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(Circulation. 2004;109:3064-3067.)
© 2004 American Heart Association, Inc.

Focused Perspective

Clopidogrel Resistance

A New Chapter in a Fast-Moving Story

Stephen D. Wiviott, MD; Elliott M. Antman, MD

From the TIMI Study Group of the Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Stephen D. Wiviott, MD, The TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail swiviott{at}partners.org

Key Words: Focused Perspectives • clopidogrel • aspirin • platelets • drug resistance

	Introduction

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Although platelets lack nuclei and are the smallest circulating human cells, they play an integral and complex role in the process of thrombosis, both physiological and pathophysiological. Activation and aggregation of platelets play a central role in the propagation of intracoronary thrombi after (1) spontaneous atherosclerotic plaque disruption that results in myocardial ischemia or infarction in the acute coronary syndromes (ACS), or (2) the mechanical disruption that results from percutaneous coronary intervention (PCI). Platelets initially adhere to collagen and von Willebrand factor at the site of the disrupted plaque, resulting in an initial platelet monolayer. After activation, platelets release secondary agonists such as thromboxane A₂ and adenosine diphosphate (ADP), which in combination with thrombin generated by the coagulation cascade result in stimulation and recruitment of additional platelets.^1,2 With this pathophysiological background, it is not surprising that antiplatelet therapy is a cornerstone of the management of patients with ACS, especially those undergoing PCI.^3–5

See p 3171

	Antiplatelet Agents

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Aspirin inhibits cyclooxygenase (COX) by irreversible acetylation, which prevents the production of thromboxane A₂. The antithrombotic effect of aspirin results from the decreased production of this prothrombotic, vasoconstrictive substance. Aspirin is effective in the short- and long-term prevention of adverse vascular events in high-risk patient groups, including those with ACS, stroke and peripheral arterial disease.⁶ Aspirin also has been shown to reduce the frequency of ischemic complications after PCI.^7,8

Despite the impressive and consistent effects of aspirin in reducing adverse events in a variety of ischemic heart disease states, a significant rate of such events persists, and more potent antiplatelet agents, glycoprotein IIb/IIIa inhibitors, and thienopyridines have been developed. The thienopyridines irreversibly inhibit ADP binding to the P2Y₁₂ receptor on the platelet surface. By blocking this receptor, these agents interfere with platelet activation, degranulation, and—by inhibiting the modification of the glycoprotein IIb/IIIa receptor—aggregation. Currently available thienopyridine antiplatelet agents include ticlopidine and clopidogrel. Both agents are rapidly absorbed prodrugs that are modified hepatically to active metabolites.² The agents have similar platelet effects and have been shown to be clinically efficacious. However, clopidogrel has largely replaced ticlopidine because of an improved safety profile, with a lower incidence of hematologic complications (neutropenia and pancytopenia) than ticlopidine.⁹ The effects of clopidogrel are time and dose dependent, with a ceiling effect at approximately 50% to 60% inhibition of platelet aggregation.² Loading doses of clopidogrel of 300 to 600 mg reach near steady-state levels of platelet aggregation by 4 to 24 hours, whereas daily maintenance dosing with 75 mg daily without a preload results in steady-state levels within 4 to 7 days.^2,10,11

Clopidogrel has been compared with aspirin in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial¹² in patients with vascular disease (stroke, myocardial infarction, or peripheral arterial disease) and was found to produce a relative reduction in vascular events by 8.7%. Clopidogrel has been tested in combination with aspirin (versus aspirin alone) in the Clopidogrel in Unstable angina Recurrent Events (CURE) trial¹³ in patients with unstable angina/non–ST-segment–elevation myocardial infarction (UA/NSTEMI). Significant reductions in clinical outcomes were seen as early as 24 hours after randomization and persisted to study completion (average of 9-month follow-up) and were seen across multiple treatment and risk groups.¹³ Studies of thienopyridines as a component of acute treatment for STEMI are ongoing.

The Clopidogrel for the Reduction of Events During Observation (CREDO) trial¹⁴ examined the effects of a loading dose (300 mg) of clopidogrel before PCI followed by maintenance dosing versus maintenance alone and found a significant reduction of early events only when pretreatment was given >6 hours before PCI. A subsequent analysis of the CREDO trial suggests the minimal efficacious time interval may be on the order of 12 to 15 hours.¹⁵ Data from a modest-sized trial examining high-dose (600-mg) clopidogrel pretreatment in the setting of low-risk PCI suggest there is no incremental advantage of adding an intravenous glycoprotein IIb/IIIa inhibitor in reducing peri-PCI ischemic events.¹⁶

	Resistance to Antiplatelet Agents

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Although antiplatelet agents reduce ischemic events, "resistance" to their effects continues to occur. The term resistance in this setting is problematic in that it has been variably used to indicate failure of an agent to prevent the clinical condition for which it is intended or failure of the agent to achieve the biochemical (pharmacokinetic and/or pharmacodynamic) effect. Because of the complex pathophysiology of ischemic heart disease, involving thrombosis, inflammation, vascular biology, hemodynamics, etc, no single agent can be expected to abolish ischemic events. Furthermore, a patient may have the appropriate platelet response to a given therapy but have recurrent events mediated by nonplatelet factors. For these reasons, it would be reasonable to classify patients who have recurrent events on therapy as having failure of therapy, while limiting the term resistance to those patients for whom the agent does not achieve its pharmacological effect. The key clinical question is what role resistance to an agent plays in failure of therapy.

To identify the failure to achieve a pharmacological effect, one must be able to measure it reliably. Several assays are available to measure platelet function and effects of antiplatelet agents.¹⁷ A commonly used test of platelet function measures platelet aggregation by light transmittance (optical aggregometry) in platelet-rich plasma in response to an agonist (arachidonic acid, ADP, collagen, epinephrine, or a thrombin receptor–activating peptide).¹⁷ This mechanism allows monitoring of different drug effects by allowing choice of agonist (eg, ADP for thienopyridines). Because of inter- and intra-patient variability, standardized responses are not meaningful, and results are often reported as a percentage of a baseline value. Other methods include the cone and plate(let) analyzer,¹⁸ a rapid test that measures whole blood platelet aggregation under conditions of high shear stress.

The presence of aspirin treatment failures in several disease states led to the concern that selected patients may be resistant to the effects of aspirin. Prevalence of resistance varied by disease condition and platelet function methodology.¹⁹ There is evidence of a link between aspirin resistance and clinical events. In patients with a prior stroke, those with aspirin resistance were 89% more likely to have a recurrent cerebrovascular accident within 2 years than were responders.^20,21 Similar results were seen in patients after peripheral intervention, with an increase in arterial reocclusion among aspirin responders.²² A case-control study from the Heart Outcomes Prevention Evaluation (HOPE) study measured urinary 11-dehydro thromboxane B₂ (a stable arachidonic acid metabolite produced by activated platelets). They found that among patients treated with aspirin, those with the highest levels (suggesting incomplete thromboxane inhibition) had a 3.5-fold increase in cardiovascular mortality and a doubling of myocardial infarction.²³ The definitive cause(s) of aspirin resistance are not known; however, several possible mechanisms have been proposed and include extrinsic factors (eg, cigarette smoking, drug–drug interactions, inadequate aspirin dosing) and intrinsic factors (eg, inducible COX-2 not inhibited by aspirin, variation in COX-1 structure preventing acetylation, thromboxane production by nonplatelet cells).¹⁹

More recently, a similar story of variable platelet response and potential resistance to therapy has emerged with thienopyridines. Analogous to aspirin resistance, there is no clear and accepted definition for clopidogrel resistance. Studies have shown a dose- and time-dependent variability in response to clopidogrel as measured by optical platelet aggregometry in response to ADP.^10,11,24,25 In a study by Gurbel et al,¹⁰ 96 patients undergoing elective coronary stenting were monitored before and at multiple time points after standard clopidogrel therapy (300-mg loading dose followed by 75 mg daily). Clopidogrel resistance, empirically defined as <10% reduction in aggregation in response to 5 µmol/L ADP compared with pretreatment values, was seen in 63% of patients at 2 hours, 31% at 24 hours, 31% at 5 days, and 15% at 30 days.¹⁰ Patients with the highest pretreatment values had the least antithrombotic protection over the first 5 days.¹⁰ In another report, Muller et al¹¹ defined nonresponders as those with <10% reduction in platelet aggregation to ADP and semiresponders as those with 10% to 29% reduction 4 hours after 600-mg clopidogrel load,¹¹ as no additional effect was seen with this treatment regimen at 24 hours. This study found that to 5 µmol/L ADP, 5% were nonresponders and 9% were semiresponders, and to 20 µmol/L ADP, 11% were nonresponders and 26% were semiresponders.¹¹ Although not designed to evaluate clinical outcomes, an intriguing finding in the Muller study was that 2 patients (of 105 tested) developed subacute stent thrombosis, and both met the definition of clopidogrel nonresponse. An additional report correlated anginal class to platelet inhibition and found that patients with higher anginal class on presentation had less inhibition of platelet aggregation after loading with 450 mg of ADP.²⁶

Several mechanisms of clopidogrel resistance are possible. Extrinsic mechanisms include inappropriate dosing or underdosing of clopidogrel and drug–drug interactions, including a possible interaction between clopidogrel and atorvastatin.^27,28 There is a positive correlation of clopidogrel response with CYP3A4 activity (measured by erythromycin breath test),²⁹ suggesting that an important mechanism may be variable conversion to the active metabolite. Other potential extrinsic mechanisms could include variable absorption of the prodrug or clearance of the active metabolite. Intrinsic mechanisms could include P2Y₁₂ receptor variability, increase in number of receptors, increased release of ADP, or upregulation of other platelet activation pathways. In contrast to aspirin resistance, there has not previously been a link between clopidogrel resistance as measured by platelet assays and clinical adverse events.

In the present issue of Circulation, Matetzky and colleagues³⁰ add a new and important piece to the emerging clopidogrel resistance picture: correlation of a laboratory measure of clopidogrel nonresponse with clinical outcomes. Patients who underwent primary PCI (n=60) with stenting and 10 patients who underwent primary angioplasty for STEMI received 300 mg aspirin on admission and eptifibatide and heparin during PCI. Those who received stents were treated with clopidogrel: 300 mg immediately after PCI and 75 mg daily for 3 months. Platelet function tests were performed with turbidometric analysis after stimulation with ADP (5 µmol/L) and epinephrine (10 µmol/L), as well as separate assays of platelet function using a cone and plate(let) analyzer.¹⁷ Patients were divided into quartiles of inhibition of platelet aggregation (platelet aggregation compared with baseline platelet aggregation), with the first quartile being considered nonresponders (day 6 aggregation 103±8% compared with baseline). Patients in quartiles 2 through 4 had varying levels of response, with platelet aggregation of 69%, 58%, and 33% of baseline values. During 6-month follow-up, 7 patients (40%) in quartile 1 (nonresponders) had 8 clinical events, including stent thrombosis, myocardial infarction, recurrent ACS, and peripheral arterial occlusion. One patient in the second quartile (6.7%) and no patients in quartiles 3 or 4 had recurrent events (P trend=0.007). Although the study population was small, these data strongly suggest that there is individual variability in response to clopidogrel in the setting of PCI after STEMI and more broadly that clopidogrel resistance may be a marker for increased risk of recurrent cardiovascular events.

Several questions arise from the growing literature on clopidogrel resistance. Should patients with ACS or those undergoing PCI routinely have platelet function measured? If so, how should it be measured? What should be considered the appropriate definition of clopidogrel resistance? What therapeutic maneuvers should clinicians undertake when they encounter a patient with clopidogrel resistance? Are there actions that can be taken prospectively to avoid the problem of resistance?

Before the first question is answered in the affirmative, the observations by Matetzky et al³⁰ need to be reproduced in larger datasets. Before these measurements become clinically useful for risk stratification, there should be easily performed and reproducible ways to measure platelet aggregation, with standardized definitions of response that correlate with clinical outcomes. Finally, to allow these observations to improve the care of patients, therapies must be found that can overcome the resistance to platelet aggregation inhibition. One approach to managing clopidogrel resistance may involve giving higher loading and maintenance doses. Another promising approach may be to utilize alternative thienopyridine agents such as CS-747 (LY640315),³¹ nonthienopyridine P2Y₁₂ inhibitors such as AR-C69931MX,^2,32 or antagonists of other platelet targets. As we learn more about the variable response to antiplatelet drugs, will the time soon come for us to think of antiplatelet agents like antibiotics, tailoring therapy when resistance is observed in the laboratory?

	Footnotes

 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

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