Julie H. Oestreich

2012 Update to The Society of Thoracic Surgeons Guideline on Use of Antiplatelet Drugs in Patients Having Cardiac and Noncardiac Operations

Division of Cardiovascular and Thoracic Surgery, University of Kentucky, Lexington, Kentucky (VAF and SPS); Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (JHO); Division of Cardiothoracic Surgery, Oregon Health and Science University Medical Center, Portland, Oregon (HKS); State University of New York, Stony Brook School of Medicine, Stony Brook, New York (TR); Department of Cardiothoracic Surgery, University of Colorado Health Sciences Center, Aurora, Colorado (TBR); Department of Anesthesia, St. Michael’s Hospital, University of Toronto, Toronto, Ontario (CDM); Division of Cardiovascular Surgery, Sanger Clinic, Charlotte, North Carolina (CRB); Departments of Anesthesiology, Immunology, and Pathology, Washington University School of Medicine, St. Louis, Missouri (GJD); and The Society of Thoracic Surgeons, Chicago, Illinois (KJ and ERC)

Pharmacokinetics and Pharmacodynamics of a Bolus and Infusion of Cangrelor: A Direct, Parenteral P2Y12 Receptor Antagonist

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers. Twenty‐two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens: a 15‐μg/kg bolus followed by a 2‐μg/kg/min infusion or a 30‐μg/kg bolus followed by a 4‐μg/kg/min infusion. The infusion is continued for 60 minutes, and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters. Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes. Moreover, extensive platelet inhibition is maintained throughout the infusion period with near‐full recovery of platelet function within 60 to 90 minutes of terminating the infusion. The effect of high‐dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate—induced P‐selectin expression; however, no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function. Cangrelor administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function.

Ticagrelor: Pharmacokinetics, pharmacodynamics, clinical efficacy, and safety

Dual antiplatelet therapy, composed of aspirin plus a P2Y12‐receptor antagonist, is the cornerstone of treatment for patients with acute coronary syndrome (ACS). A number of U.S. Food and Drug Administration–approved P2Y12‐receptor antagonists are available for treating patients with ACS, including the thienopyridine compounds clopidogrel and prasugrel. Ticagrelor, the first of a new class of antiplatelet agents, is a noncompetitive, direct‐acting P2Y12‐receptor antagonist. Unlike the thienopyridine compounds, ticagrelor does not require metabolism for activity. Also, whereas clopidogrel and prasugrel are irreversible inhibitors of the P2Y12 receptor, ticagrelor binds reversibly to inhibit receptor signaling and subsequent platelet activation. In pharmacodynamic studies, ticagrelor demonstrated faster onset and more potent inhibition of platelet aggregation than clopidogrel. These properties of ticagrelor may contribute to reduced rates of thrombotic outcomes compared with clopidogrel, as demonstrated in a phase III clinical trial. However, in addition to bleeding, distinctive adverse effects of this new chemical entity have not been reported with the thienopyridine P2Y12‐receptor inhibitors. Although ticagrelor represents an advancement in P2Y12‐receptor inhibition therapy, a thorough understanding of this compound as an antiplatelet therapy remains to be elucidated.

Considerable Variability in Platelet Activity among Patients with Coronary Artery Disease in Response to an Increased Maintenance Dose of Clopidogrel

BackgroundVariable platelet response to clopidogrel has been widely observed. Studies have shown that the mean aggregation response to clopidogrel can be changed by a higher maintenance dose. However, these studies have not focused on individual changes. ObjectivesThis study examined the platelet function effects of increasing the maintenance clopidogrel dose from 75 to 150u2009mg/day with a focus on inter-individual response. Patients/methodsTwenty patients with known coronary artery disease receiving 75u2009mg/day clopidogrel were recruited and given 150u2009mg/day clopidogrel for 30 days, then returned to 75u2009mg/day for an additional 30 days. Platelet function was assessed through light-transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay at baseline, 30 days, and 60 days. ResultsMean platelet inhibition was significantly improved with the increased maintenance dose when measured by the VerifyNow P2Y12 assay (P2Y12 reaction units: 191±15 vs. 158±17, P=0.013), but not when measured by LTA (LTA-adenosine diphosphate 5: 40±3 vs. 36±3, Pu2009=u20090.11; LTA-adenosine diphosphate 20: 50±3 vs. 47±3, Pu2009=u20090.23). However, only 50% of individual patients experienced improved platelet inhibition, as measured by the VerifyNow P2Y12 assay, when treated with the increased maintenance dose. Furthermore, poor baseline platelet response did not predict improved responsiveness at the increased dose. ConclusionDespite changing the populations mean antiplatelet response, an increased maintenance dose of clopidogrel did not improve antiplatelet response in a substantial number of patients; nor did baseline platelet function predict response to a higher maintenance dose.

Platelet function analysis: At the edge of meaning

Anti-platelet agents are a cornerstone in the treatment of symptomatic coronary artery disease and acute coronary syndromes. Despite the proven benefits of acetylsalicylic acid (ASA) and clopidogrel, ischemic events still occur in patients receiving dual anti-platelet therapy. Over the course of the last ten years, a series of published studies has examined the effects of anti-platelet therapy on ex vivo assays of platelet function and has clearly established substantial inter-individual variability in the degree of inhibition of platelet function observed in individuals taking ASA or clopidogrel or both.1-3 Individuals who display residual platelet function in ex vivo assays despite standard doses of anti-platelet therapy have been classified as “non-responders” or “resistant” to anti-platelet medications.4, 5 A major unknown is whether patients who are non-responsive to anti-platelet medications, as judged by ex vivo testing, are at higher risk of suffering an ischemic event and, if so, whether tailoring anti-platelet medications based on ex vivo functional assays will result in protection from ischemic events. n nA recent, small study supports the use of a tailored approach based on ex vivo platelet function testing to dose-adjust clopidogrel and reduce ischemic events following percutaneous coronary intervention (PCI).6 However, the most compelling evidence of a benefit from higher platelet inhibition comes from studies of prasugrel, a novel P2Y12 receptor antagonist that more completely inhibits ex vivo platelet function than does clopidogrel when assessed by light transmittance aggregometry (LTA).7 In the Trial to Assess Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombosis in Myocardial Infarction (TRITON-TIMI) 38 trial (NCT00699998), dual anti-platelet therapy with prasugrel and ASA reduced ischemic events as compared to clopidogrel and ASA, albeit at the expense of increased bleeding. 8 One possibility is that the improved ischemic outcomes in TRITON reflect a reduction in the number of patients that are “non-responders” to dual antiplatelet therapy. n nSeveral point-of-care assays of platelet function have been developed in recent years to rapidly screen individuals on anti-platelet therapy. The ideal test would be capable of distinguishing individuals at risk of ischemic and bleeding events and could be used to guide dose adjustments in therapy. The clinical data indicating that a significant number of patients respond incompletely to clopidogrel, the reduction in ischemic outcomes but increased bleeding with prasugrel in the TRITON trial, and the availability of point-of-care assays would suggest the time is right to use platelet function analysis to individualize anti-platelet therapy. Indeed, the most recent guidelines for PCI from the American College of Cardiology/American Heart Association/Society for Coronary Angiography recommend that platelet function be monitored in patients undergoing high risk procedures and that the dose of clopidogrel be increased in patients identified as non-responsive.9 However, before widespread use of platelet function assays is adopted, several key issues need to be resolved. First, for each platelet function assay, the reliability of the test in predicting ischemic and bleeding risk must be determined. This may require defining non-responsiveness in a manner that includes individuals who may benefit from higher doses of therapy and excludes those at risk of bleeding. Second, the optimal timing for platelet function analysis needs to be determined (i.e. on admission, prior to balloon inflation, following PCI). Third, the strategy of dose-adjustment based on ex vivo platelet function results must be prospectively evaluated to assure that an improvement in clinical outcomes can be realized. n nIn this issue of the Journal, Gremmel et al. provide fundamental information on the performance of four commonly used platelet function assays. Their findings are a key step in addressing the value and importance of the tests. Gremmel et al. compared the results of four platelet function assays to those of the “gold standard” LTA in a group of patients presenting for elective percutaneous stent implantation. A total of 80 patients were enrolled following stent placement in the coronary, peripheral or cerebrovascular bed. All patients were treated with ASA (100 mg/day for at least 2 weeks) and received a 300 mg loading dose of clopidogrel 24 hours before the procedure followed by 75 mg daily. Blood was sampled 24 hours after the intervention and stored in a manner consistent with the requirements of each assay. Each assay was performed by a single operator and included LTA (10 μM adenosine 5-diphosphate (ADP) as the agonist), the VerifyNow P2Y12 assay (Accumetrics, San Diego, USA), the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay (Diagnostica Stago, Biocytex, Marseille, France) assay, multiple electrode platelet aggregometry (MEA, Dynabyte, Munich, Germany) and the Impact –R test (Diamed, Cressier, Switzerland), The properties of these assays are compared in Table 1. n n n nTable 1 n nCharacteristics of platelet function assays. n n n nThe results highlight the problems encountered with platelet function analysis. Gremmel et al. report a reasonable correlation between residual platelet activity as measured by each of the four assays and LTA. However when binary comparisons were performed for responders and non-responders, the correlations were less robust. For instance, VerifyNow and LTA yielded discordant results for identification of responder/non-responders in 18 of 80 cases: nine individuals were classified as non-responders by LTA but not by VerifyNow, and nine individuals were identified as non-responders by VerifyNow but not LTA. When LTA results were used as the standard for responsiveness, the sensitivity and specificity of the VerifyNow assay were only 55% and 85%, respectively. The other assays of platelet function fared worse than the VerifyNow assay with respect to identifying non-responders by LTA. n nThe findings of Gremmel et al. indicate considerable variability among five methods to assay platelet function in patients treated with ASA and clopidogrel and are in accord with the results of similar studies from other groups.10, 11 The results may not be surprising, given that these five assays measure different platelet events/endpoints (Table 1). These findings emphasize that different platelet function tests probably cannot substitute for another. It is worth noting that LTA was chosen as the gold standard for platelet function analysis based on historical rather than clinical evidence and that universal standardization has yet to be established. As- of- yet, platelet function analysis has not been put to the ultimate test. That is to say, there is no proof that a group of patients that are prospectively and reproducibly identified by these techniques will gain more than they lose following adjustment of their anti-platelet therapy. n nSeveral ongoing studies should provide valuable insight into the role of platelet function testing in the setting of PCI. In the Assessment of Dual Anti-Platelet Therapy with Drug Eluting Stents (ADAPT-DES, NCT00638794) registry, platelet function analysis with the VerifyNow assay will be performed in a large group of patients receiving drug eluting stents to identify a cohort of patients at risk for early or late stent thrombosis. Additionally, the platelet function substudy of the ongoing A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects (TRILOGY, NCT00699998) trial aims to correlate ex vivo testing with clinical outcomes in the under-studied population of medically managed patients. Most importantly, the first major trial using platelet function analysis to tailor therapy is enrolling. In the Gauging Responsiveness with A VerifyNow Assay-Impact on Thrombosis and Safety (GRAVITAS, NCT00645918) trial, patients undergoing PCI are randomized into one of three arms depending on results of the VerifyNow assay. Responders will receive standard therapy with ASA and clopidogrel (75 mg daily). Non-responders will receive either standard therapy or tailored therapy with an additional 450 mg loading dose of clopidogrel followed by 150 mg daily. These ongoing trials should provide data on the VerifyNow assay as a point-of-care test to assess platelet function in the setting of anti-platelet therapy. The large number of patients tested in these trials should help determine the optimal “cut-off” value for non-responsiveness, may establish a set of clinical characteristics that predict the need for platelet function testing, and may provide important information regarding platelet function and the risk of adverse ischemic and bleeding events. With GRAVITAS, the first foray into tailored antiplatelet therapy is underway. However, based on the results of Gremmel and colleagues, it is not clear which, if any, of the current tests represents the best strategy for individualized anti-platelet therapy.

Prevalence of CYP2C19 variant alleles and pharmacodynamic variability of aspirin and clopidogrel in Native Americans.

BACKGROUNDnThe prevalence of variant alleles of the CYP2C19 gene has been determined for most population groups, but not Native Americans. Furthermore, the overall effectiveness of clopidogrel and aspirin has not been well studied in Native Americans, although this group has high mortality rates for cardiovascular disease and diabetes.nnnMETHODSnWe recruited 50 volunteers from the Oglala Sioux Tribe with coronary artery disease taking aspirin and clopidogrel. Whole blood was collected for analysis using the VerifyNow P2Y12 and aspirin tests. Samples from the coronary artery disease patients and 50 additional tribal volunteers (n = 100 total) were genotyped for CYP2C19 variants *2, *3, and *17.nnnRESULTSnThe allele frequencies for CYP2C19*2 and CYP2C19*17 in the population group were 11% (95% CI 7%-16%) and 9% (95% CI 5%-13%), respectively. No subjects carried the CYP2C19*3 allele. The median PRU (P2Y12 reaction units) in the population group was 194 with wide variability (range 29-400). There was no significant effect of genotype on platelet aggregation as measured by the VerifyNow P2Y12 test (P = .77). The median ARU (aspirin reaction units) for the group was 437 (range 350-659), and 73% had aspirin reaction unit values <550.nnnCONCLUSIONSnThe prevalence of variant CYP2C19 alleles is low in Native Americans of the Oglala Sioux Tribe compared with certain HapMap populations. The variable response to aspirin and clopidogrel in the Oglala Sioux Tribe is consistent with reported values for other groups as measured by the VerifyNow assay (Accumetrics, San Diego, CA).

Effect of genetic variation in P2Y12 on TRAP-stimulated platelet response in healthy subjects

In platelets, thrombin receptor signaling depends upon the release of adenosine diphosphate and subsequent activation at purinergic subtype Y (P2Y) receptors. The purpose of this study is to evaluate the influence of specific P2Y12 polymorphisms on platelet reactivity in healthy subjects mediated by thrombin receptor activating peptide (TRAP). We recruited a total of 29 healthy volunteers who had been previously genotyped for two polymorphisms of the P2Y12 receptor: the H2 haplotype (rs2046934) and 34C>T (rs6785930). Flow cytometry and the VerifyNow assay were used to assess platelet activation and aggregation stimulated by TRAP in the presence and absence of specific receptor antagonists for the P2Y1, P2Y12, and thromboxane A2 receptors. We identified a significant recessive effect of the P2Y12-receptor H2 haplotype on TRAP-induced flow cytometry. Specifically, H2/H2 carriers (nxa0=xa05) demonstrated a significant reduction in both glycoprotein IIb/IIIa receptor activation (pxa0<xa00.001) and CD62P expression (pxa0=xa00.035). While the VerifyNow assay did not reveal any effect of haplotype on TRAP-mediated platelet aggregation (pxa0=xa00.72), the H2/H2 subjects demonstrated greater platelet inhibition in the presence of cangrelor, a specific receptor antagonist for the P2Y12 receptor (pxa0=xa00.023). No consistent effects of the separate 34C>T genotype (rs6785930) were demonstrated under the conditions evaluated. The findings of this study suggest a potential association between P2Y12-receptor H2/H2 carriers and reduced platelet function mediated by TRAP in healthy volunteers.

High residual platelet reactivity on standard clopidogrel maintenance dose predicts increased responsiveness to the double-standard dose in an assay-dependent manner

High residual platelet reactivity on standard clopidogrel maintenance dose predicts increased responsiveness to the double-standard dose in an assay-dependent manner -

Impact of genetic polymorphisms on clinical response to antithrombotics

Antithrombotic therapy, including anticoagulants as well as antiplatelet drugs, is an important component in the treatment of cardiovascular disease. Variability in response to such medications, of which pharmacogenetic response is a major source, can decrease or enhance the benefits expected. This review is a comprehensive assessment of the literature published to date on the effects of genetic polymorphisms on the actions of a variety of antithrombotic medications, including warfarin, clopidogrel, prasugrel, and aspirin. Literature evaluating surrogate markers in addition to the impact of pharmacogenetics on clinical outcomes has been reviewed. The results of the studies are conflicting as to what degree pharmacogenetics will affect medication management in cardiovascular disease. Additional research is necessary to discover, characterize, and prospectively evaluate genetic and non-genetic factors that impact antithrombotic treatment in order to maximize the effectiveness and limit the harmful effects of these valuable agents.

Novel Direct-Acting Anticoagulants for Risk Reduction in ACS

Acute coronary syndrome (ACS) is a devastating adverse cardiovascular event with a massive burden on patient morbility and mortality, as well as the economy. Approximately 1.2 million people are hospitalized annually for ACS in the United States, with direct medical costs estimated at