, Herzog WR, Tantry acute coronary syndrome. J Thromb Haemost 2006;4: US. The relation of dosing to clopidogrel responsiveness and 542–9. the incidence of high post-treatment platelet aggregation [40] Bliden KP, Tantry U, Zaman K, Bassi A, Hayes K, Yoho J, et al. in patients undergoing coronary stenting. J Am Coll Cardiol High platelet reactivity is a risk factor for post-discharge 2005;45:1392–6. ischemic complications following elective coronary stent-[26] Gurbel PA, Lau WC, Bliden KP, Tantry US. Clopidogrel ing. J Am Coll Cadriol 2005;45:33A. resistance: implications for coronary stenting. Curr Pharm [41] Barragan P, Bouvier JL, Roquebert PO, Macaluso G, Des 2006;12:1261–9. Commeau P, Comet B, et al. Resistance to thienopyridines:[27] Jaremo P, Lindahl TL, Fransson SG, Richter A. Individual clinical detection of coronary stent thrombosis by monitor- variations of platelet inhibition after loading doses of ing of vasodilator-stimulated phosphoprotein phosphoryla- clopidogrel. J Intern Med 2002;252:233–8. tion. Catheter Cardiovasc Interv 2003;59:295–302.[28] Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. [42] Ajzenberg N, Aubry P, Huisse MG, Cachier A, et al. Enhanced Prevalence of clopidogrel non-responders among patients shear-induced platelet aggregation in patients who experi- with stable angina pectoris scheduled for elective coronary ence subacute stent thrombosis: a case-control study. J Am stent placement. Thromb Haemost 2003;89:783–7. Coll Cardiol 2005;45:1753–6.[29] Mobley JE, Bresee SJ, Wortham DC, Craft RM, Snider CC, [43] Taubert D, Kastrati A, Harlfinger S, Gorchakova O, Lazar A, Carroll RC. Frequency of nonresponse antiplatelet activity von Beckerath N, et al. Pharmacokinetics of clopidogrel of clopidogrel during pretreatment for cardiac catheteri- after administration of a high loading dose. Thromb Haemost zation. Am J Cardiol 2004;93:456–8. 2004;92:311–6.[30] Lepantalo A, Virtanen KS, Heikkila J, Wartiovaara U, Lassila [44] Beer JH, Pederiva S, Pontiggia L. Genetics of platelet R. Limited early antiplatelet effect of 300 mg clopidogrel in receptor single-nucleotide polymorphisms: clinical implica- patients with aspirin therapy undergoing percutaneous tions in thrombosis. Ann Med 2000;32:10–4. coronary interventions. Eur Heart J 2004;25:476–83. [45] Fontana P, Gaussem P, Aiach M, Fiessinger JN, Emmerich J,[31] Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Reny JL. P2Y12 H2 haplotype is associated with peripheral Barrera-Ramirez C, Sabate M, et al. Identification of low arterial disease: a case-control study. Circulation 2003;16 responders to a 300-mg clopidogrel loading dose in (108):2971–3. patients undergoing coronary stenting. Thromb Res 2005; [46] Von Beckerath N, von Beckerath O, Koch W, Eichinger M, 115:101–8. Schomig A, Kastrati A. P2Y12 gene H2 haplotype is not[32] Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, associated with increased adenosine diphosphate-induced Goldenberg I, et al. Clopidogrel resistance is associated platelet aggregation after initiation of clopidogrel therapy with increased risk of recurrent atherothrombotic events in with a high loading dose. Blood Coagul Fibrinolysis patients with acute myocardial infarction. Circulation 2005;16:199–204. 2004;109:3171–5. [47] Kastrati A, von Beckerath N, Joost A, Pogatsa-Murray G,[33] Dziewierz A, Dudek D, Heba G, Rakowski T, Mielecki W, Gorchakova O, Schomig A. Loading with 600 mg clopidogrel Dubiel JS. 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