Clopidogrel Nonresponders Research Articles

A New Clopidogrel (Plavix) Point-of-Care Assay: Rapid Determination of Antiplatelet Activity in Trauma Patients

An increasing proportion of trauma patients are on anticoagulation or antiplatelet therapy. Unlike warfarin, where measuring international normalized ratio can help direct management, measuring platelet inhibition from clopidogrel (Plavix) is not standardized. We report the use of a new P2Y12 point-of-care assay (VerifyNow; Accumetrics, San Diego, CA) to determine the magnitude of platelet inhibition in trauma patients using clopidogrel. Trauma patients in 2009 were queried for clopidogrel use by prehospital personnel and the trauma team. Blood was obtained on admission for patients reportedly taking clopidogrel and was assayed for platelet inhibition using the VerfiyNow-P2Y12 device that measures P2Y12 reaction units and photometrically determines platelet inhibition percentage within 30 minutes. Patient demographics including age, Injury Severity Score, mechanism of injury, and complications from hemorrhage were also analyzed. In the time studied, 46 patients taking clopidogrel were assayed for platelet inhibition. The mean age was 75.9 years±11.8 years, and the most common mechanism of injury was fall (86.9%). Platelet inhibition ranged from 0% to 89%. There were no deaths, and only two patients, from the 0% and>30% inhibition group, had hemorrhagic complications (increased intracranial hemorrhage). The P2Y12 point-of-care assay determined that a large percentage of patients had undetectable or low platelet inhibition despite reportedly being on clopidogrel therapy. These patients may be clopidogrel nonresponders or noncompliant. It is unlikely that clopidogrel reversal therapies, such as platelet transfusions or Desmopressin, would be beneficial in this group. Further studies stratifying the percent platelet inhibition needed to increase bleeding complications is warranted to optimize management strategies.

Platelet function variability and non-genetic causes

Dual antiplatelet therapy (DAPT) has been established for the treatment of coronary artery disease, especially in and after acute coronary syndromes, and after coronary interventions. Data suggest that a significant percentage of individuals treated with clopidogrel do not receive the expected therapeutic benefit because of a decreased responsiveness of their platelets, which is caused by several extrinsic and intrinsic mechanisms. The clinical consequence of clopidogrel non-responsiveness is severe cardiovascular complications. Besides genetic variability in response to antiplatelet therapy, non-genetic causes such as drug interactions (proton-pump inhibitors, statins, calcium-channel blockers, coumarin derivates, antibiotics, antimycotics) and co-morbidities (diabetes mellitus, renal failure, obesity) are responsible for this phenomenon. Large clinical trials with standardised laboratory methods and hard clinical endpoints are needed to identify these interactions with clopidogrel and predictors for its non-responsiveness.

ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use

This expert consensus document was developed by the American College of Cardiology Foundation (ACCF), the American College of Gastroenterology (ACG), and the American Heart Association (AHA). Expert consensus documents inform practitioners, payers, and other interested parties of the opinion of ACCF and document cosponsors concerning evolving areas of clinical practice or medical technologies. Expert consensus documents cover topics for which the evidence base, experience with technology, or clinical practice is not considered sufficiently well developed to be evaluated by the formal ACCF/AHA Practice Guidelines process. Often, the topic is the subject of considerable ongoing investigation. Thus, the reader should view the expert consensus document as the best attempt of the ACCF and document cosponsors to inform clinical practice in areas where rigorous evidence may not yet be available. To avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the writing committee, all members of the writing committee, as well as peer reviewers of the document, are asked to disclose all current healthcare-related relationships and those existing 12 months before initiation of the writing effort. The ACCF Task Force on Clinical Expert Consensus Documents (CECD) reviews these disclosures to determine which companies make products (on market or in development) that pertain to the document under development. Based on this information, a writing committee is formed to include a majority of members with no relevant relationships with industry (RWI), led by a chair with no relevant RWI. Authors with relevant RWI are not permitted to draft or vote on text or recommendations pertaining to their RWI. RWI are reviewed on all conference calls and updated as changes occur. Author and peer reviewer RWI pertinent to this document are disclosed in Appendixes 1 and 2, respectively. Additionally, to ensure complete transparency, …

Nonresponders to clopidogrel: pharmacokinetics and interactions involved

Importance of the field: The use of clopidogrel and aspirin has become standard therapy in patients with acute coronary syndromes and stent implantation. However, concern arises because about 25% of subjects are nonresponders to clopidogrel. This nonresponsiveness is associated with a threefold increase in adverse outcomes. Clopidogrel resistance is multifactorial, but genetic polymorphisms in clopidogrel's metabolic activation (e.g., cytochrome P450 2C19) and drug–drug interactions at this level (e.g., between proton pump inhibitors (PPIs) and clopidogrel) are both associated with decreased clopidogrel efficacy. Despite all PPIs being potent inhibitors of CYP2C19, evidence about their clinical impact is controversial.Areas covered in this review: Pharmacogenomic and pharmacokinetic aspects of clopidogrel nonresponsiveness were considered in detail.What the reader will gain: The reader will gain an exhaustive review of the current state of the controversial issues regarding genetic polymorphisms and drug–drug interactions affecting clopidogrel efficacy.Take home message: It is important to consider clopidogrel resistance in some patients and establish strategies to handle this problem (e.g., genotyping, platelet aggregability tests, new antiplatelet drugs). The combined use of PPIs and clopidogrel is at present regulated by the FDA and EMEA; however, the risk/benefit balance should be made for each patient individually.

Predictors of Biochemical Aspirin and Clopidogrel Resistance in Patients With Ischemic Stroke

Variable platelet response to aspirin and clopidogrel is a well-established phenomenon in patients with coronary artery disease. We sought to determine the predictors of an impaired biochemical response to aspirin and clopidogrel in patients with ischemic stroke. Patients with established cerebrovascular disease who underwent an aspirin/clopidogrel response panel (ie, light transmittance aggregometry) between June 2003 and March 2007 were identified through an electronic database. The medical records of these patients were retrospectively reviewed, and demographic characteristics, medical history, and laboratory results were recorded. Univariate and multivariate logistic regression analyses were performed to assess for factors associated with antiplatelet resistance. Of the 465 patients included in this study, 120 (28%) were biochemical aspirin nonresponders and 83 (28%) were biochemical clopidogrel nonresponders. Of the 270 patients on dual antiplatelet therapy, 25 (9.3%) were dual biochemical nonresponders. In binary logistic regression modeling, patients with congestive heart failure (odds ratio [OR] = 4.54; 95% confidence interval [CI] = 1.33-15.5; P = .02) and those with higher hemoglobin A1c values (OR = 1.41; 95% CI = 1.12-1.79; P = .004) had a significantly greater likelihood of having a biochemical nonresponse to aspirin therapy. African-American patients (OR = 2.19; 95% CI = 1.23-3.91; P < .007) were significantly more likely to be nonresponders to clopidogrel. This preliminary study shows that aspirin and clopidogrel biochemical nonresponse frequently occurs in ischemic stroke patients. In addition, some associated variables may affect the biochemical response to antiplatelet therapy. Further study is needed to explore whether this nonresponse has an impact on clinical outcomes.

ACCF/AHA Clopidogrel Clinical Alert: Approaches to the FDA “Boxed Warning”

The recent US Food and Drug Administration (FDA) “boxed warning” on clopidogrel raises important questions for practitioners and patients. The warning addresses the need for pharmacogenomic testing to identify patients’ altered clopidogrel metabolism and thus their risk for a suboptimal clinical response to clopidogrel. Although there is an expanding database on genetic polymorphisms that may affect clopidogrel metabolism and thus clinical outcomes, there are no evidence-based data upon which todevelop specific recommendations on the role of genetic testing in routine care nor strategies proven to improve the safety/efficacy of specific pharmacologic approaches. To provide guidance on this issue, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) convened a writing committee. The ACCF and AHA adhere to a rigorous policy regarding relationships with industry and other entities (RWI) of authors and peer reviewers for clinical document development (see http://www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/Relationships-With-Industry-Policy.aspx). This policy requires that a majority of writing committee members have no relevant relationships with industry to this topic, a standard that has been achieved for this document as indicated in Appendix 1. In the spirit of full disclosure, comprehensive RWI (RWI not relevant to this document) for all authors is available online for public view. RWI …

Early stent thrombosis with progressive brainstem infarction in a clopidogrel non-responder

Nonor hypo-response to clopidogrel has been observed frequently in patients with cardiovascular disease resulting in worsened cardiovascular outcome and a higher complication rate after coronary stenting [1, 2]. However, relevance of a clopidogrel non-response for the incidence of cerebrovascular events as well as for adverse events after supraaortic stenting is unclear. This case illustrates the risk of severe complications associated with a clopidogrel nonresponse for patients receiving intracranial stent-angioplasty and argues for peri-interventional monitoring of clopidogrel induced platelet inhibition and modified treatment in hypo-responders. A 68-year old male patient was admitted to our hospital 12 h after onset of progressing neurological symptoms including dysarthria, a left-sided facial paresis and a rightsided hemiparesis. Cranial MRI and MR angiography revealed an acute ischemic lesion in the left anteriormedial upper medulla oblongata, old infarctions (left cerebellum, right basal ganglia), white matter microangiopathy and stenoses in the V4-segment of the left vertebral artery (LVA) and the basilar artery (BA). Conventional cerebral angiography confirmed a high-grade stenosis of the LVA’s distal V4-segment and moderate stenoses of the proximal V4-segment and the BA’s mid-section as probable causes of acute brainstem infarction (Fig. 1). With clinical symptoms progressing, we decided for endovascular therapy. After deployment of a 4 mm 9 2 cm ‘‘Wingspan ’’stent reaching from the LVA to the BA with subsequent dilatation (3.5 mm Maverick balloon, balloon inflation by slowly increasing pressure to 6 atm) we observed regular flow (TIMI 3) in these vessels (Fig. 1). Medication at admission had included acetylsalicylic acid (ASA; 100 mg/d); during intervention the patient received heparin (ACT 200–300 s), 500 mg ASA and weightadjusted standard dose tirofiban intravenously. After stenting clopidogrel was added (loading dose: 300 mg; subsequent daily dose: 75 mg). Tirofiban was terminated 6 h after clopidogrel loading, ASA (100 mg/d) and enoxaparin (40 mg/d subcutaneously) were continued. Control MRI upon worsening of clinical symptoms (tetraparesis, anarthria) 1 day after stenting revealed increased medulla oblongata infarction, new paramedian infarction of the right pons (Fig. 1) and new small infarcts within the cerebellum and the left posterior cerebral artery territory. Invisibillity of the LVA in the MR angiography was attributed to stent artefact. The patient had to be intubated after developing sepsis with respiratory and partial renal failure. Transcranial ultrasound examination 5 days after stenting revealed reduced flow in the V2-segment and no flow in the LVA’s V3and V4-segment suggesting an in-stent thrombosis. Another MRI control demonstrated progressive brainstem infarction with new pontine and medullar lesions (Fig. 1). Cerebral angiography confirmed stent occlusion in the V4-segment (Fig. 1) with sufficient BA perfusion via the right VA (not shown). Analysing the patient’s platelet inhibition using impedance aggregometry (Multiple Platelet Function Analyzer, J. Weise (&) O. W. Witte Department of Neurology, University of Jena Medical School, Erlanger Allee 101, 07747 Jena, Germany e-mail: jens.weise@med.uni-jena.de

The Cone-and-Plate(let) analyzer is not suitable to monitor clopidogrel therapy: A comparison with the flowcytometric VASP assay and optical aggregometry

Introduction High on-clopidogrel platelet reactivity has been associated with an increased risk for atherothrombotic events. A new player on the horizon is the IMPACT- R ADP-test using ADP pre-stimulation. We here report the results of a thorough evaluation of this new device. Materials and methods The IMPACT- R ADP-test was evaluated in different categories of subjects. First, normal range values were determined in healthy subjects (n = 46). Second, the effect of 600 mg of clopidogrel was evaluated with the IMPACT- R ADP-test and two other well-validated methods (flowcytometric VASP-analysis and optical aggregometry) in 21 patients. Third, a head-to-head comparison between the IMPACT- R ADP-test and optical aggregometry was performed in a large cohort of patients on dual antiplatelet therapy. Results The results of the IMPACT- R ADP-test were highly variable throughout healthy subjects. The administration of a high clopidogrel loading dose resulted in a small but significant increase in surface coverage but 61.9% of the patients were still identified as clopidogrel nonresponder. In contrast, optical aggregometry and VASP-analysis identified 24% and 33% of these patients as a clopidogrel nonresponder, respectively. Head-to-head comparison with optical aggregometry in 451 patients showed only a modest correlation between both methods ( r ∼ 0.20, p < 0.0001 ). Conclusions The IMPACT- R ADP-test is relatively insensitive to the effects of clopidogrel and cannot substitute for methods such as flowcytometric VASP-analysis and optical aggregometry. Further studies are required to establish the clinical usefulness of IMPACT- R ADP-test to accurately predict the occurrence of major adverse cardiovascular events in patients with high on-clopidogrel platelet reactivity before it can be implemented in clinical practice.

Implications of Inter-Individual Differences in Clopidogrel Metabolism, with Focus on Pharmacogenetics.

Increasing evidence for the role of pharmacogenetics in treatment resistance to the antiplatelet agent clopidogrel has been gained during the last years. Apart from CYP2C19 genetic polymorphisms, nongenetic factors, particularly drug-drug interactions, age and other clinical characteristics influence the interindividual variability in clopidogrel response to varying degrees. The present article reviews the so far accumulated evidence on the role of pharmacogenetic traits influencing CYP-activity as determinants of the antiplatelet response to clopidogrel, and its clinical implications. The genetic variation in CYP2C19 activity seems to influence short- and long-term antithrombotic effects of clopidogrel to a substantial extent. Prediction models for clopidogrel non-responsiveness that include CYP2C19 genotyping together with relevant non-genetic risk factors are needed to be verified for their potential benefit in individualization of antithrombotic therapy.

Factors Associated with Clopidogrel Nonresponsiveness

Clopiodgrel therapy is the standard of care in patients with acute coronary syndrome and in those undergoing percutaneous coronary intervention. However, there is a significant amount of interindividual variability in clopidogrel responsiveness. Clopidogrel is a prodrug and requires metabolism via several CYP450 enzymes in order to exert its antiplatelet effects. Interference in these activation steps is the primary cause of clopidogrel nonresponsiveness. This review focuses on genetic polymorphisms in, and drug interactions with, the CYP450 enzymes that are associated with clopidogrel nonresponsiveness. In addition, clinical factors that effect clopidogrel responsiveness are also reviewed. Particular emphasis is placed on those factors that are not only associated with a change in clopidogrel pharmacokinetics or pharmacodynamics, but are also associated with an increased risk of adverse cardiovascular events. Currently, the majority of data assessing clopidogrel nonresponsiveness focus on genetic variation in CYP2C19 and drug interactions with proton pump inhibitors. However, genetic variation in other CYP450 enzymes, other drug interactions and clinical causes have been studied and are also reviewed here. It is important for healthcare practitioners to recognize all of the causes of clopidogrel nonresponsiveness, especially as novel antiplatelet alternatives become available.

Response to Ticagrelor in Clopidogrel Nonresponders and Responders and Effect of Switching Therapies

The antiplatelet effects of the Platelet Inhibition and Patient Outcomes (PLATO) trial dose of ticagrelor in patients nonresponsive to clopidogrel and after they switch agents are unknown. Patients with stable coronary artery disease on aspirin therapy received a 300-mg clopidogrel load; nonresponders were identified by light transmittance aggregometry. In a 2-way crossover design, nonresponders (n=41) and responders (n=57) randomly received clopidogrel (600 mg/75 mg once daily) or ticagrelor (180 mg/90 mg twice daily) for 14 days during period 1. In period 2, all nonresponders switched treatment; half of the responders continued the same treatment, whereas the others switched treatment. Inhibition of platelet aggregation was higher in nonresponders treated with ticagrelor compared with clopidogrel (P<0.05). Treatment with ticagrelor among nonresponders resulted in a >10%, >30%, and >50% decrease in platelet aggregation from baseline in 100%, 75%, and 13% of patients, respectively. Platelet aggregation fell from 59+/-9% to 35+/-11% in patients switched from clopidogrel to ticagrelor and increased from 36+/-14% to 56+/-9% in patients switched from ticagrelor to clopidogrel (P<0.0001 for both). Platelet reactivity was below the cut points previously associated with ischemic risk measured by light transmittance aggregometry, VerifyNow P2Y(12) assay, and vasodilator-stimulated phosphoprotein phosphorylation in 98% to 100% of patients after ticagrelor therapy versus 44% to 76% of patients after clopidogrel therapy. Ticagrelor therapy overcomes nonresponsiveness to clopidogrel, and its antiplatelet effect is the same in responders and nonresponders. Nearly all clopidogrel nonresponders and responders treated with ticagrelor will have platelet reactivity below the cut points associated with ischemic risk. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00642811.

Role of Ticagrelor in Clopidogrel Nonresponders: Resistance Is Futile?

Dual antiplatelet therapy with aspirin and a thienopyridine drug that blocks the platelet adenosine diphosphate receptor P2Y12 is the cornerstone of management in patients presenting with acute coronary syndrome (ACS). Clopidogrel is the most widely used thienopyridine, with evidence of benefit in non–ST-elevation myocardial infarction (MI),1 percutaneous coronary intervention (PCI),2 and ST-elevation MI treated with thrombolysis or primary PCI.3,4 Article see p 1188 However, clopidogrel has several suboptimal characteristics. First, despite administration of a 600 mg loading dose, clopidogrel requires at least 2 hours to achieve effective platelet inhibition, which is clearly disadvantageous during urgent PCI. Second, the irreversible P2Y12 receptor inhibition may be associated with an increased risk of hemorrhagic complications, particularly in patients requiring urgent coronary artery bypass grafting or other surgery. Furthermore, clopidogrel is a prodrug that requires 2-stage hepatic activation by cytochrome P450 (CYP) enzymes. This is susceptible to genetic polymorphisms, resulting in a variable response and an attenuated antiplatelet effect. Indeed, reduced function alleles (especially CYP2C19*2), which are present in ≈30% of the population, lead to diminished production of the active metabolite.5 This phenomenon, often called clopidogrel resistance, is associated with increased risk of atherothrombotic complications, including stent thrombosis.5,6 Clopidogrel’s limitations have stimulated the search for alternative antiplatelet agents. The development of prasugrel was a major step forward. Prasugrel is a thienopyridine with 10-fold more potent anti-P2Y12 receptor inhibitory activity than clopidogrel and a more rapid onset of action. Like clopidogrel, prasugrel also requires biotransformation to active metabolites via CYP enzymes. In contrast, CYP polymorphisms do not affect active metabolite levels, platelet inhibition, or clinical cardiovascular event rates in patients treated with prasugrel.7 In the study by Mega et al,7 the common CYP functional variants associated with clopidogrel resistance were assessed in healthy volunteers and a cohort of …

Genetic Causes of Clopidogrel Nonresponsiveness: Which Ones Really Count?

Clopidogrel decreases the morbidity and mortality associated with several cardiovascular diseases. However, clopidogrel is a prodrug that needs to be metabolized to the active thiol metabolite by the cytochrome P450 (CYP) system. This activation is a source of significant interindividual variability in clopidogrel responsiveness. Drug interactions with and genetic variation in CYP3A4, CYP3A5, and CYP2C19 enzymes have been implicated in decreasing active metabolite production. In addition, polymorphisms in the genes encoding P-glycoprotein (an efflux transporter) and purinergic receptor P2Y(12) (the active site for clopidogrel) have been studied for their role in clopidogrel responsiveness. Several large studies have recently assessed the role of genetic variation in clopidogrel responsiveness as characterized by clinical outcomes. In this review, we summarize the genetic causes of clopidogrel nonresponsiveness, with a focus on larger outcomes-based studies. A MEDLINE search of the English-language literature (1990-2008) was conducted to identify studies that examined these relationships; additional citations were obtained from the articles retrieved from the literature search. Polymorphisms in CYP2C19 and, to a lesser extent, the adenosine 5'-triphosphate-binding cassette gene, ABCB1, contribute to variability in clopidogrel responsiveness. Specifically, patients possessing at least one variant CYP2C19 allele (CYP2C19*2, *3) have impaired clopidogrel responsiveness due to decreased formation of the active metabolite. In addition, one study found that considering ABCB1 genotype in addition to CYP2C19 allowed better prediction of clopidogrel nonresponsiveness. However, routine genotyping for CYP2C19 or ABCB1 polymorphisms in order to predict clopidogrel responsiveness cannot be recommended at this time because of logistic and cost considerations.

Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis.

BSUMMARY BACKGROUND: Previous studies have shown an important risk of cardiovascular events in patients with clopidogrel biological non-response, and data have shown considerable, unexplored heterogeneity. To evaluate the magnitude of cardiovascular risk associated with clopidogrel non-response and to explore heterogeneity. This was a systematic review and meta-analysis of prospective studies of patients treated with clopidogrel for symptomatic atherothrombosis, evaluated by light transmission aggregometry with ADP and monitored prospectively for clinical ischemic events. Fifteen studies were included, totaling 3960 patients, of whom 25% were considered to be clopidogrel non-responders. The global relative risk (RR) for recurrent ischemic events in clopidogrel non-responders was 3.5 [95% confidence interval (CI) 2.4-5.2, P < 0.0001]. The results of the different studies were heterogeneous (Cochran P = 0.01 and I(2) = 52%). The most recent studies yielded lower RRs [global RR = 2.9 (95% CI 2.3-3.8) after 2007, and global RR = 6.6 (95% CI 3.7-11.9) before 2007, P = 0.01]. Heterogeneity was present in the group of studies in which more than 10% of patients took glycoprotein (GP)IIb-IIIa inhibitors [Cochran P = 0.003 and I(2) = 70%; RR = 3.8 (95% CI 2.9-5.1)] and was absent in the other studies [Cochran P = 0.88 and I(2) = 0; RR = 2.5 (95% CI 1.7-3.6)]. The RR was significantly higher in studies using higher ADP maximal aggregation cut-offs (> 65%) for clopidogrel non-response than in studies using lower cut-offs [RR = 5.8 (95% CI 3.2-10.3) and RR = 2.9 (95% CI 2.2-3.7), respectively, P = 0.03]. The risk of ischemic events associated with clopidogrel non-response is now more precisely defined. The risk is heterogeneous across studies, possibly because of an interaction with GPIIb-IIIa inhibitors and the use of different cut-offs to identify non-responders.

Combination Antithrombotic Therapies

Atherothrombosis is the major pathophysiological process responsible for the occurrence of severe ischemic events in patients with cardiovascular diseases. In the United States, atherothrombosis strongly influenced mortality in 2004: One in 2.8 deaths was due to CVD, 1 in 5 deaths to coronary heart disease, and 1 in 17 deaths to stroke.1 Because cardiovascular disease is a progressive and systemic disease, long-term antithrombotic therapies that effectively target the entire arterial vasculature and modulate the key components responsible for thrombus generation are essential to improve patient outcomes. Because platelet activation is determined by multiple receptor-mediated signaling pathways, clinical studies have evaluated the efficacy of multidrug administration in the prevention of atherothrombotic complications.2,3 The major concern with these therapies is the critical balance between anti-ischemic effect and bleeding risk. This review summarizes our understanding of the role of combination antiplatelet therapies in the treatment and prevention of atherothrombosis. Platelet activation and aggregation play a pivotal role in the generation of occlusive thrombus at the site of coronary arterial plaque rupture. In addition, platelets influence various endothelial and inflammatory responses during the initiation and progression of atherosclerosis. Under normal conditions, anucleate circulating platelets are in a quiescent state. Healthy vascular endothelium prevents adhesion and activation of platelets by producing antithrombotic factors such as CD39 (ectoADPase), prostaglandin I2, nitric oxide, heparin, matrix metalloproteinase-9, protein S, and thrombomodulin.3,4 Endothelial activation and denudation and frank atherosclerotic plaque rupture expose the subendothelial matrix and release prothrombotic factors during acute coronary syndromes (ACS) and percutaneous interventions. These processes result in localized platelet adhesion and platelet activation. After adhesion to the exposed subendothelial matrix, platelets are activated by shear and the soluble agonists thromboxane A2 (TxA2), ADP, and thrombin. TxA2 is produced from arachidonic acid, which originates from membrane phospholipids and …

Assessment of clopidogrel non-response by the PFA-100® system using the new test cartridge INNOVANCE® PFA P2Y

Until now, the PFA-100 system has been considered unsuitable for monitoring clopidogrel efficacy. The authors evaluated platelet function in peripheral arterial occlusive disease (PAOD) patients using a new PFA-100(R) test cartridge (product name: INNOVANCE PFA P2Y*) specifically designed for this purpose. Twenty-two stable PAOD patients on antithrombotic therapy with clopidogrel alone (n = 22) and 18 patients undergoing a peripheral catheter intervention, preliminarily treated with 100 mg/day of aspirin followed by co-administration of clopidogrel (loading dose 300 mg, maintenance dose 75 mg/day), were enrolled in this study. Defining non-responsiveness to clopidogrel as an aggregation response within the reference range (90% central interval), four (18.2%) non-responders using light transmittance aggregometry (LTA) induced by 5 microM adenosine diphosphate (ADP) and six (27.3%) non-responders using LTA induced by 2 microM ADP (LateAggr >72.1% and >42.9%, respectively) were identified. INNOVANCE PFA P2Y* determined six (27.3%) non-responders (CT < 87 s). Agreement between the two aggregometry assays and INNOVANCE PFA P2Y* on the definition of clopidogrel response and non-response exceeded 70%. Only three patients were uniformly identified as clopidogrel non-responders by all three assays. When clopidogrel was co-administered with aspirin, two (11.1%) non-responders to clopidogrel were detected with INNOVANCE PFA P2Y*, whereas ADP-induced LTA found all patients to be responsive. INNOVANCE PFA P2Y* appears to be suitable for monitoring the effect of clopidogrel on platelet function. Its sensitivity in detecting responsiveness or non-responsiveness to clopidogrel is comparable to ADP-induced LTA. Additional prospective studies are needed to clarify the clinical relevance of the test results and classification obtained with INNOVANCE PFA P2Y*.

038 Glycoprotein IIbIIIa Inhibitors Improve Clinical Outcome after Coronary Stenting in Clopidogrel non Responders: a Prospective, Randomized Study

Numerous biological studies have reported inter-individual variability in platelet response to clopidogrel with clinical relevance. High Post treatment platelet reactivity (ADP-induced aggregation >70%) has been proposed to define Non response to clopidogrel. We assessed in clopidogrel non responders undergoing elective percutaneous coronary intervention (PCI) the benefit of adjusted antiplatelet therapy with glycoprotein IIbIIIa (GPIIbIIIa) antagonist administration during PCI for one month clinical outcome. 149 clopidogrel non-responders referred for elective PCI were prospectively included and randomized to “conventional group” (n=75) or “active group” with GPIIbIIIa antagonist (n=74). All patients received 250 mg aspirin and 600 mg clopidogrel before PCI and platelet testing. The rate of CV events at one month was significantly lower in the “active group” than in the “conventional group”: 19% (n=14) vs. 40% (n=30), p=0.006, [OR (95%CI): 2.8(1.4-6.0)]. No patient in either group had post procedural TIMI major bleeding or required transfusions. The present study suggested benefit of tailored antiplatelet therapy during elective PCI with GPIIbIIIa antagonist for clopidogrel non responders without increased bleeding risk.

Clopidogrel non-responsiveness and risk of cardiovascular morbidity

We performed this meta-analysis to update the clinical evidences on the relation between clopidogrel non-responsiveness and clinical outcomes in patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention. An electronic literature search through MEDLINE, EMBASE, Web of Science, and the Cochrane Library and bibliographies of retrieved articles up to January, 2009 was conducted. Studies were included if they had a cohort prospective design, if they analysed clopidogrel responsiveness in CAD patients in relation to death and/or occurrence of adverse coronary events during follow-up, and if they reported an adequate statistical analysis. Fourteen studies, totalling 4,564 CAD patients followed for a time ranging from 14 days to one year, were included. The cumulative analysis reported that residual platelet reactivity despite clopidogrel treatment was significantly associated with an increased risk of death and/or thrombotic recurrences (odds ratio [OR] 5.67, 95% confidence interval [CI] 2.97 to 10.84; p<0.00001). However, four studies contributed to a consistent heterogeneity of the model and evidenced a significant risk of publication bias, so were excluded from the analysis. This exclusion, however, did not influence the overall result, by confirming the increased risk of cardiovascular recurrences for patients with a poor response to clopidogrel treatment (OR 3.58, 95%CI 2.54 to 5.05; p<0.00001). The present updated meta-analysis documents a significant association between residual platelet reactivity under clopidogrel treatment and recurrent cardiovascular events, so suggesting the relevance of ongoing interventional studies aimed at tailoring the antithrombotic therapy in CAD patients.

Clopidogrel and proton pump inhibitor (PPI) interaction: separate intake and a non-omeprazole PPI the solution?

BackgroundDual therapy with aspirin and clopidogrel increases the risk of gastrointestinal bleeding. Therefore, co-therapy with a proton pump inhibitor (PPI) is recommended by most guidelines. However, there are warnings against combining PPIs with clopidogrel because of their interactions with cytochrome P450 isoenzyme 2C19 (CYP2C19).MethodsThe effects of the combined or separate intake of 20 mg of omeprazole and 75 mg of clopidogrel on the clopidogrel-induced inhibition of platelet aggregation were measured in four healthy subjects whose CYP2C19 exon sequences were determined. The effects of co-therapy with 10 mg of rabeprazole were also examined.ResultsTwo subjects showed the wild-type CYP2C19 sequence. The concurrent intake of omeprazole had no effect on clopidogrel-induced platelet inhibition in these subjects. Two subjects were heterozygous for the *2 allele, with predicted reduced CYP2C19 activity. One of them was a clopidogrel non-responder. In the second heterozygous subject, omeprazole co-therapy reduced the clopidogrel anti-platelet effect when taken simultaneously or separately. However, the simultaneous intake of rabeprazole did not reduce the clopidogrel effect.ConclusionThe clopidogrel-PPI interaction does not seem to be a PPI class effect. Rabeprazole did not affect the clopidogrel effect in a subject with a clear omeprazole-clopidogrel interaction. The separate intake of PPI and clopidogrel may not be sufficient to prevent their interaction.

Aspirin and clopidogrel hyporesponsiveness and nonresponsiveness in patients with coronary artery stenting

Patients undergoing coronary artery stenting receive an antiplatelet regimen to reduce the risk of antithrombotic complications. Current guidelines recommend the use of acetyl salicylic acid (aspirin) and clopidogrel as evidenced by large clinical trials. There has been a concern about variable responses of patients to aspirin and clopidogrel which may predispose them to subacute stent thrombosis or late stent thrombosis. Up to 25% of patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) were found to have hyporesponsiveness or resistance to clopidogrel which may predispose them to recurrent events. Dual antiplatelet regimen is a standard therapy in these patients and there is always a concern about variable responses to aspirin and clopidogrel predisposing them to acute coronary syndrome (ACS). Prevalence of this hyporesponsiveness or resistance may be due to noncompliance, genetic mutations, co-morbid situations and concomitant use of other drugs. This issue is of considerable importance in the era of coronary drug eluting stents when a long-term dual antiplatelet regimen is needed. This paper is a review for clinicians taking care of such patients with hyporesponsiveness or nonresponsiveness to dual antiplatelet regimen.