Clopidogrel Nonresponders Research Articles

Neuro-Interventional Use of Oral Antiplatelets: A Survey of Neuro-Endovascular Centers in the United States and Review of the Literature

Background: Intra- and postprocedural thrombosis are major complication of aneurysmal coil embolization, stent-assisted coiling, and pipeline embolization. The common but unproven practice of dual antiplatelet therapy with aspirin and a P2Y12 inhibitor in neuro-endovascular patients is inferred from the cardiology literature without large clinical trials to support it in neuro-endovascular patients. Objective: We conducted an electronic survey to identify practice variations surrounding the use of oral antiplatelets in patients undergoing endovascular neuro-interventional procedures across neuro-endovascular centers in the United States. Methods: An electronic survey was distributed via the Web. Any practicing neuro-intensive care unit (ICU), neuro-interventional or stroke physician, pharmacist, physician assistant, or nurse practitioner was eligible to respond to this survey between June and October 2017. Results: A total of 33 responses were collected during the survey period. A response rate of 16% was calculated after taking into account all comprehensive stroke centers in the United States. Aspirin and clopidogrel was the standard-of-care antiplatelet regimen utilized in the majority of institutions (82%). Alternatively, 4 institutions used monotherapy (aspirin [n = 2], clopidogrel [n = 1], either aspirin or clopidogrel [n = 1]) and 2 institutions reported practitioner-dependent practices. Just under half of the centers reported ticagrelor as the primary alternative in clopidogrel nonresponders (48%). Conclusion: Dual antiplatelet therapy with aspirin and clopidogrel appears to be standard of care in this setting based on our survey. About half of responding institutions use ticagrelor in cases where clopidogrel resistance is suspected. Large society-wide patient registries are needed to provide data for future safety and efficacy studies.

Pipeline embolization of posterior circulation aneurysms: a multicenter study of 131 aneurysms.

Flow diversion for posterior circulation aneurysms performed using the Pipeline embolization device (PED) constitutes an increasingly common off-label use for otherwise untreatable aneurysms. The safety and efficacy of this treatment modality has not been assessed in a multicenter study. A retrospective review of prospectively maintained databases at 8 academic institutions was performed for the years 2009 to 2016 to identify patients with posterior circulation aneurysms treated with PED placement. A total of 129 consecutive patients underwent 129 procedures to treat 131 aneurysms; 29 dissecting, 53 fusiform, and 49 saccular lesions were included. At a median follow-up of 11 months, complete and near-complete occlusion was recorded in 78.1%. Dissecting aneurysms had the highest occlusion rate and fusiform the lowest. Major complications were most frequent in fusiform aneurysms, whereas minor complications occurred most commonly in saccular aneurysms. In patients with saccular aneurysms, clopidogrel responders had a lower complication rate than did clopidogrel nonresponders. The majority of dissecting aneurysms were treated in the immediate or acute phase following subarachnoid hemorrhage, a circumstance that contributed to the highest mortality rate in those aneurysms. In the largest series to date, fusiform aneurysms were found to have the lowest occlusion rate and the highest frequency of major complications. Dissecting aneurysms, frequently treated in the setting of subarachnoid hemorrhage, occluded most often and had a low complication rate. Saccular aneurysms were associated with predominantly minor complications, particularly in clopidogrel nonresponders.

Aspirin and Clopidogrel Resistance in Indian Patients with Ischemic Stroke and its Associations with Gene Polymorphisms: A Pilot Study.

Introduction:Antiplatelet resistance is one of the urgent issues in current stroke care. One-third to one-half of the patients who experience a recurrent stroke is already on antiplatelet medications. We studied resistance to aspirin and clopidogrel in Indian stroke patients and its association with gene polymorphisms.Methods:Platelet function testing by light transmission aggregometry was performed on 65 patients with ischemic stroke who were stable on dual antiplatelet therapy (clopidogrel 75 mg OD and aspirin 75 mg OD) along with 65 age-matched controls. Aspirin resistance was considered as mean platelet aggregation ≥70% with 10 μM adenosine diphosphate (ADP) and ≥20% with 0.75 mM arachidonic acid. Clopidogrel resistance was defined as <10% decrease from the baseline in platelet aggregation in response to ADP 10 μM and semi-response as <30% decrease from the baseline. Polymorphisms CYP2C19 * 2 and GPIIb/IIIa (PLA1/A2) were genotyped by polymerase chain reaction-restriction fragment length polymorphism.Results:We found 64.6% (42/65) patients with inadequate response to clopidogrel (15.4% [10/65] resistant and 49.2% [32/65] semi-responders) and 4.6% (3/65) patients with inadequate response to aspirin (3.1% [2/65] resistant and 1.5% [1/65] semi-responder). The frequency of CYP2C19*2 mutant genotype was significantly higher in clopidogrel nonresponders compared to responders (P = 0.014). Clopidogrel nonresponsiveness was much higher in small vessel stroke.Conclusion:Unlike aspirin, a high proportion of nonresponders to clopidogrel was identified. In an interim analysis on 65 Indian patients, a significant association was found between CYP2C19*2 and clopidogrel nonresponsiveness.

Aspirin & clopidogrel non-responsiveness & its association with genetic polymorphisms in patients with myocardial infarction.

Background & objectives:Cytochrome P450, P2Y12, cyclooxygenase-1 (COX1) and glycoprotein V1 (GPVI) gene polymorphisms are known to affect patient responsiveness towards aspirin and clopidogrel dual antiplatelet therapy (DAPT). The present study was undertaken to identify aspirin and clopidogrel non-responsiveness and its association with genetic polymorphism in patients with myocardial infarction (MI).Methods:A total of 207 MI patients who were on DAPT, were included. The DAPT non-responsiveness was determined by light transmittance aggregometry using arachidonic acid and adenosine diphosphate and high platelet reactivity by collagen. Platelet activation biomarkers, thromboxane B2 (TxB2) and soluble CD40 ligand (sCD40L) were measured in plasma. Patient compliance was checked by estimating drug and its metabolite levels (aspirin and clopidogrel) in plasma using liquid chromatography-mass spectrometry/mass spectrometry. Genomic DNA was extracted, amplified by polymerase chain reaction and subsequently sequenced to identify CYP450, P2Y12, COX1 and GPVI gene polymorphisms.Results:Of the 207 patients, 32 were non-responders. The DAPT non-responsiveness was found in 15.5 per cent patients. The non-responsiveness showed a significant and an independent association with gender [odds ratio (OR)=0.18, 95% confidence interval (CI)=0.01-0.78, P=0.023], TxB2 (OR=1.00, 95% CI=1.00-1.01, P=0.013), CYP2C19*2 G>A (OR=3.33, 95% CI=1.04-10.69, P=0.044) and GPVI T>C (OR=0.23, 95% CI=0.08-0.67, P=0.007) after adjusting the demographic, clinical and genetic confounding factors when assessed between non-responder and responder compliant patients.Interpretation & conclusions:The study showed a significant association of genetic polymorphisms (CYP2C19*2 G>A and GPVI T>C) with DAPT non-responsiveness in MI patients. The findings of this study need further validation in a large cohort of patients with clinical follow up.

Whole blood aggregometry prior to Pipeline embolization device treatment of intracranial aneurysms: defining an optimal platelet inhibition cutoff value for clopidogrel.

Dual antiplatelet therapy is required for the treatment of intracranial aneurysms with the Pipeline embolization device (PED). Platelet function testing (PFT) is often used to assess the efficacy of the antiplatelet regimen prior to PED placement. The optimal impedance values for whole blood aggregometry in this setting have not been defined. A retrospective review of a prospectively maintained database was performed for the years 2011-2015 to identify patients with intracranial aneurysms treated with the PED who underwent pretreatment PFT using whole blood aggregometry. Antiplatelet therapy was not altered based on PFT results; all patients remained on standard doses of aspirin and clopidogrel. Clinical, radiographic, and laboratory data were analyzed to identify the optimal cutoff impedance value for clopidogrel responsiveness using the receiver operating characteristic curve and Youden's index. Forty-nine patients underwent 53 endovascular procedures for the treatment of 76 aneurysms using the PED. The majority of these aneurysms were located in the anterior circulation (90.8%) and affected the internal carotid artery (89.5%). Patients in 30 procedures (56.6%) were identified as clopidogrel responders based on the manufacturer cutoff value (< 6 Ω). Thromboembolic complications occurred in 13 (24.5%) procedures; patients in 6 (11.3%) cases were symptomatic and those in 3 (5.7%) cases had ischemic strokes. Eleven of the 13 (84.6%) thromboembolic complications occurred in clopidogrel nonresponders. An impedance value of ≥ 6 Ω was independently associated with thromboembolic complications. The optimal electrical impedance value was identified as ≥ 6 Ω (sensitivity 84.6%, specificity 70.0%, area under the curve 0.77) for identifying clopidogrel nonresponders. Thromboembolic complications are more common following PED placement in patients who do not respond adequately to clopidogrel. Clopidogrel nonresponders can be identified using pretreatment whole blood aggregometry. The optimal cutoff value to categorize a patient as a clopidogrel nonresponder when using whole blood aggregometry is ≥ 6 Ω.

Acetylsalicylic acid and clopidogrel hyporesponsiveness following acute coronary syndromes.

This review discusses the response variability to acetylsalicylic acid (ASA) and particularly to clopidogrel, and their relation to adverse recurrent ischaemic events in patients with arterial diseases. The higher rate of ASA resistance reported in the literature may be mainly due to the cyclooxygenase-1 non-specific assays, non-compliance, and underdosing. Clopidogrel response variability and non-responsiveness are established concepts. Moreover, high platelet reactivity (HPR) to adenosine diphosphate during clopidogrel therapy is now a known risk factor for recurrent ischaemic events in high-risk percutaneous coronary intervention/acute coronary syndrome patients. Variable active metabolite generation is the primary explanation for clopidogrel response variability and non-responsivenes. Variable levels of active metabolite generation following clopidogrel administration could be mainly explained by functional variability in hepatic cytochrome (CYP)P450 isoenzyme activity that is influenced by drug-drug interactions and single nucleotide polymorphisms of specific genes encoding CYP450 isoenzymes. Treatment with more potent P2Y12 receptor blockers, such as prasugrel and ticagrelor are credible alternative strategies to overcome HPR during clopidogrel therapy.

Clopidogrel utilization in patients with coronary artery disease and diabetes mellitus: should we determine CYP2C19*2 genotype?

Clopidogrel non-responsiveness is multifactorial; several genetic and non-genetic factors may contribute to impaired platelet inhibition. The goal of this study is to determine the effect of the cytochrome P450 CYP2C19*2 polymorphism on the platelet response to clopidogrel in patients with and without diabetes mellitus (DM). We conducted an observational study in patients with coronary artery disease and consequent exposure to clopidogrel therapy (75mg/day for at least 7 consecutive days). We have analyzed two groups of patients: group I (DM patients) and group II (non-diabetes mellitus patients). Platelet reactivity was assessed by the VerifyNow P2Y12 assay and high on clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) ≥ 208. Genotyping for CYP2C19*2 polymorphism was performed by PCR-RFLP. We have included 150 subjects (76 DM and 74 non-diabetes mellitus patients). The carriage of CYP2C19*2 allele, in DM patients, was significantly associated to HPR (odds ratio (OR) 4.437, 95% confidence interval (CI) 1.134 to 17.359; p= 0.032). Furthermore, 8.4% of the variability in percent inhibition by clopidogrel could be attributed to CYP2C19*2 carrier status. However, in non-diabetes mellitus patients, there was no significant difference in platelet response to clopidogrel according to the presence or absence of CYP2C19*2 allele carriage (OR 1.260, 95% CI 0.288 to 5.522; p = 0.759). Our study suggests that the carriage of CYP2C19*2 polymorphism, in DM patients, might be a potential predictor of persisting HPR in these high-risk individuals. Clinical Trials.gov NCT03373552 (Registered 13 December 2017).

Comparison of antiplatelet treatment in patients with clopidogrel nonresponders with or without carriage of CYP2C19 polymorphism.

Several interventions exist for overcoming high platelet reactivity (HPR) on clopidogrel therapy. The goal of this study was to identify strategies that improve inhibition of platelet reactivity in clopidogrel nonresponders with or without loss of function CYP2C19 genotypes, resulting in platelet reactivity similar to that in responders. A total of 376 patients with stenting for coronary artery disease underwent platelet function testing in three centers. Blinded platelet function tests were performed after 75 mg daily clopidogrel treatment for 28 days. In total, 183 nonresponders were genotyped, were randomized to four treatment groups with each treatment lasting approximately 28 days, and underwent repeated measurements of platelet reactivity after treatment. With 75 mg of daily clopidogrel, nonresponders had significantly higher HPR than did responders (multiple electrode aggregometry [MEA, arbitrary platelet aggregation unit]: mean, 71.4; 95% confidence intervals [CI], 68.6 to 74.3; and mean, 27.5; 95% CI, 26.0 to 28.9, respectively; p < 0.001). Ticagrelor or ticlopidine treatment in nonresponders resulted in platelet reactivity similar to that in responders in intermediate metabolizers (mean, 24.0; 95% CI, 19.6 to 28.4; p > 0.05; and mean, 30.0; 95% CI, 24.7 to 37.5; p > 0.05, respectively) and poor metabolizers (mean, 23.2; 95% CI, 18.0 to 28.3; p > 0.05; and mean, 30.3; 95% CI, 24.5 to 6.0; p > 0.05, respectively). However, in extensive metabolizers, only ticagrelor treatment showed platelet reactivity similar to that in responders (mean, 26.1; 95% CI, 24.1 to 28.0; p > 0.05). Among clopidogrel nonresponders with cardiovascular disease on 75 mg daily clopidogrel, ticagrelor resulted in a comparable degree of platelet inhibition in all nonresponders compared with 150 mg daily clopidogrel or triple therapy with clopidogrel and cilostazol, irrespective of phenotype.

Abstract TP84: Safety and Effectiveness of Ticagrelor in Patients With Clopidogrel Resistance Undergoing Angioplasty, Stent or Flow Diverter Placement

Background and Purpose: Nearly 30% of the patients have clopidogrel resistance and are at high risk for in-stent thrombosis and adverse ischemic events. Ticagrelor is an allosteric platelet antagonist that reversibly inhibits the P2Y12 platelet receptor more potently than clopidogrel. We report upon the safety and effectiveness of ticagrelor in patients with cerebrovascular diseases and clopidogrel resistance undergoing angioplasty and/or stent or flow diverter placement. Methods: We analyzed data from our prospectively maintained endovascular database and identified patients treated with ticagrelor and underwent treatment with a stent or flow diverter. The patients were divided into an acutely loaded dose group and those converted from clopidogrel due to clopidogrel resistance, defined by platelet aggregation value of 200 PRU VerifyNow P2Y12 test. Patients received standard dual antiplatelet therapy, however, despite repeat clopidogrel loading doses, were found to be clopidogrel non-responders and were then administered ticagrelor 180mg loading dose and maintained on 90mg BID dosing. We ascertained occurrence of any bleeding complications, classified as major (hgb decrease &gt;5 g/dl), minor (hgb decrease 3-5 g/dl), or insignificant. Results: A total of 36 (13.8%) patients (mean age 64.7±13.8 years; 58.3% females) had clopidogrel resistance out of 260 patients screened. Of those, 29 patients were switched from clopidogrel to ticagrelor due to an elevated PRU (avg 294.76±41.32 PRU) and 7 patients without previous antiplatelet use received a bolus and maintenance dose. Only one patient experienced a transient ischemic event within 24 hours after starting ticagrelor. Patients who were acutely loaded did not experience any ischemic events. No patient experienced symptomatic or asymptomatic hemorrhage on ticagrelor in the post-op period. A total of 43 procedures were performed in 36 patients with clopidogrel resistance: 26 pipeline placements, 8 wingspan stent placements, 2 LVIS stents, 1 neuroform stent with pipeline, and 7 angioplasties. Conclusions: Our study demonstrates the safety and effectiveness of loading or switching patients to ticagrelor with cerebrovascular diseases undergoing angioplasty, stent or flow diverter placement.

Haplotype analyses of CYP2C19*2 and CYP2C19*17 genetic polymorphisms in clopidogrel non-responsiveness after percutaneous coronary intervention with stent implantation

Haplotype analyses of CYP2C19*2 and CYP2C19*17 genetic polymorphisms in clopidogrel non-responsiveness after percutaneous coronary intervention with stent implantation

Clopidogrel non-responsiveness in patients undergoing percutaneous coronary intervention using the VerifyNow test: frequency and predictors

ObjectivesStent thrombosis and death after percutaneous coronary intervention (PCI) can be caused by a phenomenon known as clopidogrel non-responsiveness which has been shown to occur in approximately 5%–44% of patients....

Caesarean delivery during dual antiplatelet therapy after acute myocardial infarction and stenting

Abstract Background Cardiac disease is the leading cause of maternal mortality during pregnancy in high-resource countries. Case A 31-year-old woman had an ST-elevated myocardial infarction (STEMI) at 16 gestational weeks. The patient received three coronary drug-eluting stents followed by dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. An elective caesarean delivery was performed under general anesthesia at 37+1 gestational weeks. Due to subnormal response to clopidogrel, administration was paused only 24 h perioperatively without bridging with tirofiban because of the slightly increased risk of stent thrombosis in clopidogrel nonresponders. There was no postoperative bleeding. Conclusions There is a lack of evidence-based guidelines regarding the management of acute myocardial infarction (AMI) during pregnancy; thus, delivery should be performed in a tertiary center with a multidisciplinary approach.

Impact of CYP2C19 genotype and platelet function on clinical outcome in coronary atherosclerotic heart diseases patients received clopidogrel post percutaneous coronary intervention

Objective: To analyze association of CYP2C19 genotype and platelet function phenotype and their impact on clinical outcomes including bleeding events of coronary artery disease(CAD) patients received clopidogrel post percutaneous coronary intervention(PCI). Methods: Coronary atherosclerotic heart diseases patients underwent elective PCI and coronary stent implantation in Fuwai hospital were prospectively enrolled during May 2012 to April 2013. Patients were assigned into groups by genotype of CYP2C19 (extensive metabolizers, intermediate metabolizers, and poor metabolizers) and phenotype of platelet function (clopidogrel responders, semi-responders, and non-responders). The rates of major adverse cardiovascular events, combined cardiovascular events, and bleeding events were recorded during a at least 12 months follow-up period and compared among above defined groups. The association between genotype or phenotype and clinical outcome was assessed using multivariable Cox regression hazards model. Results: Three hundred and eighty patients received coronary stent implantation and met the inclusion criteria of the study, including 157(41.3%) clopidogrel extensive metabolizers, 176(46.3%) intermediate metabolizers, and 47(12.4%) poor metabolizers according to the genotype grouping; 98(25.8%) were responders to clopidogrel, 149(39.2%) were semi-responders, and 133 (35.0%) were non-responders according to the phenotype grouping. Three hundred and seventy-six patients accomplished follow-up. The highest combined cardiovascular events rate was observed in the poor metabolizers (34.0%(16/47)) as compared to the intermediate metabolizers (19.0%(33/174), P=0.026) and the extensive metabolizers (15.5%(24/155), P=0.005). The highest bleeding events rate was observed in the clopidogrel responders (33.7%(33/98)) as compared to the semi-responders (18.9%(28/149), P=0.008) and non-responders (17.7%(23/130), P=0.008). In multivariable Cox regression analysis, the adjusted risk of cardiovascular death, acute myocardial infarction, stent embolism, target lesion revascularization and angina onset was 2.305 times higher in clopidogrel poor metabolizers than in extensive and semi-metabolizers (95%CI=1.208-4.399, P=0.011). The adjusted HR for bleeding events was 0.540 (95%CI=0.321-0.909, P=0.021) among semi-responders vs. responders, was 0.52 (95%CI=0.301-0.905, P=0.021) among non-responders vs. responders during the 12 months follow-up period. Conclusions: Among CAD patients underwent stenting and clopidogrel treatment, poor CYP2C19 metabolizers group carries a significantly higher risk for combined cardiovascular events than in extensive metabolizers group, while clopidogrel responders patients are at significantly higher risk for bleeding as compared to the semi-responders and non-responders.

PCI and clopidogrel: antiplatelet responsiveness and patient characteristics.

This study on responsiveness to clopidogrel and aspirin evaluates its interaction with: (i) patient characteristics; (ii) procedure characteristics; (iii) antiplatelet dose. After elective PCI, 60 patients receiving aspirin 100 mg daily, and clopidogrel 75 mg daily were monitored with the PFA 100 test and VASP assay. Non-responsiveness to aspirin and clopidogrel was found in 23 (38%) and 18 (30%) of 60 patients, respectively. Seven (12%) patients were dual nonresponders. Non-responders to both aspirin and clopidogrel were more often smokers. Non-responders to clopidogrel, in addition had elevated inflammatory markers (P < 0.05). Dual non-responders had (i) a higher platelet count, LDL, and CRP; (ii) a lower HDL (P < 0.05). Clopidogrel non-responders were receiving 150 mg clopidogrel, with a positive response in 72%. Eighty % of non-responders to 150 mg clopidogrel were also non-responders to aspirin. Baseline patient characteristics and clopidogrel dose modify the antiplatelet response. Also, patients resistant to both aspirin and clopidogrel do no benefit from an increased clopidogrel dose.

Use of Platelet Function Testing Before Pipeline Embolization Device Placement: A Multicenter Cohort Study.

Thromboembolic complications constitute a significant source of morbidity after neurointerventional procedures. Flow diversion using the pipeline embolization device for the treatment of intracranial aneurysms necessitates the use of dual antiplatelet therapy to reduce this risk. The use of platelet function testing before pipeline embolization device placement remains controversial. A retrospective review of prospectively maintained databases at 3 academic institutions was performed from the years 2009 to 2016 to identify patients with intracranial aneurysms treated with pipeline embolization device placement. Clinical and radiographic data were analyzed with emphasis on thromboembolic complications and clopidogrel responsiveness. A total of 402 patients underwent 414 pipeline embolization device procedures for the treatment of 465 intracranial aneurysms. Thromboembolic complications were encountered in 9.2% of procedures and were symptomatic in 5.6%. Clopidogrel nonresponders experienced a significantly higher rate of thromboembolic complications compared with clopidogrel responders (17.4% versus 5.6%). This risk was significantly lower in nonresponders who were switched to ticagrelor when compared with patients who remained on clopidogrel (2.7% versus 24.4%). In patients who remained on clopidogrel, the rate of thromboembolic complications was significantly lower in those who received a clopidogrel boost within 24 hours pre-procedure when compared with those who did not (9.8% versus 51.9%). There was no significant difference in the rate of hemorrhagic complications between groups. Clopidogrel nonresponders experienced a significantly higher rate of thromboembolic complications when compared with clopidogrel responders. However, this risk seems to be mitigated in nonresponders who were switched to ticagrelor or received a clopidogrel boost within 24 hours pre-procedure.

Contribution of whole platelet aggregometry to the endovascular management of unruptured aneurysms: an institutional experience

BackgroundStent-assisted coiling of intracranial aneurysms is an efficient alternative treatment to surgical clipping but requires prolonged antiplatelet therapy. Some patients are non-responsive to aspirin and/or clopidogrel.ObjectiveTo analyze the implications of...

P2Y12 Reaction Units Threshold for Implementing Modified Antiplatelet Preparation in Coil Embolization of Unruptured Aneurysms: A Prospective Validation Study.

Purpose To identify and apply an optimized P2Y12 reaction units (PRU) threshold for implementing modified antiplatelet preparation to prevent thromboembolic events in patients nonresponsive to clopidogrel (clopidogrel nonresponders) undergoing coil embolization of unruptured aneurysms and to evaluate the clinical validity. Materials and Methods The optimal PRU threshold for prediction of thromboembolic events was determined with the Youden index in post hoc analysis of a previous, prospectively enrolled cohort of 165 patients in whom the antiplatelet regimen was not modified. This optimal PRU threshold was used to define clopidogrel nonresponders in a prospective validation study of 244 patients. Standard preparation (aspirin, clopidogrel) was maintained for 126 patients responsive to clopidogrel (clopidogrel responders, 51.6%), and modified preparation (aspirin, prasugrel) was prescribed prior to embolization for 118 clopidogrel nonresponders (48.4%). Fifty-seven clopidogrel nonresponders from the previous cohort who did not receive the modified preparation were included as a historical control group. Thromboembolic and bleeding events were compared among groups by using logistic regression analysis. Results Post hoc analysis from the previous cohort yielded PRU of at least 220 as the optimal threshold for modified preparation selection. The thromboembolic event rate of the clopidogrel responders (one of 126 [0.8%]) was lower than that of the historical control group that received standard preparation (seven of 57 patients [12.3%]; adjusted risk difference [RD], -10.1%; 95% confidence interval [CI]: -18.5, -1.7; P = .015) and was similar to that of clopidogrel nonresponders who received modified preparation (one of 118 [0.8%]; adjusted RD, -0.5%; 95% CI: -3.1, 2.1; P = .001 for noninferiority; P = .699 for superiority). Bleeding event rates did not differ among groups (four of 126 clopidogrel responders [3.2%] vs four of 57 clopidogrel nonresponders that received standard preparation [7.0%] [adjusted RD, -4.5%; 95% CI: -11.1, 3.4; P = .228] vs five of 118 clopidogrel nonresponders that received modified preparation [4.2%] [adjusted RD, -0.6%; 95% CI: -5.8, 4.2; P = .813]). Conclusion Patients undergoing coil embolization of unruptured aneurysms, regardless of clopidogrel responsiveness, had low thromboembolic risk when using PRU of at least 220 as the threshold for implementing modified antiplatelet preparation with prasugrel. © RSNA, 2016 Online supplemental material is available for this article.

304 The Contribution of Whole Platelet Aggregometry to the Endovascular Management of Unruptured Aneurysms

Abstract Stent-assisted coiling of intracranial aneurysms is a viable and efficient treatment alternative to surgical clipping but requires prolonged antiplatelet therapy. Some patients can be nonresponsive to aspirin and/or clopidogrel. This is the first study analyzing the implications of this assessment using the whole blood aggregometry (WBA) by impedance technique. The Southwestern Tertiary Aneurysm Registry (STAR) was reviewed between 2002 and 2012 for patients with unruptured aneurysms treated with stent-assisted coiling. The study population was divided into patients who were tested preoperatively for platelet responsiveness to aspirin and clopidogrel (tested patients) and those who were not (nontested patients). Where necessary, a majority of tested patients received additional doses of antiplatelet drugs to achieve adequate platelet inhibition. End points included the incidence of antiaggregant nonresponsiveness, the rates of thrombotic and hemorrhagic complications, and the rates of permanent morbidity and mortality. A total of 266 patients fulfilled our selection criteria. There were 114 nontested patients who underwent 121 procedures, and 152 tested patients who underwent 171 procedures. The 2 groups did not vary significantly in patient age, sex, and aneurysms location. Aspirin nonresponsiveness was detected in 3 patients (1.75%) and clopidogrel nonresponsiveness was detected in 21 patients (12.3%). Nontested patients had an 11.5% rate of thrombotic complications with a 4.23% permanent morbidity or mortality rate vs 2.3% and 0.58% in tested patients (P = .001). The incidence of hemorrhagic complications was similar between the 2 groups. Preoperative platelet inhibition testing using WBA can be useful to assess and correct antiaggregant nonresponsiveness, and may reduce postoperative mortality and permanent morbidity.

Effect of CYP2C19 Polymorphisms on the Platelet Response to Clopidogrel and Influence on the Effect of High Versus Standard Dose Clopidogrel in Carotid Artery Stenting

Genetic background has been identified to be a major predictor of post-clopidogrel platelet inhibition in patients undergoing coronary stenting. However, there is a lack of data on clopidogrel response regarding genotype in patients undergoing carotid artery stenting (CAS). The influence of the most common allelic variants of CYP2C19 phenotypes and genotypes on response to baseline clopidogrel and on the pharmacodynamic effect of dose adjustment (high or standard dose of clopidogrel) in patients with high on-treatment reactivity after CAS was investigated. Platelet reactivity was assessed before and 30 days after carotid stenting using the VerifyNow P2Y12 assay to obtain P2Y12 reactivity unit (PRU) values. A total of 209 patients (79.4% male, 44.1% currents smokers) were treated by CAS. Smokers improved responsiveness to clopidogrel (p = .034). With respect to CYP2C19 enzymatic function, 61 subjects (29.1%) were ultra-rapid metabolizers, 95 patients (45.5%) were extensive metabolizers, 51 (24.4%) were intermediate metabolizers, and two (0.96%) were poor metabolizers. Baseline PRU was significantly higher among intermediate-poor metabolizers compared with ultra-rapid (p = .001) or extensive metabolizers (p = .005). At 30 days follow up, in non-responding patients with the intermediate-poor metabolizer phenotype, the PRU value and inhibition percentage were significantly reduced with standard dose (p = .008; p = .0029) and high dose of clopidogrel (p = .00 0; p = .000). However, high dose clopidogrel did not achieve a more intense pharmacodynamic effect at 30 days (p = .994) compared with standard dose. In patients undergoing carotid stenting, those with the CYP2C19*2 allele had increased basal PRU values and in fact clopidogrel non-responders increased significantly among intermediate-poor metabolizers. Although high dose and standard dose clopidogrel therapy was effective in lowering the 30 day PRU values in patients with high on-treatment reactivity who are intermediate-poor metabolizers, the use of high dose clopidogrel did not result in statistically significantly greater reductions in reactivity compared with the standard dose.

Association of CYP2C19, CYP3A5 and GPIIb/IIIa gene polymorphisms with Aspirin and Clopidogrel Resistance in a cohort of Indian patients with Coronary Artery Disease.

Dual antiplatelet therapy with clopidogrel and aspirin is the current standard of care in the management of patients with coronary artery disease (CAD) and acute coronary syndrome (ACS). The variability in response to these antiplatelet agents may be due to the underlying genetic diversity. This study was designed to determine the resistance to aspirin and clopidogrel in Indian patients and to look for correlation, if any, with selected polymorphisms. Platelet function testing by light transmission aggregometry was performed on 72 patients with CAD/ACS who were stable on dual antiplatelet therapy (clopidogrel 75 mg OD and aspirin 150 mg OD) along with 72 controls. Aspirin resistance was considered as mean platelet aggregation ≥ 70% with 10 μm ADP and ≥ 20% with 0.75 mm arachidonic acid. Clopidogrel resistance was defined as <10% decrease from the baseline in platelet aggregation in response to ADP 10 μm and semi-response as <30% decrease from the baseline. Polymorphisms CYP2C19*2, *3, CYP3A5*3 and PLA1/A2 were genotyped. We found 51.4% patients with inadequate response to clopidogrel (1.4% resistant and 50% semi-responders) and 5.5% patients semi-responders to aspirin, none being completely resistant. The genotype and allele frequencies of CYP2C19*2 and PLA1/A2 gene polymorphisms were significantly different between clopidogrel semi-responders and responders. Carriers of CYP2C19*2 and CYP3A5*3 showed diminished inhibition of platelet aggregation. No significant correlation was found between coronary events, type of coronary intervention with clopidogrel nonresponsiveness. Unlike aspirin, a high proportion of partial responders to clopidogrel were identified. In an interim analysis on 72 Indian patients, a significant association was found between CYP2C19*2 and PLA1/A2 in clopidogrel semi-responders.