Thienopyridine Treatment Research Articles

Routine CYP2C19 Genotyping to Adjust Thienopyridine Treatment After Primary PCI for STEMI: Results of the GIANT Study

ObjectivesThe aim of this study was to evaluate prospectively the clinical impact of routine transmission of CYP2C19 genotype in the management of acute ST-segment elevation myocardial infarction with primary percutaneous coronary intervention. BackgroundResponse to clopidogrel differs widely among patients, notably because of CYP2C19 genetic polymorphisms. MethodsCYP2C19 genotype (6 alleles) was determined centrally and communicated within 4.1 ± 1.9 days of primary percutaneous coronary intervention in 1,445 patients with ST-segment elevation myocardial infarction recruited at 57 centers in France. CYP2C19 metabolic status was predicted from genotype and served to adjust thienopyridine treatment. The primary endpoint was differences in 12-month outcomes (death, myocardial infarction, and stent thrombosis) between patients with the wild-type genotype or gain-of-function allele (class 1, n = 1,118) and those with loss-of-function (LOF) alleles (class 2, n = 272) who received optimized thienopyridine treatment. ResultsDetection of LOF alleles resulted in adjustment of P2Y12 inhibition in 85% of patients, with significantly higher use of prasugrel or double-dose clopidogrel. The primary endpoint did not differ between class 1 and class 2 patients (3.31% vs. 3.04%, respectively; p = 0.82). In contrast, carriers of LOF alleles without treatment adjustment had significantly worse outcomes (15.6%; p < 0.05). Bleeding rates were not different between groups. ConclusionsIn a real-world setting, a complete CYPC2C19 genotype can be mostly determined in <7 days using analysis of saliva deoxyribonucleic acid collected during the in-hospital phase among patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Genotype information led to stronger platelet inhibition treatment in the vast majority of LOF allele carriers and to similar clinical outcomes as in patients carrying the wild-type genotype or gain-of-function allele. (Genotyping Infarct Patients to Adjust and Normalize Thienopyridine Treatment [GIANT]; NCT01134380)

Aspirin Is Associated with Improved Survival in Severely Thrombocytopenic Cancer Patients with Acute Myocardial Infarction.

Patients with hematologic malignancies are at risk for severe thrombocytopenia (sTP). The risk and benefit of aspirin are not known in thrombocytopenic cancer patients experiencing acute myocardial infarction (AMI). Medical records of patients with hematologic malignancies diagnosed with AMI at Memorial Sloan Kettering Cancer Center during 2005-2014 were reviewed. sTP was defined as a platelet count <50,000 cells per µL within 7 days of AMI. Of 118 patients with hematologic malignancies who had AMI, 58 (49%) had sTP. Twenty-five patients (43%) with sTP received aspirin as a treatment for AMI. Compared with patients without sTP with AMI, patients with sTP with AMI were less likely to receive aspirin (83% vs. 43%; p = .0001) and thienopyridine treatment (27% vs. 3%; p = .0005). During median follow-up of 3.7 years after AMI, survival was lower in patients with sTP than in those with no sTP (23% vs. 50% at 1 year; log rank p = .003). Patients with sTP who received aspirin for AMI had improved survival compared with those who did not (92% vs. 70% at 7 days, 72% vs. 33% at 30 days, and 32% vs. 13% at 1 year; log rank p = .008). In multivariate regression models, aspirin use was associated with improved 30-day survival both in the overall patient cohort and in sTP patients. No fatal bleeding events occurred. Major bleeding was not associated with sTP or aspirin use. Treatment of AMI with aspirin in patients with hematologic malignancies and sTP is associated with improved survival without increase in major bleeding. The Oncologist 2017;22:213-221Implications for Practice: In patients with hematologic malignancies and acute myocardial infarction with severe thrombocytopenia (platelet count < 50,000 cells/µL), guideline-recommended medical therapy is often withheld because of the fear of major bleeding. In this study, aspirin therapy was associated with improved survival without an increase in major bleeding in this high-risk patient cohort.

Comparison of Immature Platelet Count to Established Predictors of Platelet Reactivity During Thienopyridine Therapy

BackgroundPrevious data suggest that reticulated platelets significantly affect antiplatelet response to thienopyridines. It is unknown whether parameters describing reticulated platelets can predict antiplatelet response to thienopyridines. ObjectivesThe authors sought to determine the extent to which parameters describing reticulated platelets can predict antiplatelet response to thienopyridine loading compared with established predictors. MethodsThis study randomized 300 patients undergoing elective coronary stenting to loading with clopidogrel 600 mg, prasugrel 30 mg, or prasugrel 60 mg. Adenosine diphosphate (ADP)-induced platelet reactivity was assessed by impedance aggregometry before loading (intrinsic platelet reactivity) and again on day 1 after loading. Multiple parameters of reticulated platelets were assessed by automated whole blood flow cytometry: absolute immature platelet count (IPC), immature platelet fraction, and highly fluorescent immature platelet fraction. ResultsEach parameter of reticulated platelets correlated significantly with ADP-induced platelet reactivity (p < 0.01 for all 3 parameters). In a multivariable model including all 3 parameters, only IPC remained a significant predictor of platelet reactivity (p < 0.001). In models adjusting each of the 3 parameters for known predictors of on-treatment platelet reactivity including cytochrome P450 2C19 (CYP2C19) polymorphisms, age, body mass index, diabetes, and intrinsic platelet reactivity, only IPC prevailed as an independent predictor (p = 0.001). In this model, IPC was the strongest predictor of on-treatment platelet reactivity followed by intrinsic platelet reactivity. ConclusionsIPC is the strongest independent platelet count–derived predictor of antiplatelet response to thienopyridine treatment. Given its easy availability, together with its even stronger association with on-treatment platelet reactivity compared with known predictors, including the CYP2C19*2 polymorphism, IPC may become the preferred predictor of antiplatelet response to thienopyridine treatment. (Impact of Extent of Clopidogrel-Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate—Advanced Loading Strategies [ExcelsiorLOAD]; DRKS00006102)

0010: Impact of thienopyridines on platelet CD40L biodisponibility after an acute coronary syndrome in relation with bleeding events

CD40 Ligand (CD40L) is expressed on platelets upon ADP stimulation and is involved in haemostasis. CD40L deficient mice exhibit thrombus instability and increased bleeding time. We investigated the relationships between plasma and platelet-associated CD40L, ADP signaling and bleeding event occurrence in patients receiving thienopyridines one month after a stented Acute Coronary Syndrome (ACS). Basal platelet CD40L surface expression (pCD40L), pCD40L after PAR-1 agonist stimulation (TRAP pCD40L) and platelet released CD40L (rCD40L) were quantified. Results were compared to VASP as a measure of P2Y12 inhibition level. We included 318 patients between November 2012 and June 2014. Thienopyridines treated patients exhibit low pCD40L, TRAP pCD40L and rCD40L in comparison with controls. pCD40L and rCD40L were correlated with PRI-VASP. Thienopyridine treatment strongly reduces rCD40L. Hyperesponder to thienopyridine status is associated with high levels of TRAP pCD40L. pCD40L and TRAP pCD40L levels are reduced in the bleeding cohort. In multivariate analysis pCD40L significantly contributes to bleeding risk independently of PRI-VASP. pCD40L and rCD40L levels are reduced by thienopyridines. pCD40L associates with the bleeding risk independently of the VASP levels and may represent a novel target to assess bleeding risk in thienopyridine-treated ACS patients.

Abstract 12267: Clinical Significance of Very Late Ischemic and Bleeding Events After Percutaneous Coronary Intervention

Background: Ischemic and bleeding events following percutaneous coronary intervention are associated with increased mortality, but the prognosis of events occurring beyond 1 year is unknown. Methods: The Dual Antiplatelet Therapy study randomized 11,648 subjects following percutaneous coronary intervention who completed 12 months of dual antiplatelet therapy to either continued thienopyridine plus aspirin treatment for another 18 months versus aspirin therapy alone. Subjects were followed for 21 months after randomization. Ischemic events were defined as Academic Research Consortium definite or probable stent thrombosis, myocardial infarction, ischemic stroke and other cardiovascular deaths. Bleeding events were defined by GUSTO classification (moderate or severe). Kaplan-Meier methods were used to estimate the cumulative incidence of death (regardless of cause) following ischemic and bleeding events over the full study follow-up. Results: At 21 months after randomization, 566 (4.9%) patients had ischemic events and 232 (2.0%) patients had bleeding events. Of the ischemic events, 58.8% were myocardial infarctions, 16.4% were stent thromboses and 12.8% were other cardiovascular deaths. Of all myocardial infarctions and stent thromboses, 8 (2.0%) were fatal on presentation. Among bleeding events, 66.0% were moderate and 34.0% were severe. Of all bleeding events, 3 (1.3%) were immediately fatal. In patients with ischemic events, 24.7% died, and the cumulative incidence of death preceded by an ischemic event was greater following myocardial infarction (0.39%) compared with stent thrombosis (0.13%) and ischemic stroke (0.11%). Among patients with a bleed, 17.7% died, and the cumulative incidence of death preceded by a bleed was 0.14% after a moderate bleed and 0.24% after a severe bleed (see Figure). Conclusions: Very late ischemic and bleeding events were infrequent, but patients who suffered these events are subject to high mortality risk.

THERAPEUTIC WINDOW FOR P2Y12-RECEPTOR INHIBITION: A COLLABORATIVE ANALYSIS OF THE RELATION BETWEEN PLATELET REACTIVITY, STENT THROMBOSIS AND BLEEDING

background: Although residual platelet reactivity during treatment with P2Y12-inhibitors is associated with stent thrombosis (ST) and bleeding, clinically validated, standardized cut-offs for platelet function testing are lacking. We sought to determine the prognostic impact of low (LPR), optimal (OPR), or high platelet reactivity (HPR) by applying standardized cut-off criteria in patients undergoing PCI treated with clopidogrel or prasugrel. methods: Authors of studies published before January 2014, reporting the association between platelet reactivity, ST and major bleeding were contacted for a collaborative analysis using a priori defined, uniform cut-off values for standardized platelet function assays. Based on the best available evidence (exploratory studies), LPR-OPR-HPR categories were defined as 208 PRU for VerifyNow, 46U for the Multiplate analyzer and 50% for VASP assay. Results: Fifteen studies including 18,169 patients were used for the analysis. Patients with HPR had a 2.6-fold higher risk of ST (p<0.00001) but a similar risk for bleeding (p=0.053) compared to those with OPR. In contrast, patients with LPR had a 1.8-fold higher risk for bleeding (p<0.0001), but identical risk for ST (p=0.81) as those with OPR. Mortality was 1.6-fold higher in patients with HPR compared to others (p<0.001). Validation cohorts confirmed the clinical relevance of cut-off values suggested by exploratory studies. conclusion: During thienopyridine treatment, mortality and ST is significantly higher in HPR, while LPR is a predictor of bleeding. Potential benefits of targeting OPR as a therapeutic window for P2Y12-inhibition need to be confirmed in randomized trials.

Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents

BackgroundDual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain.MethodsPatients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding.ResultsA total of 9961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P<0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 [95% CI, 1.00 to 1.85]; P=0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P=0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment.ConclusionsDual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938.)

Antithrombotic therapy in patients undergoing TAVI: an overview of Dutch hospitals

PurposeTo assess current antithrombotic treatment strategies in the Netherlands in patients undergoing transcatheter aortic valve implantation (TAVI).MethodsFor every Dutch hospital performing TAVI (n = 14) an interventional cardiologist experienced in performing TAVI was interviewed concerning heparin, aspirin, thienopyridine and oral anticoagulation treatment in patients undergoing TAVI.ResultsThe response rate was 100 %. In every centre, a protocol for antithrombotic treatment after TAVI was available. Aspirin was prescribed in all centres, concomitant clopidogrel was prescribed 13 of the 14 centres. Duration of concomitant clopidogrel was 3 months in over two-thirds of cases. In 2 centres, duration of concomitant clopidogrel was based upon type of prosthesis: 6 months versus 3 months for supra-annular and intra-annular prostheses, respectively.ConclusionsLeaning on a small basis of evidence and recommendations, the antithrombotic policy for patients undergoing TAVI is highly variable in the Netherlands. As a standardised regimen might further reduce haemorrhagic complications, large randomised clinical trials may help to establish the most appropriate approach.Electronic supplementary materialThe online version of this article (doi:10.1007/s12471-013-0496-6) contains supplementary material, which is available to authorized users.

Comparison of the Degree of Platelet Aggregation Inhibition With Prasugrel Versus Clopidogrel and Clinical Outcomes in Patients With Unprotected Left Main Disease Treated With Everolimus-Eluting Stents

The everolimus-eluting stent (EES) performs better than the first generation drug-eluting stent. Prasugrel compared with clopidogrel in acute coronary syndromes treated invasively is associated with improved clinical outcome and decreased risk of stent thrombosis. The aim of the study was to compare the clinical outcome and degree of platelet aggregation inhibition of patients treated with EES for unprotected left main disease (ULMD) and receiving clopidogrel or prasugrel. Patients receiving an EES for ULMD and with low residual platelet reactivity on clopidogrel or prasugrel treatment were included in the analysis. The primary end point of the study was the composite of cardiac mortality and myocardial infarction at 1 year. The secondary end point was the degree of platelet aggregation inhibition as assessed by light transmittance aggregometry. From January 2009 to December 2011, 252 patients with low residual platelet reactivity on thienopyridine treatment were treated with EES for ULMD. Of these, 104 patients received clopidogrel and 148 received prasugrel. The primary end point rate was lower in the prasugrel group compared with clopidogrel group: 1.3% and 9.6%, respectively (p= 0.002). Residual platelet reactivity was less in the prasugrel group compared with clopidogrel group (adenosine diphosphate 10μmol/L 37 ± 17% and 45 ± 15%, respectively, p <0.001). At multivariate analysis, prasugrel treatment was related to the primary end point (hazard ratio 0.17; 95% confidence interval 0.04 to 0.77, p= 0.022). In conclusion, in patients treated with EES for ULMD, prasugrel compared with clopidogrel is associated with increased platelet aggregation inhibition and a better clinical outcome.

Persistent platelet reactivity in patients with unprotected left main disease treated by percutaneous coronary intervention

Purpose: Angioplasty is emerging as an alternative technique for patients with unprotected left main disease (ULMD). Persistent platelet reactivity (PPR) under aspirin or thienopyridines is associated with acute events after angioplasty. We aimed to determine the rate and potential clinical impact of PPR in patients treated by angioplasty for ULMD. Methods: We prospectively included 125 patients referred for angioplasty for ULMD in a single-centre registry. For the first 64 patients (ALMA-1), angioplasty was performed under aspirin and clopidogrel treatment without previous platelet reactivity assessment. For the last 61 patients (ALMA-2), platelet reactivity was assessed (light transmission aggregometry triggered by arachidonic acid and ADP and VASP index) systematically before angioplasty: patients found to have aspirin-related PPR were administered aspirin twice daily and those with clopidogrel-related PPR had their daily clopidogrel dose doubled or replaced by prasugrel. Results: Overall, patients mean age was 69±13y.o., 37% were diabetic, 37% had NSTEMI and 62% had multivessel disease. The left main lesion was ostial in 23%, medial in 8% and distal or both in 69%. Mean SYNTAX score was 22.8±9.2. More than 30% of the patients have an additive EuroSCORE≥6. Procedural characteristics were similar in both groups. Follow-up was successful at 1 year in all patients. In ALMA-2, concerning aspirin pathway, mean maximal aggregation intensity (MAI) was 15.4±17.0%. The proportion of patients with aspirin-related PPR (MAI≥20%) was 28% and aspirin was switched twice a day in those patients. Concerning thienopyridines pathway, mean MAI triggered by ADP 20μmol was 53.6±18.5%, mean VASP index was 46±19% and considering both MAI>65% and VASP>50%, 26% of patients (n=16) had PPR under thienopyridines. Following these results, 31% of patients (n=19) were switched to prasugrel and 26% (n=16) were treated by high-dose clopidogrel. Finally, 8% of patients (n=5) had PPR under both, aspirin and thienopyridine treatment. Dual antiplatelet therapy at 1 year was continued in 86% of patients in ALMA-1 and 92% in ALMA-2 (p=NS). The rate of 1-year major cardiovascular events was significantly decreased in ALMA-2 vs. ALMA-1 (8.2% vs. 20.8%; p=0.04) as a composite endpoint of cardiovascular death and stent thrombosis (0.0% vs. 8.3%; p=0.02). Conclusion: In our real life study, PPR for dual antiplatelet therapy is frequent in patients undergoing angioplasty for ULMD and appears to be strongly associated with subsequent major events.

Thienopyridines resistance and recovery of platelet function after discontinuation of thienopyridines in cardiac surgery patients

Patients who undergo cardiac operations under the effects of thienopyridines have a greater risk of major postoperative bleeding, transfusions and surgical revision due to bleeding. Discontinuation of thienopyridine is suggested but an adequate recovery period following discontinuation is still under debate, with opinions ranging from 3 to 7 days. The aim of this study was to assess the rate of recovery of thienopyridine-resistant patients and the time taken for resumption of platelet function after discontinuation of thienopyridine, in the setting of patients scheduled for cardiac operations. This was a retrospective study, based on 344 patients screened for platelet aggregation before cardiac operations. All the patients received thienopyridines within 7 days prior to the test. Multiple electrode aggregometry adenosine diphosphate test was used to assess platelet aggregation before the operation. Thienopyridine resistance rate was 28%. Patients receiving clopidogrel had a significantly higher rate (32%) of resistance, compared with those receiving ticlopidine (14%) and thienopyridine resistance was significantly associated with platelet count (P = 0.006). The time taken to recover platelet function after thienopyridine discontinuation was variable between individuals; the only factor associated with a faster recovery time was the serum bilirubin value (P = 0.002). Platelet aggregation values high enough to avoid major bleeding were reached 3 days after discontinuation (95% confidence interval: 2-4 days); however, a complete recovery of platelet function was reached only after 8 days (95% confidence interval: 7-9 days). Patient-specific factors determine the effectiveness of thienopyridine treatment and platelet function recovery rate. Among these, platelet count (for thienopyridine resistance) and serum bilirubin values (for platelet function recovery rate) should be considered.

High platelet reactivity – the challenge of prolonged anticoagulation therapy after ACSI

Despite dual antiplatelet therapy (DAPT), one-year event rates after acute coronary syndrome (ACS) vary from 9-12%. The development of novel oral anticoagulants (NOAC) without a need for monitoring has initiated renewed interest for prolonged adjunctive anticoagulation. Importantly, the cornerstone of treatment after ACS consists of long-term DAPT. In that context, the NOACs have only been tested as adjunctive therapy. Of all new agents, only rivaroxaban -in a substantially lower dose than used for atrial fibrillation- has been demonstrated to improve outcome, albeit at the cost of bleeding. In selected cases, adjunctive therapy with dose-adjusted vitamin-K antagonists (international normalized ratio [INR] 2.0-3.0) can be considered as well. These two strategies of prolonged anticoagulation can be considered in case of 'high platelet reactivity', i.e. in patients at high risk of recurrent thrombotic events despite DAPT. Both during admission and after discharge for ACS, the use of NOACs in doses indicated for atrial fibrillation is strictly contra-indicated in patients on DAPT. In case of post-discharge anticoagulation therapy for atrial fibrillation, patients should preferably receive vitamin-K antagonists (INR 2.0-3.0), with discontinuation of one antiplatelet agent as soon as clinically justifiable. Importantly, the impact of prolonged anticoagulation (low-dose rivaroxaban, vitamin-K antagonists) as adjunctive to DAPT after ACS has not been addressed with the most potent antiplatelet agents (prasugrel, ticagrelor) and merits further study. Despite the potential indication of prolonged oral anticoagulation as adjunctive treatment, it remains to be established whether anticoagulation therapy could also be an alternative for either aspirin or thienopyridine treatment in selected ACS patients on DAPT.

The Cost Effectiveness of Genetic Testing for CYP2C19 Variants to Guide Thienopyridine Treatment in Patients with Acute Coronary Syndromes

A recent clinical trial has demonstrated that patients with acute coronary syndromes (ACS) and the reduced function allele CYP2C19*2 (*2 allele), who are treated with thienopyridines, have an increased risk of adverse cardiac events with clopidogrel, but not with prasugrel. The frequency of the *2 allele varies by ethnicity and the Maoris, Asians and Pacific Islanders of New Zealand have a relatively high incidence. Our objective was to evaluate, from a New Zealand health system perspective, the cost effectiveness of treating all ACS patients with generic clopidogrel compared with prasugrel, and also compared with the genetically guided strategy that *2 allele carriers receive prasugrel and non-carriers receive clopidogrel. A decision-tree model consisting of five health states (myocardial infarction, stroke, bleeding, stent thrombosis and cardiovascular death) was developed. Clinical outcome data (two TRITON-TIMI 38 genetic sub-studies) comparing clopidogrel and prasugrel for both *2 allele carriers and non-carriers were combined with the prevalence of the heterozygosity for the *2 allele in New Zealand Europeans (15%), Maoris (24%), Asians (29%) and Pacific Islanders (45%) to determine the predicted adverse event rate for the New Zealand population. National hospital diagnosis-related group (DRG) discharge codes were used to determine alternative adverse event rates, along with the costs of hospitalizations during the 15 months after patients presented with an ACS. The primary outcome measure was the incremental cost per QALY (calculated using literature-reported weights). Monte Carlo simulations and alternative scenario analysis based on both clinical trial and national hospital incidence were used. Additional analysis considered the overall TRITON-TIMI 38 rates. Costs (in New Zealand dollars [$NZ], year 2009 values) and benefits were discounted at 3% per annum. Actual hospital-based adverse event rates were higher than those reported in the TRITON-TIMI 38 randomized controlled trial and the genetic sub-studies, especially for myocardial infarction and cardiovascular death, and for Maoris and Pacific Islanders. For both sources of adverse event rates, treating the population with prasugrel was associated with worse outcomes (QALYs) than clopidogrel. However, prasugrel became cost effective ($NZ31 751/QALY) when the overall TRITON-TIMI 38 rates were used. A genetic test to guide the selected use of prasugrel was cost effective ($NZ8702/QALY versus $NZ24 617/QALY) for hospital and clinical trial incidence, respectively. Based on the hospital rates, the genetically guided strategy was especially cost effective for Maoris ($NZ7312/QALY) and Pacific Islanders ($NZ7041/QALY). These results were robust to the sensitivity analysis, except the genetically guided strategy under the 15-month clinical trial event rate scenario ($NZ168 748/QALY) did not remain cost effective under a $NZ50 000 threshold. Use of a genetic test to guide thienopyridine treatment in patients with ACS is a potentially cost-effective treatment strategy, especially for Maoris and Pacific Islanders. This treatment strategy also has the potential to reduce ethnic health disparities that exist in New Zealand. However, the results comparing clopidogrel and prasugrel are sensitive to whether the genetic sub-studies or the overall TRITON-TIMI 38 rates are used. While the national hospital event rates may be more appropriate for the New Zealand population, many assumptions are required when they are used to adjust the genetic sub-studies rates.

Genetic testing good to guide thienopyridine treatment

Genetic testing good to guide thienopyridine treatment

Dual thienopyridine low-response to clopidogrel and prasugrel in a patient with STEMI, cardiogenic shock and early stent thrombosis is overcome by ticagrelor

Little is known about the antiplatelet action of the thienopyridines, clopidogrel and prasugrel, as well as the non-thienopyridine, ticagrelor, in patients suffering from ST-elevation myocardial infarction (STEMI) complicated by cardiogenic shock since systematic comparisons of these antiplatelet agents in this devastating condition are limited so far. This is a report of a patient with STEMI undergoing urgent PCI in cardiogenic shock followed by repeated angioplasty after suffering early stent thrombosis (ST) who showed dual thienopyridine treatment failure of clopidogrel and prasugrel, which was successfully overcome by switching the patient to the non-thienopyridine derivative ticagrelor.

Rationale and design of the TAXUS Libertē Post-Approval Study: Examination of patients receiving the TAXUS Liberté stent with concomitant prasugrel therapy in routine interventional cardiology practice

Observational studies of new coronary stents are necessary to assess performance in a variety of complex patient and lesion types. Furthermore, the optimal dose and duration of thienopyridine treatment is unclear, particularly in patients with complex clinical conditions. The TAXUS Libertē Post-Approval Study is designed to provide 5-year data on the TAXUS Liberté paclitaxel-eluting stent with concomitant prasugrel therapy in routine clinical practice and to contribute data to the DAPT study. The TAXUS Libertē Post-Approval Study is a prospective, multicenter, observational study. Enrollment of approximately 4,200 patients receiving ≥1 TAXUS Liberté stents is planned. All patients without a contraindication will be prescribed prasugrel plus aspirin for 1 year. The 12-month primary end point of cardiac death or myocardial infarction in on-label stent patients will be compared with historical TAXUS Express stent data from the TAXUS ATLAS and TAXUS ARRIVE studies. Secondary clinical end points include stent thrombosis, all-cause death, stroke, revascularization, and bleeding in all patients. In addition, this study will be the first to evaluate prasugrel use in a routine practice setting (including 5 and 10 mg daily doses) and will contribute data to the DAPT Study, comparing 12 versus 30 months of dual antiplatelet therapy after drug-eluting stent placement. The TAXUS Libertē Post-Approval Study will be the first to provide long-term real-world data on use of the TAXUS Liberté Stent with prasugrel treatment. The study is currently enrolling, and primary end point data are expected in mid 2013.

Impact of Anemia on Platelet Response to Clopidogrel in Patients Undergoing Percutaneous Coronary Stenting

High residual platelet reactivity (HRPR) on clopidogrel is a predictor of recurrent ischemic events in patients undergoing percutaneous coronary interventions (PCI). Significant intraindividual variability in platelet aggregation on repeat testing has been reported. To understand factors contributing to the variability in platelet aggregation testing, we examined clinical and laboratory elements linked to HRPR in 255 consecutive patients tested ≥12 hours after PCI using light transmission aggregometry (LTA) in response to adenosine diphosphate 5 μmol/L and VerifyNow P2Y12 assay (VNP2Y12; Accumetrics). HRPR was defined as >46% residual aggregation for LTA and >236 P2Y12 response units (PRUs) for VNP2Y12. On multivariate analysis the only variable independently associated with HRPR with both LTA and VNP2Y12 was laboratory-defined anemia. Prevalences of HRPR by LTA were 34.3% in anemic patients, 15.6% in patients with normal hemoglobin levels, and 59.8% versus 25.9% by VNP2Y12 (p <0.005 for the 2 comparisons). In a subgroup of 50 patients, testing was done before and after the clopidogrel loading dose. At baseline there were no differences in platelet aggregation with either assay; however, absolute decrease in reactivity after the clopidogrel load was significantly less in anemic patients compared to patients with normal hemoglobin (change in residual aggregation by LTA 15.8 ± 5.8% vs 28.8 ± 3.2%, p <0.05; change in PRU by VNP2Y12 56.5 ± 35.5 vs 145.0 ± 14.2 PRUs, p <0.05, respectively). In conclusion, anemia is an important contributor to apparent HRPR on clopidogrel and may explain some of the intraindividual variability of platelet aggregation testing.

Lack of association between serum paraoxonase-1 activity and residual platelet aggregation during dual anti-platelet therapy

High residual platelet aggregability during thienopyridine treatment occurs because of low levels of the active drug metabolite, and is associated with an increased rate of major adverse cardiovascular events. Recent findings suggest that paraoxonase-1 (PON1) is a major determinant for clopidogrel efficacy. The aim of this study was to assess the impact of serum PON1 activity on platelet aggregability in thienopyridine-treated patients. In 72 patients receiving treatment with aspirin and ticlopidine after acute coronary syndrome, various laboratory data including the formation of platelet aggregations induced by agonists were compared with serum PON1 activities, measured as paraoxonase and homocysteine thiolactone hydrolase (HTLase). Serum paraoxonase activity was significantly associated with HTLase activity (R=0.4487, P<0.0001). These PON1 activities were not correlated with any parameters for platelet aggregation, hypertension, sleep apnea, and diabetes mellitus. In contrast, serum PON1 activities seemed to be involved in cardiac function, with brain natriuretic peptide and ejection fraction being significantly correlated with serum HTLase activity (R=−0.2767, P=0.0214) and paraoxonase activity (R=0.2558, P=0.0339), respectively. Paraoxonase activity also demonstrated a significant association with increased levels of ankle-brachial index (R=0.267, P=0.0255). Serum PON1 activities did not influence platelet aggregability during treatment with thienopyridine. However, they might modulate cardiac function after acute coronary syndrome and progression of atherosclerosis.

Current Evidence for Genetic Testing in Clopidogrel-Treated Patients Undergoing Coronary Stenting

A combined dual antiplatelet treatment consisting of aspirin and the P2Y12 receptor inhibitor clopidogrel is still considered the standard of care treatment in most of the patients undergoing percutaneous coronary intervention (PCI). Numerous research studies during the last decade, however, have highlighted possible shortcomings of the oral antiplatelet agent clopidogrel, namely its large response variability resulting in an unpredictable response for the individual patient,1,2 the association of both a low3 or enhanced response4,5 with a worse clinical outcome and the dependency of individual responsiveness on nongenetic and genetic variables.6 Response by Pare and Eikelboom on p 513 Clopidogrel is a prodrug that requires bioactivation into its active thiol metabolite before it targets the P2Y12 receptor on blood platelets. In vivo bioactivation of the drug is a 2-step process that is closely linked to the cytochrome P450 (CYP) system. Different isoenzymes are responsible for clopidogrel bioactivation and among them the isoenzyme CYP2C19 was found to play a key role in this setting by contributing to both clopidogrel bioactivation steps.7 In this context, common genetic variants within the CYP2C19 gene have been the subject of considerable attention and have stimulated numerous research projects in recent years.8–14 Beyond CYP2C19, other genes involved in clopidogrel absorption, bioactivation or interplay with the blood platelet and their receptors have been associated with drug responsiveness and clinical outcome as well. Indeed, a growing body of evidence suggests a possible role of genotyping in patients undergoing coronary stenting with a view on optimizing response to P2Y12 receptor inhibitors during and after the procedure. We review available evidence on the need of individualizing antiplatelet treatment regimens in everyday clinical practice. ### Genetic Determinants for Clopidogrel Response and Clinical Outcome In recent years, multiple genetic factors within different candidate genes being involved in clopidogrel absorption, bioactivation, and …

Pharmacogenetics and pharmacogenomics of thienopyridines: clinically relevant?

Pharmacogenetics have been touted as the future of personalized medicine where genetic biomarkers will guide therapeutic approach. The currently approved thienopyridines, prasugrel and clopidogrel, are prodrugs requiring conversion to active metabolite through the cytochrome P450 system. Genetic variation has been associated with the pharmacokinetic, pharmacodynamic, and clinical response to clopidogrel, but not to prasugrel. This review aims to summarize the recent pharmacogenetic findings associated with the response to thienopyridine treatment. Additionally, considerations for the incorporation of genetic biomarkers into clinical practice will be discussed in the context of thienopyridines.