Inhibition Of Platelet Responses Research Articles

Perioperative use of point-of-care devices in cardiac surgery may improve bleeding and transfusion outcome

Background Hemostatic disorder and massive bleeding are common complications after cardiac surgery procedures, particularly in procedures requiring prolonged cardiopulmonary bypass. Conventional laboratory coagulation tests failed to predict hemostatic disorder and consequent proclivity to excessive bleeding. On the other hand there is evergrowing proportion of patients who need antiplatelet therapy (APT) in perioperative setting. Platelet inhibitory response to antiplatelet therapy varies widely among individuals, thus reflecting bleeding tendency as well as risk for adverse ischemic events. Bedside suitable devises for assessment of platelet function as well as assessment of viscoelastic blood properties are desired. Herein, we present our institutional experience in hemostatic and antiplatelet therapy administration management.

Effect of antiplatelet therapy on thromboembolism after flow diversion with the Pipeline Embolization Device

Flow-diverting stents offer a novel treatment approach to intracranial aneurysms. Data regarding the incidence of acute procedure-related thromboembolic complications following deployment of the Pipeline Embolization Device (PED) remain scant. The authors sought to determine the rate of embolic events in a bid to identify potential risk factors and assess the role of platelet inhibition. Data in all patients receiving a PED for treatment of an intracranial aneurysm were prospectively maintained in a database. Diffusion-weighted 3-T MRI was performed within 24 hours of PED deployment. The incident rate of procedural embolism was established, and univariate analysis was then performed to determine any associations of embolic events with measured variables. The degree of platelet inhibition in response to aspirin and clopidogrel was evaluated by challenging the platelet samples with arachidonic acid and adenosine diphosphate, respectively, and then performing formal light transmission platelet aggregometry. Twenty-three patients with 26 aneurysms were eligible for inclusion in the study. Thirty-one PEDs were deployed in 25 procedures. All ischemic lesions detected on diffusion-weighted 3-T MRI were identified as embolic based on their location and distribution, with none appearing to be due to perforator artery occlusion. Procedural embolic events were found in the target parent vessel territory in 13 (52%) of 25 procedures, with no patients harboring lesions contralateral to the deployed PED. The number of embolic events per procedure ranged from 3 to 16, with a mean of 5.4. There was no significant difference between cases with and without procedural embolism in platelet inhibition by aspirin (mean 15% vs 12% residual activation; p = 0.28), platelet inhibition by clopidogrel (mean 41% vs 41% residual activation; p = 0.98), or intraprocedural heparin-induced anticoagulation (mean activated clotting time 235 seconds vs 237 seconds; p = 0.81). By multivariate analysis, the authors identified larger aneurysm size (p = 0.03) as the single variable significantly associated with procedural embolism. There was no significant relationship between aneurysm size and the number of embolic events (p = 0.32) or the total burden of the embolism lesion area (p = 0.53). Acute embolism following use of the PED for treatment of intracranial aneurysms is more common than hypothesized. The only identifiable risk factor for embolism appears to be greater aneurysm size, perhaps indicating significant disturbed flow across the aneurysm neck with ingress and egress through the PED struts. The strength of antiplatelet therapy, as measured by residual platelet aggregation, did not appear to be associated with cases of procedural embolism. Further work is needed to determine the implications of these findings and whether anticoagulation regimens can be altered to lower the rate of complications following PED deployment.

Antiplatelet therapy at the time of coronary artery surgery: can a personalized approach improve outcomes?

We read with great interest the recently published multicentre cohort study by Kremke et al. [1]. Patients exposed to antiplatelet therapy (APT) at the time of coronary artery surgery (CAS) had greater postoperative bleeding volumes and greater transfusion requirements [1]. Exposure to clopidogrel, but not aspirin, was associated with greater reoperation rates and was an independent risk factor for severe postoperative bleeding, although mean bleeding volumes were not significantly different in the aspirin and clopidogrel subgroups [1]. Despite current guidelines, it is apparent that many patients are proceeding with CAS without the 5-day delay off clopidogrel. The efficacy of platelet inhibition with clopidogrel varies widely among patients, from intensive platelet inhibition to poor platelet response [2], and these variations could, to some degree, explain the non-significant differences in mean bleeding volumes in the aspirin and clopidogrel subgroups [1]. The effect of clopidogrel on bleeding mainly depends on two factors: (i) observed platelet inhibition, which depends on inherent platelet activity prior to clopidogrel administration and platelet inhibitory response to clopidogrel and (ii) newborn platelets ability to restore normal aggregation after clopidogrel discontinuation. Therefore, the use of suitable point-of-care platelet function analysers seems to be reasonable in this field. Recently, we found aspirin(P = 0.014) and clopidogrel(P = 0.003) sensitive platelet function tests to be predictive of excessive postoperative bleeding in patients following CAS [2]. Of note, 76.3% patients were transfused with no significant differences among the groups with regard to the preoperative APT administration regime (P = 0.636) [2]. However, transfused patients had significantly lower values of aspirin-sensitive platelet function tests (P = 0.002) [2]. In our opinion, the study cohort is somehow heterogeneous. Eligible procedures were either isolated CAS or CAS combined with aortic valve replacement (AVR) [1]. AVR certainly extends the duration of cardiopulmonary bypass, which was recently described as a predictor of transfusion requirements [3]. After matching, authors reported a slightly greater use of antifibrinolytic drugs in the APT group [1]. Both on-pump and off-pump procedures were included [1]. Authors reported that off-pump surgery and perioperative use of tranexamic acid were associated with a lower risk of severe postoperative bleeding [1]. The use of antifibrinolytic drugs should be equally balanced since there is evidence that antifibrinolytic therapy reduces bleeding and transfusion outcomes [4]. It would be interesting to see if exclusion of CAS + AVR and off-pump CAS patients would bring different results. During the study period, thromboelastometry-guided blood component therapy became available at two of three participating centres [1]. At the same time, multivariate analysis revealed that surgery at one of the participating centres was one of independent risk factors for severe postoperative bleeding [1]. Spiess et al. [5] reported thromboelastography-guided haemostatic management to have significantly reduced the incidence of overall transfusion and mediastinal re-exploration due to excessive bleeding. Thus, perhaps one could assume that one centre, which was found to be independent risk factor for severe postoperative bleeding, was in fact the one without thromboelastometry guided transfusion therapy available. The largest extent of chest tube output together with the greatest transfusion rates, was observed in the subgroup of patients exposed to dual APT [1]. Those results are in line with the results recently published by Miceli et al. [6]. Further incremental platelet inhibition may be observed in the group of patients receiving dual APT. Therefore, the role of aspirin and clopidogrel administration management should be separately assessed by drug-specific platelet function tests, thus facilitating an individual therapeutic approach for discontinuation management of each antiplatelet agent preoperatively.

High Glucose Inhibits the Aspirin-Induced Activation of the Nitric Oxide/cGMP/cGMP-Dependent Protein Kinase Pathway and Does Not Affect the Aspirin-Induced Inhibition of Thromboxane Synthesis in Human Platelets

Since hyperglycemia is involved in the “aspirin resistance” occurring in diabetes, we aimed at evaluating whether high glucose interferes with the aspirin-induced inhibition of thromboxane synthesis and/or activation of the nitric oxide (NO)/cGMP/cGMP-dependent protein kinase (PKG) pathway in platelets. For this purpose, in platelets from 60 healthy volunteers incubated for 60 min with 5–25 mmol/L d-glucose or iso-osmolar mannitol, we evaluated the influence of a 30-min incubation with lysine acetylsalicylate (L-ASA; 1–300 μmol/L) on 1) platelet function under shear stress; 2) aggregation induced by sodium arachidonate or ADP; 3) agonist-induced thromboxane production; and 4) NO production, cGMP synthesis, and PKG-induced vasodilator-stimulated phosphoprotein phosphorylation. Experiments were repeated in the presence of the antioxidant agent amifostine. We observed that platelet exposure to 25 mmol/L d-glucose, but not to iso-osmolar mannitol, 1) reduced the ability of L-ASA to inhibit platelet responses to agonists; 2) did not modify the L-ASA–induced inhibition of thromboxane synthesis; and 3) prevented the L-ASA–induced activation of the NO/cGMP/PKG pathway. Preincubation with amifostine reversed the high-glucose effects. Thus, high glucose acutely reduces the antiaggregating effect of aspirin, does not modify the aspirin-induced inhibition of thromboxane synthesis, and inhibits the aspirin-induced activation of the NO/cGMP/PKG pathway. These results identify a mechanism by which high glucose interferes with the aspirin action.

TCT-726 Residual Platelet Reactivity Threshold After Clopidogrel Loading Dose to Predict Long-term Clinical Outcome in Patients with Acute Coronary Syndrome: Insights from the RECLOSE2-ACS Study

validated laboratory-based genotyping method. Methods: 74 stable CAD patients on clop 75 mg daily were tested by clinical nurses with no genetic laboratory experience and 1 hour of basic training on the device. The patients were defined as EM (*1/*1, *1/*17, *17/*17), RM (*1/*2A, *1/*8, *2A/*2A, *2A/*3). Genetic testing was conducted on 1 mL of whole blood using the Verigene® System and compared to an Affymetrix® DMET assay. Pharmacokinetic (PK) exposure to clop’s active metabolite (AM) was measured and platelet reactivity (PD) was assessed with the VerifyNowTM P2Y12 system (PRU) and VASP (PRI) assays. Results: There was an overall 99.9% concordance of marker-level data between the Verigene® and the reference (DMET ) in measuring the CYP2C19 markers of interest. There was a 100% agreement between Verigene® and the reference test in classifying the patients into established EM and RM groups. The POC assay identified 59 EM, 15 RM. The EM group had significantly lower PRU (LS means 158 vs. 212; p 0.003), and PRI (LS means 48 vs. 63, p 0.01) than RM group treated with clopidogrel 75 mg. The EM group also had significantly higher AM exposure by AUC(0-last) than the RM group (LS means 12.6 vs. 7.7; p 0.0009). Conclusions: This is the first report of a POC genetic testing platform performing a comprehensive CYP2C19 polymorphism characterization in CAD patients and validating the genotypes against the PK and PD phenotype. There was a high concordance between the two platforms in measuring the star allele marker data. The POC genetic test identified EM and RM phenotypes based on 11 gene variants with high accuracy and predicted a reduced platelet inhibition in response to clop. A rapid, reliable POC CYP2C19 genetic test could make clop pharmacogenetic testing feasible for all patients.

Modern antiplatelet agents in coronary artery disease

Dual antiplatelet therapy is well recognized in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions. Despite clinical benefits of aspirin and clopidogrel therapy, a number of limitations curtail their efficacy: slow onset of action, variability in platelet inhibitory response and potential drug–drug interactions. Furthermore, the single platelet-activation pathway targeted by these agents allows continued platelet activation via other pathways, ensuring incomplete protection against ischemic events, thus, underscoring the need for alternate antiplatelet treatment strategies. A number of novel antiplatelet agents are currently in advance development and many have established superior effects on platelet inhibition, clinical outcomes and safety profile than clopidogrel in high-risk patients. The aim of this review is to provide an overview of the current status of P2Y12 receptor inhibition and PAR-1 antagonists in determining a future strategy for individualized antiplatelet therapy.

Diabetes and sex: from pathophysiology to personalized medicine

The prevalence and incidence of diabetes is similar in the two sexes but the long-term impact of diabetes on vascular and non-vascular complications is more gender specific. Men, in comparison with women, seem to be at higher risk for micro-vascular complications, such as severe retinopathy and nephropathy. On the other hand, the impact of diabetes on the risk of major cardiovascular events is different in women in comparison with men. Both type 1 and type 2 diabetes are associated with a significant increase in the incidence of bone fractures. Although this phenomenon is present in both sexes, its impact is greater in women, due to the higher baseline incidence of fractures. Diabetes negatively affects mood, leading to an increased risk of depressive disorders, due to the burden and side effects of therapy, together with the fear of complications. This phenomenon can be more evident in women, who are at greater risk of depressive disorders. Non-pharmacological treatments (i.e. diet and exercise), which are the backbone of therapy for type 2 diabetes, do not differ across genders. On the other hand, some drugs could have diverse profiles of action in women and in men. In relation to diabetes, the sex-related difference in platelet activity and platelet inhibitory response to anti-aggregating therapy, reported in the general population, was observed also in diabetic women.

Letter by Petricevic and Biocina Regarding Article, “Platelet Function Measurement-Based Strategy to Reduce Bleeding and Waiting Time in Clopidogrel-Treated Patients Undergoing Coronary Artery Bypass Graft Surgery: The Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG (TARGET-CABG) Study”

HomeCirculation: Cardiovascular InterventionsVol. 5, No. 3Letter by Petricevic and Biocina Regarding Article, “Platelet Function Measurement-Based Strategy to Reduce Bleeding and Waiting Time in Clopidogrel-Treated Patients Undergoing Coronary Artery Bypass Graft Surgery: The Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG (TARGET-CABG) Study” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Petricevic and Biocina Regarding Article, “Platelet Function Measurement-Based Strategy to Reduce Bleeding and Waiting Time in Clopidogrel-Treated Patients Undergoing Coronary Artery Bypass Graft Surgery: The Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG (TARGET-CABG) Study” Mate Petricevic, MD and Bojan Biocina, MD, PhD Mate PetricevicMate Petricevic University of Zagreb School of Medicine University Hospital Center Zagreb Cardiac Surgery Department Zagreb, Croatia (Petricevic, Biocina) Search for more papers by this author and Bojan BiocinaBojan Biocina University of Zagreb School of Medicine University Hospital Center Zagreb Cardiac Surgery Department Zagreb, Croatia (Petricevic, Biocina) Search for more papers by this author Originally published1 Jun 2012https://doi.org/10.1161/CIRCINTERVENTIONS.112.970061Circulation: Cardiovascular Interventions. 2012;5:e47To the Editor:We read with great interest the recently published study by Mahla et al.1 The efficacy of platelet inhibition with aspirin and clopidogrel varies widely among patients from intensive platelet inhibition to poor platelet response.The effect of clopidogrel on bleeding mainly depends on 2 factors: (1) observed platelet inhibition, which is dependent on inherent platelet activity before clopidogrel administration and platelet inhibitory response to clopidogrel; and (2) newborn platelets' ability to restore normal aggregation after clopidogrel discontinuation. In addition to increased costs of hospitalization, clopidogrel discontinuation 5 days before coronary artery bypass surgery could place patients with high residual adenosine diphosphate-induced platelet-fibrin clot strength to risk of preoperative ischemic adverse events.The study enrolled patients with a wide range of aspirin daily dose, from 81 to 325 mg.1 Percent inhibition of arachidonic acid-induced aggregation did not differ between clopidogrel-naive and clopidogrel-treated patients despite treatment with lower aspirin doses observed in the clopidogrel-naive group.1 In addition, clopidogrel-treated patients had a more frequent history of coronary artery stenting.1 Was preoperative aspirin dose targeted after arachidonic acid-induced aggregation test to achieve adequate platelet inhibitory response? If so, can we assume that a higher proportion of clopidogrel-treated patients had a poor platelet-inhibitory response to lower aspirin doses?There is evidence that certain patients have an accentuated response to the usual doses of preoperative aspirin that may result in increased perioperative blood loss.2 It would be very valuable if authors correlated arachidonic acid-induced aggregation test values with chest tube drainage. Did authors detect patients with accentuated response to aspirin and compare chest tube drainage between patients with respect to presence of pronounced versus poor platelet inhibitory response to aspirin treatment? In our opinion, when assessing the influence of preoperative antiplatelet therapy administration management on bleeding and adverse ischemic events, the role of aspirin should inextricably be included in considerations by objective quantification.Adenosine diphosphate-induced platelet-fibrin clot strength cutoff associated with ischemia in patients with coronary artery disease undergoing stenting is not a reliable surrogate for adequate hemostasis. A correlation between drug-specific platelet function test (adenosine diphosphate-induced platelet-fibrin clot strength and arachidonic acid-induced aggregation test) with chest tube drainage could bring the most precise and reliable cutoff values that delineating bleeding tendency.The role of aspirin and clopidogrel on bleeding should separately be assessed by drug-specific platelet function tests, facilitating an individual therapeutic approach for each antiplatelet agent preoperatively. Such an approach could distinguish patients with high residual platelet activity, thus proclivity to ischemic events, or enhanced platelet inhibition, thus proclivity to excessive bleeding. In a group of patients with pronounced platelet inhibition after aspirin administration, early aspirin discontinuation should be considered. Such an approach requires further studies to provide cutoff values that predict excessive chest tube drainage and, according to obtained cutoff values, evaluate antiplatelet therapy management in the context of chest tube drainage and clinical outcome.We congratulate the authors on their elegant and timely research.Mate Petricevic, MDBojan Biocina, MD, PhD University of Zagreb School of Medicine University Hospital Center Zagreb Cardiac Surgery Department Zagreb, CroatiaDisclosuresNone.

How to prevent bleeding events in on- and off-pump coronary artery bypass patients exposed to clopidogrel preoperatively

The effect of clopidogrel on bleeding mainly depends on two factors: (1) observed platelet inhibition, which is depending on inherent platelet activity prior to clopidogrel administration and platelet inhibitory response to clopidogrel and (2) newborn platelets ability to restore normal aggregation after clopidogrel discontinuation.The role of aspirin and clopidogrel on bleeding should separately be assessed by drug specific platelet function tests, facilitating individual therapeutic approach for each antiplatelet agent preoperatively. Such an approach could distinguish patients with high residual platelet activity, thus proclivity to ischemic events, or enhanced platelet inhibition, thus proclivity to excessive bleeding. It would be interesting if authors compared preoperative ischemic events incidence between patients groups with respect to preoperative clopidogrel treatment. Timing of discontinuation as well as intensity of preoperatively administered aspirin and clopidogrel should be tailored according to drug specific platelet function tests in order to minimize both ischemic and bleeding events. In group of patients with pronounced platelet inhibition after aspirin and/or clopidogrel administration, early antiplatelet drug discontinuation should be considered. For elective patients, delaying of surgery in cases of pronounced platelet inhibition after antiplatelet drugs administration should be considered if clinically condition allows. For urgent and/or emergent cases with observed preoperative deep platelet inhibition, the desmopressin administration should be considered [5] as well as intraoperative thromboelastography guided hemostatic therapy which significantly reduces incidence of overall transfusion and mediastinal re-exploration due to excessive bleeding [6]. However, such an approach requires further studies in order to provide platelet function test cut-off values that delineate bleeding as well as ischemic events. According to obtained cut-off values, antiplatelet therapy management should be evaluated in context of clinical outcome.

Oral antiplatelet therapy for atherothrombotic disease: overview of current and emerging treatment options.

Clinical presentations of atherothrombotic vascular disease, such as acute coronary syndromes, ischemic stroke or transient ischemic attack, and symptomatic peripheral arterial disease, are major causes of morbidity and mortality worldwide. Platelet activation and aggregation play a seminal role in the arterial thrombus formation that precipitates acute manifestations of atherothrombotic disease. As a result, antiplatelet therapy has become the cornerstone of therapy for the prevention and treatment of atherothrombotic disease. Dual antiplatelet therapy with aspirin and a P2Y12 adenosine diphosphate (ADP) receptor inhibitor, such as clopidogrel or prasugrel, is the current standard-of-care antiplatelet therapy in patients with acute coronary syndromes managed with an early invasive strategy. However, these agents are associated with several important clinical limitations, including significant residual risk for ischemic events, bleeding risk, and variability in the degree of platelet inhibition. The residual risk can be attributed to the fact that aspirin and P2Y12 inhibitors block only the thromboxane A2 and ADP platelet activation pathways but do not affect the other pathways that lead to thrombosis, such as the protease-activated receptor-1 pathway stimulated by thrombin, the most potent platelet agonist. Bleeding risk associated with aspirin and P2Y12 inhibitors can be explained by their inhibitory effects on the thromboxane A2 and ADP pathways, which are critical for protective hemostasis. Interpatient variability in the degree of platelet inhibition in response to antiplatelet therapy may have a genetic component and contribute to poor clinical outcomes. These considerations underscore the clinical need for therapies with a novel mechanism of action that may reduce ischemic events without increasing the bleeding risk.

Novel Platelet ADP P2Y12 Inhibitors in the Treatment of Acute Coronary Syndrome

Inhibition of the platelet P2Y12 receptor plays an important role in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions. Despite clinical benefits with clopidogrel therapy in these high risk patients, efficacy of clopidogrel is limited by slow onset of action, variability in platelet inhibitory response and potential drug-drug interactions. Importantly, suboptimal platelet inhibition by clopidogrel is associated with worse prognosis. This underscores the need for alternate antiplatelet treatment strategies. A number of novel P2Y12 antagonists are approved or in advanced development and some have demonstrated superior platelet inhibition effect, clinical outcomes, and safety profile than clopidogrel in patients with acute coronary syndrome. The aim of this manuscript is to provide an overview on the current status in P2Y12 receptor inhibition and to review the pharmacology and clinical development of four of these agents: prasugrel, cangrelor, ticagrelor, and elinogrel.

Genetic determinants of platelet response to clopidogrel

Antiplatelet agents are the mainstay treatment in the prevention and management of atherothrombotic complications. However, a substantial interpatient variability in response to clopidogrel has been reported. Furthermore, patients with coronary artery disease and lesser platelet inhibition in response to clopidogrel are at increased risk for cardiovascular events. Clopidogrel after absorption requires two-step oxidation by the hepatic cytochrome P450 to generate its active metabolite. Polymorphisms of genes encoding the cytochrome enzymes and P-glycoprotein involved in clopidogrel absorption are regarded as major determinants of the interindividual variability in the clopidogrel-induced platelet inhibition. In our review we discuss the prevalence and clinical significance of various alleles of the genes: CYP2C19 and ABCB1 in the setting of coronary artery disease. Allele CYP2C19*2 is associated with excess of ischaemic events including myocardial infarction and stent thrombosis. On the other hand, CYP2C19*17 allele poses a serious threat of bleeding. Data concerning the prognostic value of genetic variant 3435C→T of ABCB1 remain inconclusive.

Early double stent thrombosis associated with clopidogrel hyporesponsivenesss

A 57-year-old male patient without cardiovascular history suffered an acute myocardial infarction and underwent drug-eluting stent implantation in the left anterior descending artery. A few days later, the right coronary artery was also stented (drug-eluting stent). Three days later, he was re-admitted to our hospital in cardiogenic shock. Emergent coronary angiography showed total occlusion of both stents. Platelet function analysis (PFA) showed attenuated platelet inhibition in response to clopidogrel treatment. The patient was the carrier of a loss-of-function polymorphism in the CYP2C19 gene, which has been associated with increased incidence of adverse thrombotic events. Antiplatelet therapy was switched to prasugrel and PFA revealed an adequate antiplatelet effect.

Clopidogrel Responsiveness Regardless of the Discontinuation Date Predicts Increased Blood Loss and Transfusion Requirement After Off-Pump Coronary Artery Bypass Graft Surgery

the purpose of this study was to evaluate the association of the percentage of platelet inhibitory response to clopidogrel as assessed by modified thromboelastography with bleeding and transfusion requirement after off-pump coronary artery bypass graft (OPCABG) surgery. Interindividual variability of clopidogrel responsiveness may influence bleeding and transfusion requirement. one hundred patients who received clopidogrel within 5 days of OPCABG were prospectively enrolled. The primary end point was to compare post-operative bleeding and transfusion requirement in relation to the tertile distribution of the percentage of platelet inhibitory response to clopidogrel. blood loss in the patients in the third tertile was 914 ± 264 ml compared with 623 ± 249 ml in those in the first and 683 ± 254 ml in those in the second tertiles (p = 0.001). Significantly more patients in the third tertile were transfused, and the number of units transfused was also larger. On multivariate analysis, the third tertile was associated with an 11-fold increased risk of transfusion (95% confidence interval: 2.77 to 47.30, p = 0.001). The optimal cutoff value for the transfusion requirement measured by receiver-operator characteristic curve analysis was 70% platelet inhibitory response to clopidogrel (area under the curve: 0.771; 95% confidence interval: 0.674 to 0.868; p < 0.001). a high percentage of platelet inhibitory response to clopidogrel, regardless of the proximity of clopidogrel exposure, predicts increased blood loss and transfusion requirement after OPCABG with a cutoff value of 70% for increased risk of transfusion. These findings might implicate a potential role of modified thromboelastography in deciding the timing of OPCABG in patients who need continued clopidogrel therapy.

Cytochrome P450 2C19 polymorphism is associated with poor clinical outcomes in coronary artery disease patients treated with clopidogrel

Patients with lesser degrees of platelet inhibition in response to clopidogrel appear to be at increased risk for recurrent ischemic events. Cytochrome P450 (CYP) polymorphisms have been proposed as possible mechanisms for nonresponsiveness to clopidogrel. Published data on the association between CYP2C19*2 polymorphism and atherothrombotic events are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of eight prospective cohort studies including 2,345 patients carrying CYP2C19*2 variant allele and 5,935 cases with the wild-type genotype were included in this meta-analysis. Overall, borderline statistically significantly elevated risk of adverse clinical events was associated with genotyping 681G>A polymorphism (for AA + GA vs. GG: OR, 1.46; 95% CI, 1.01 to 2.13; P = 0.05). The summary odds ratio showed a significant association between the CYP2C19*2 polymorphism and an increased risk of cardiac mortality in the follow-up period (OR, 2.07; 95% CI, 1.22 to 3.52; P = 0.007). When studies evaluating myocardial infarction, stent thrombosis, and ischemic stroke, the presence of the variant allele was associated with significantly increased risks of recurrent atherothrombotic events. In summary, this meta-analysis indicated that CYP2C19*2 carrier status is significantly associated with an increased risk of adverse cardiovascular events.

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 …

The Evidence Base for Platelet Function Testing in Patients Undergoing Percutaneous Coronary Intervention

Clopidogrel therapy significantly reduces cardiovascular events in patients presenting with acute coronary syndrome (ACS)1,2 and in patients undergoing percutaneous coronary intervention (PCI),3 yet cardiovascular events, including stent thrombosis, continue to occur after PCI despite the ischemic benefit conferred by clopidogrel. Minimizing the incidence of stent thrombosis is a central goal for stent manufacturers, pharmaceutical companies, regulatory bodies, and practicing interventional cardiologists, and professional societies have formally recommended prolonged thienopyridine therapy after drug-eluting stent implantation in the absence of randomized controlled clinical trials.4 A growing body of data supports the contention that the level of platelet reactivity on clopidogrel therapy (“on-treatment” platelet reactivity) is an independent risk factor for ischemic and thrombotic events post-PCI and that the intensification of platelet inhibition may improve outcomes in at-risk patients. The introduction of point-of-care and clinical laboratory-based platelet function assays has made it feasible to consider the routine evaluation of on-treatment platelet reactivity in the patient undergoing PCI.5,6 The current data set provides clinicians with a strong scientific rationale for the use of platelet function assays in daily practice. Response by Kalyanasundaram and Berger on p 283 Clopidogrel is a prodrug that requires biotransformation into an active metabolite to exert its inhibitory effect on platelet aggregation. Approximately 85% of absorbed clopidogrel is hydrolyzed by esterases in the gut into an inactive form, and the remainder is converted into an active metabolite by the hepatic cytochrome P450 (CYP) system through a 2-step oxidative process.7 The active metabolite irreversibly binds and antagonizes the P2Y12 ADP receptor for the life of the platelet. The platelet inhibitory response to clopidogrel varies substantially among patients according to ex vivo measurements,8 with many patients having persistently high platelet reactivity despite clopidogrel treatment. Genetic polymorphisms that affect the catalytic activity …

Impaired anti-platelet effect of aspirin, inflammation and platelet turnover in cardiac surgery☆☆☆

A reduced platelet inhibitory response to acetyl salicylic acid (ASA) has been associated with an increased risk of graft thrombotic occlusion after coronary artery bypass grafting (CABG). We performed a prospective, observational study of 18 patients on 100 mg/day ASA before and after CABG. We assessed antiplatelet response to ASA and its relationship with platelet turnover, inflammatory markers, and soluble thrombomodulin (sTM) levels. All patients showed optimal response to ASA preoperatively but had higher values during follow-up. Platelet aggregation and platelet count in the perioperative period were significantly associated (P=0.05). Platelet turnover was defined as the average daily turnover (ADTO). The lowest inhibitory value (28% of patients > or =6 Omega) was recorded at the same time of the highest platelet turnover (>10% daily in 77.77% of patients), one week after CABG. ADTO >10% was associated with an increased risk of platelet aggregation > or =6 Omega. Levels of sTM were significantly higher one week after CABG (median 13 vs. 3 ng/ml preoperatively, P=0.0011). There is a transient impairment in ASA antiplatelet effect after CABG related to an increased platelet turnover caused by the inflammatory process. This could be responsible for the high risk of occlusive thrombosis.

Effects of extended release niacin/laropiprant, laropiprant, extended release niacin and placebo on platelet aggregation and bleeding time in healthy subjects

Laropiprant (LRPT) has been shown to reduce flushing symptoms induced by niacin and has been combined with niacin for treatment of dyslipidemia. LRPT, a potent PGD2 receptor (DP1) antagonist that also has modest activity at the thromboxane receptor (TP), may have the potential to alter platelet function either by enhancing platelet reactivity through DP1 antagonism or by inhibiting platelet aggregation through TP antagonism. Studies of platelet aggregation ex vivo and bleeding time have shown that LRPT, at therapeutic doses, does not produce clinically meaningful alterations in platelet function. The present study was conducted to assess platelet reactivity to LRPT using methods that increase the sensitivity to detect changes in platelet responsiveness to collagen and ADP. The responsiveness of platelets was quantified by determining the EC50 of collagen to induce platelet aggregation ex vivo. At 24 hours post-dose on Day 7, the responsiveness of platelets to collagen-induced aggregation was similar following daily treatment with extended-release niacin (ERN) 2 g/LRPT 40 mg or ERN 2 g. At 2 hours post-dose on Day 7, the EC50 for collagen-induced platelet aggregation was approximately two-fold higher in the presence of LRPT, consistent with a small, transient inhibition of platelet responsiveness to collagen. There was no clinical difference between treatments for bleeding time, suggesting that this small effect on collagen EC50 does not result in a clinically meaningful alteration of platelet function in vivo. The results of this highly sensitive method demonstrate that LRPT does not enhance platelet reactivity when given alone or with ERN.

Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel

Both clopidogrel and prasugrel require biotransformation to active metabolites by cytochrome P450 (CYP) enzymes. Among persons treated with clopidogrel, carriers of reduced-function CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events. The effect of CYP polymorphisms on the clinical outcomes in patients treated with prasugrel remains unknown. The associations between functional variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to prasugrel were tested in 238 healthy subjects. We then examined the association of these genetic variants with cardiovascular outcomes in a cohort of 1466 patients with acute coronary syndromes allocated to treatment with prasugrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 trial. Among the healthy subjects, no significant attenuation of the pharmacokinetic or the pharmacodynamic response to prasugrel was observed in carriers versus noncarriers of at least 1 reduced-function allele for any of the CYP genes tested (CYP2C19, CYP2C9, CYP2B6, CYP3A5, and CYP1A2). Consistent with these findings, in subjects with acute coronary syndromes treated with prasugrel, no significant associations were found between any of the tested CYP genotypes and risk of cardiovascular death, myocardial infarction, or stroke. Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel. These pharmacogenetic findings are in contrast to observations with clopidogrel, which may explain, in part, the different pharmacological and clinical responses to the 2 medications.