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Wiśniewski, Adam, and Karolina Filipska. "The Phenomenon of Clopidogrel High On-Treatment Platelet Reactivity in Ischemic Stroke Subjects: A Comprehensive Review." International Journal of Molecular Sciences 21, no. 17 (September 3, 2020): 6408. http://dx.doi.org/10.3390/ijms21176408.
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Clopidogrel is increasingly being used for the secondary prevention of ischemic stroke according to the updated guidelines on acute stroke management. Failure to achieve a drug response is referred to as clopidogrel resistance. Similarly, a higher activation of platelets during clopidogrel therapy—high on-treatment platelet reactivity—is equivalent to a reduced effectiveness of a therapy. Clopidogrel resistance is considered to be a common and multifactorial phenomenon that significantly limits the efficacy of antiplatelet agents. The aim of the current study is to review the latest literature data to identify the prevalance and predictors of clopidogrel high on-treatment platelet reactivity among stroke subjects and to establish the potential impact on clinical outcomes and prognosis. Clinical databases were searched by two independent researchers to select relevant papers on the topic, including all types of articles. Several important predictors contributing to clopidogrel resistance were identified, including genetic polymorphisms, the concomitant use of other drugs, or vascular risk factors, in particular nonsmoking and diabetes. Clopidogrel high on-treatment platelet reactivity has a negative impact on the clinical course of stroke, worsens the early- and long-term prognoses, and increases the risk of recurrent vascular events. Platelet function testing should be considered in selected stroke individuals, especially those predisposed to clopidogrel resistance, for whom an improvement in the efficacy of antiplatelet therapy is essential. This particular group may become the greatest beneficiaries of the modification of existing therapy based on platelet function monitoring.
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Akinosoglou, Karolina, Angelos Perperis, Spyridoula Theodoraki, Dimitrios Alexopoulos, and Charalambos Gogos. "Sepsis favors high-on-clopidogrel platelet reactivity." Platelets 29, no. 1 (June 21, 2017): 76–78. http://dx.doi.org/10.1080/09537104.2017.1319919.
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Frelinger III, Andrew L., Alan D. Michelson, Stephen D. Wiviott, Dietmar Trenk, Franz-Josef Neumann, Debra L. Miller, Joseph A. Jakubowski, et al. "Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel." Thrombosis and Haemostasis 106, no. 08 (2011): 219–26. http://dx.doi.org/10.1160/th11-03-0185.
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SummaryIt was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, twophase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18–24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18–24 h and 15 day reactivity to ADP (correlations 0.24–0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade with high-dose clopidogrel or even higher level P2Y12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.
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Kristensen, Steen, Willibald Hochholzer, Franz-Josef Neumann, and Dietmar Trenk. "High on-treatment platelet reactivity and P2Y12 antagonists in clinical trials." Thrombosis and Haemostasis 109, no. 05 (2013): 834–45. http://dx.doi.org/10.1160/th12-08-0588.
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SummaryDual antiplatelet therapy with aspirin and clopidogrel in patients undergoing percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes (ACS) has substantially decreased the rate of cardiovascular events. Within the past decade, the variability in pharmacodynamic response as well as the moderate antiplatelet efficacy of clopidogrel has raised major concerns, since high on-clopidogrel platelet reactivity has consistently been associated with increased risk for ischaemic events in PCI patients. The variability in response could be linked to genetic polymorphisms impacting on activity of cytochrome P450 enzymes as well as clinical and demographic variables, but, taken together, factors identified so far can explain only up to approximately 12% of this variability in adenosine diphosphate-induced platelet aggregation on clopidogrel. Regulatory agencies as well as major cardiac societies suggest the use of other anti-platelet medications or alternative dosing strategies for clopidogrel in patients with reduced effectiveness of clopidogrel. This review will focus on the current status of alternate strategies for more sufficient suppression of high platelet reactivity.
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Hildemann, Steven, Christian Schulz, Daniela Fraccarollo, Corinna Schöpp, Ulrike Flierl, Kerstin Wissel, Jaroslav Pelisek, Steffen Massberg, Johann Bauersachs, and Andreas Schäfer. "Fractalkine promotes platelet activation and vascular dysfunction in congestive heart failure." Thrombosis and Haemostasis 111, no. 04 (2014): 725–35. http://dx.doi.org/10.1160/th13-08-0640.
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SummaryEndothelial dysfunction and enhanced platelet reactivity in congestive heart failure (CHF) contribute to poor prognosis. CHF patients display an impaired responsiveness to clopidogrel. Fractalkine activates platelets and elevated plasma levels of this chemokine are a feature of CHF. We here addressed the interrelation of fractalkine, platelet reactivity and clopidogrel efficacy in humans and rats with CHF. Fractalkine serum levels determined by ELISA were increased in CHF patients (CHF: 1548 ± 650 pg/ml; Control: 968 ± 575 pg/ml, p<0.01) and following CHF induction in rats (CHF: 1509 ± 753 pg/ ml; Sham: 1181 ± 275 pg/ml, p<0.05). Expression of fractalkine and its receptor CX3CR1 was enhanced in aortas of CHF rats as determined by immunofluorescence microscopy and molecular analysis. Fractalkine significantly aggravated endothelial dysfunction and augmented P-selectin expression on platelets from CHF rats. Platelet surface expression of CX3CR1 was increased in CHF rats, who displayed an impaired response to clopidogrel (platelet reactivity to ADP: CHF 30 ± 22%; Sham: 8 ± 5%, p<0.05). Similarly in humans with CHF, elevated fractalkine levels were accompanied by reduced clopidogrel responsiveness. Patients with high on-clopidogrel treatment platelet P2Y12 reactivity displayed higher fractalkine levels (1525 ± 487 pg/ml) than those with sufficient clopidogrel response (684 ± 315 pg/ml, p<0.01). In conclusion, in CHF fractalkine was increased on the endothelium and in blood serum, and platelet surface- expression of CX3CR1 was enhanced. Fractalkine diminished endothelial function beyond the impairment already observed in CHF and was associated with a reduced responsiveness to the platelet inhibitor clopidogrel. These findings may indicate a novel pathophysiological mechanism contributing to impaired clopidogrel responsiveness in CHF.
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Mangiacapra, Fabio, Bernard De Bruyne, Olivier Muller, Catalina Trana, Argyrios Ntalianis, Jozef Bartunek, Guy Heyndrickx, Germano Di Sciascio, William Wijns, and Emanuele Barbato. "High Residual Platelet Reactivity After Clopidogrel." JACC: Cardiovascular Interventions 3, no. 1 (January 2010): 35–40. http://dx.doi.org/10.1016/j.jcin.2009.10.024.
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Campo, Gianluca, Matteo Miccoli, Matteo Tebaldi, Jlenia Marchesini, Luca Fileti, Monia Monti, Marco Valgimigli, and Roberto Ferrari. "Genetic determinants of on-clopidogrel high platelet reactivity." Platelets 22, no. 6 (May 31, 2011): 399–407. http://dx.doi.org/10.3109/09537104.2011.579648.
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Nührenberg, Thomas, Michael Amann, Marco Cederqvist, Pascal Kleiner, Christian M. Valina, Dietmar Trenk, Franz-Josef Neumann, Willibald Hochholzer, and Christian Stratz. "Impact of reticulated platelets on antiplatelet response to thienopyridines is independent of platelet turnover." Thrombosis and Haemostasis 116, no. 11 (September 2016): 941–48. http://dx.doi.org/10.1160/th16-03-0191.
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SummaryReticulated platelets are associated with impaired antiplatelet response to thienopyridines. It is uncertain whether this interaction is caused by a decreased drug exposure due to high platelet turnover reflected by elevated levels of reticulated platelets or by intrinsic properties of reticulated platelets. This study sought to investigate if the impact of reticulated platelets on early antiplatelet response to thienopyridines is mainly caused by platelet turnover as previously suggested. Elective patients undergoing coronary intervention were randomised to loading with clopidogrel 600 mg or prasugrel 60 mg (n=200). Adenosine diphosphate (ADP)-induced platelet reactivity was determined by impedance aggregometry before, at 30, 60, 90, and 120 minutes and at day 1 after loading. Immature platelet count was assessed as marker of reticulated platelets by flow cytometry. Platelet reactivity increased with rising levels of immature platelet count in both groups. This effect was more distinctive in patients on clopidogrel as compared to patients on prasugrel. Overall, immature platelet count correlated well with on-treatment platelet reactivity at all timepoints (p < 0.001). These correlations did not change over time in the entire cohort as well as in patients treated with clopidogrel or prasugrel indicating an effect independent of platelet turnover (comparison of correlations 120 minutes/day 1: p = 0.64). In conclusion, the association of immature platelet count with impaired antiplatelet response to thienopyridines is similar early and late after loading. This finding suggests as main underlying mechanism another effect of reticulated platelets on thienopyridines than platelet turnover.Supplementary Material to this article is available online at www.thrombosis-online.com.
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Kuliczkowski, Wiktor, Ewa Żurawska-Płaksej, Maria Podolak-Dawidziak, Magdalena Cielecka-Prynda, Bożena Karolko, Jakub Dębski, Konrad Kaaz, et al. "Platelet Reactivity and Response to Aspirin and Clopidogrel in Patients with Platelet Count Disorders." Cardiology Research and Practice 2021 (April 17, 2021): 1–7. http://dx.doi.org/10.1155/2021/6637799.
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Background. Platelet reactivity and response to antiplatelet drugs, acetylsalicylic acid (ASA) and clopidogrel, in patients with thrombocytopenia and thrombocythemia can have a potentially important effect on the outcome. The effectiveness and safety of antiplatelet drugs in such patients has not been well examined. Measuring the effect of ASA and clopidogrel on platelets could help guide the therapy. Nevertheless, platelet response to antiplatelet drugs is not routinely measured in platelet count disorders and relevant evidence is scarce. Aims. The study aimed to measure platelet reactivity and response to ASA and clopidogrel in patients with platelet count disorders. Materials and Methods. This was a cross-sectional study of consecutive patients hospitalized in cardiology and hematology departments in the years 2018–2019. The study included patients with thrombocytopenia (PLT < 150 G/L) and thrombocythemia (PLT > 450 G/L) on ASA or dual antiplatelet therapy (DAPT; ASA plus clopidogrel). Controls included patients on antiplatelet drugs with normal platelet count. Platelet reactivity was measured in whole blood (Multiplate aggregometer, Roche, Switzerland) using arachidonic acid (AA), adenosine-5′-diphosphate (ADP), and thrombin receptor agonist peptide-6 (TRAP) as agonists. Platelet aggregation was expressed in arbitrary units (AU). AA-induced aggregation was used as a measure of response to ASA with a cut-off above 30 AU showing high on-treatment platelet reactivity to ASA (HTPR-A). ADP-induced aggregation measured response to clopidogrel with a cut-off above 48 AU for high on-treatment platelet reactivity to clopidogrel (HTPR-C). TRAP-induced aggregation measured baseline platelet reactivity not affected by oral antiplatelet drugs. Results. The study included 174 patients. There were 64 patients with thrombocytopenia, 30 patients with chronic thrombocythemia, and 80 controls. All patients were on 75 mg of ASA and 32% of them additionally on 75 mg of clopidogrel due to a history of recent coronary artery angioplasty. AA- and ADP-induced aggregation was comparable between thrombocytopenic patients and controls (median (IQR) 19 (7–28) vs. 23 (15–38) for AA AU and 32 (16–44) vs. 50 (32–71) for ADP AU, respectively), while it was significantly higher in thrombocythemic patients (median (IQR) 80 (79–118) for AA AU and 124 (89–139) for ADP AU). TRAP-induced aggregation showed significantly lowest aggregation in thrombocytopenic (median (IQR) 41 (34–60) for TRAP AU) and highest in thrombocythemic patients (median (IQR) 137 (120–180) for TRAP AU). HTPR-A was frequent in thrombocythemic patients in comparison with thrombocytopenic patients and controls (60% vs. 4% vs. 15%, respectively; p < 0.0002 ). HTPR-C was highly common in thrombocythemic patients and least common in thrombocytopenic ones in comparison with controls (80% vs. 8% vs. 40%, respectively; p < 0.001 ). Conclusion. Chronic thrombocytopenia does not significantly affect platelet reactivity and response to ASA and clopidogrel in comparison with controls. Thrombocytosis significantly increases platelet reactivity and attenuates response to both ASA and clopidogrel.
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Tousek, Petr, Viktor Kocka, Jakub Sulzenko, Frantisek Bednar, Hana Linkova, and Petr Widimsky. "Pharmacodynamic Effect of Clopidogrel in Patients Undergoing Transcatheter Aortic Valve Implantation." BioMed Research International 2013 (2013): 1–3. http://dx.doi.org/10.1155/2013/386074.
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The aim of this study was to analyze periprocedural and mid-term effect of clopidogrel on platelet function using the VerifyNow P2Y12point-of-care assay in patients undergoing TAVI. Platelet reactivity was measured at the beginning of the procedure after 300 mg clopidogrel bolus administration and during the follow-up (at 1 month after the procedure) in 52 patients undergoing TAVI using the Medtronic CoreValve prosthesis (Medtronic CoreValve). A cutoff value of 240 PRU was used to identify nonresponders to clopidogrel treatment with high residual platelet reactivity (HRPR). Baseline HRPR was identified in 80% of patients and in 72% of patients during 6-month follow-up. There was no significant difference in the pharmacodynamic effects of clopidogrel on platelet reactivity from baseline to 6-months follow-up (297±57vs.275±62;P=0.058). Ischemic event occurred only in 3 patients (5.8%) from the study group. In conclusion, majority of patients undergoing TAVI had high residual platelet reactivity after pretreatment with 300 mg of clopidogrel and during the 6-month follow-up at dual antiplatelet treatment. The noneffectiveness of clopidogrel in the TAVI population raises the question of the routine use of dual antiplatelet treatment in this setting.
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Wiśniewski, Adam, Joanna Sikora, Aleksandra Karczmarska-Wódzka, and Przemysław Sobczak. "A Combination of Aspirin and Clopidogrel Predict More Favorable Dynamics of Platelet Reactivity versus Clopidogrel Alone in the Acute Phase of Minor Stroke." Healthcare 9, no. 6 (May 25, 2021): 628. http://dx.doi.org/10.3390/healthcare9060628.
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Background: The combined use of clopidogrel and aspirin is recommended for the short-term (21 days) therapy of minor stroke or transient ischemic attack. Previous studies have demonstrated its efficacy and superiority over treatment with a single antiplatelet agent. However, there is insufficient support for the advantages of such therapy based on platelet function testing. We aimed to compare the effect of the concomitant use of clopidogrel and aspirin versus clopidogrel alone on the dynamics of platelet reactivity over time to determine the appropriate antiplatelet treatment strategy for minor strokes. Methods: We enrolled 74 ischemic stroke subjects, including 38 minor strokes. Platelet reactivity was assessed by impedance aggregometry (Multiplate Analyzer) 48 and 96 h after a first 75 mg dose of clopidogrel, using the acetylsalicylic acid platelet inhibition (ASPI) test and the adenosine diphosphate (ADP) test. Dual antiplatelet therapy was strictly reserved only to minor strokes, as the other strokes received clopidogrel alone in the secondary prevention. The dynamics of platelet reactivity refer to the difference between two assessments, and a decrease in values over time was considered favorable. Results: The incidence of clopidogrel non-responsiveness was 64.8%, and this was similar in the group of minor strokes and the group of more disabling strokes. We indicated diabetes mellitus as an independent predictor of high on-clopidogrel platelet reactivity (Odds ratio OR 5.69 95% Confidence Interval CI 1.13–41.26, p = 0.0386). Among minor strokes treated with dual antiplatelet therapy, in relation to clopidogrel, we reported a trend toward more favorable dynamics of platelet reactivity over time compared to the group using clopidogrel alone (p = 0.0652 vs. p = 0.3384, respectively). We identified five predictors (sex, female; small-vessel disease; no diabetes; no hyperlipidemia; and no alcohol abuse) related to a significant decrease in platelet reactivity over time with respect to clopidogrel. No significant dynamics of platelet reactivity when using aspirin were found. Conclusions: Our findings, based on the favorable dynamics of platelet reactivity over time in relation to clopidogrel, confirm the usefulness of dual antiplatelet therapy in minor strokes and support the continuation of the secondary prevention with clopidogrel alone rather than aspirin, particularly among identified beneficiaries of such a strategy.
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Kille, Alexander, Kilian Franke, Noé Corpataux, Julia Hromek, Christian M. Valina, Franz-Josef Neumann, Dietmar Trenk, Thomas G. Nührenberg, and Willibald Hochholzer. "Impact of On-Clopidogrel Platelet Reactivity on Incidence of Peri-Interventional Bleeding in Patients Undergoing Transcatheter Aortic Valve Implantation." Journal of Clinical Medicine 11, no. 10 (May 19, 2022): 2871. http://dx.doi.org/10.3390/jcm11102871.
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Dual anti-platelet therapy (DAPT) with clopidogrel and acetylsalicylic acid (ASA) has previously been recommended after transcatheter aortic valve implantation (TAVI) and is still the standard of care in patients who underwent coronary stent placement within 3 months prior to TAVI. This study sought to evaluate whether on-treatment platelet reactivity is a predictor for the occurrence of bleeding events after TAVI. This study enrolled 484 patients undergoing TAVI from November 2013 until April 2018. Patients were either on long-term DAPT with clopidogrel and ASA or received loading doses of both drugs before TAVI, reflecting the standard of care at the time of the patient’s enrollment. Platelet reactivity was determined by multi-electrode impedance aggregometry before TAVI, at days 1 and 5 thereafter. Peri-interventional bleeding was assessed up to 5 days following TAVI and coded according to BARC-classification. Bleeding events were seen in 199 (41.1%) patients. The most frequent were BARC 2 bleeding cases (24.2%), followed by BARC 1 (6.0%), BARC 3b (5.2%), and BARC 3a (4.5%) cases. Low on-clopidogrel platelet reactivity before TAVI was present in 243 patients, of which 44.4% had a bleeding event. In contrast, the incidence of bleeding was 30.5% in the 95 patients with high on-clopidogrel platelet reactivity. Multivariate logistic regression analysis identified low/normal/high on-clopidogrel platelet reactivity (OR: 0.533; CI: 0.309–0.917; p = 0.023) and use of oral anticoagulation (OR: 1.766; CI: 1.209–2.581; p = 0.003) as strongest predictors for peri-interventional bleeding events. These findings support current recommendations advocating against the routine use of dual antiplatelet therapy following TAVI.
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Hernandez-Suarez, Dagmar F., Hector Núñez-Medina, Stuart A. Scott, Angel Lopez-Candales, Jose M. Wiley, Mario J. Garcia, Kyle Melin, et al. "Effect of cilostazol on platelet reactivity among patients with peripheral artery disease on clopidogrel therapy." Drug Metabolism and Personalized Therapy 33, no. 1 (March 28, 2018): 49–55. http://dx.doi.org/10.1515/dmpt-2017-0032.
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AbstractBackground:Antiplatelet therapy with clopidogrel is recommended to reduce cardiovascular events in patients with peripheral artery disease (PAD); however, clopidogrel efficacy has not been adequately studied in this patient population. Therefore, we aimed to determine the effects of cilostazol therapy on platelet reactivity among PAD patients on clopidogrel.Methods:We performed a cross-sectional pilot study of 46 Puerto Rican patients diagnosed with PAD. The cohort was divided based on use of clopidogrel and cilostazol (n=24) or clopidogrel alone (n=22). Platelet function was measuredex vivousing the VerifyNow P2Y12 assay. Genomic DNA was extracted from peripheral blood samples using the QIAamp DNA Blood Midi Kit, which was subjected to candidate variant genotyping (CYP2C19,ABCB1,PON1andP2RY12) using TaqMan quantitative polymerase chain reaction assays. All analyses were performed using SAS version 9.4 (SAS Institute).Results:Among all enrolled patients, 18 (39%) had high on-treatment platelet reactivity (HTPR). The mean platelet reactivity was 207±53 (range, 78–325) with higher P2Y12 reaction units in the non-cilostazol group, 224±45 vs. 191±55 on the cilostazol group (p=0.03). No significant differences were observed in the clinical or genetic variables between the two groups. A multiple regression analysis determined that history of diabetes mellitus (p=0.03), use of cilostazol (p=0.03) and hematocrit (p=0.02) were independent predictors of platelet reactivity.Conclusions:In Puerto Rican PAD patients on clopidogrel therapy, history of diabetes mellitus, use of cilostazol and hematocrit are independent predictors of platelet reactivity. Adjunctive cilostazol therapy may enhance clopidogrel efficacy among PAD patients with HTPR.
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Chen, Haoxuan, Zhenzhen Lou, Yibo Zhan, Huiying Ouyang, Guixian Chen, Changlin Zhang, Hui Mao, et al. "Admission hyperglycemia as an independent predictor of clopidogrel high on-treatment platelet reactivity in ischemic stroke patients." Neurology Asia 27, no. 4 (December 2022): 835–43. http://dx.doi.org/10.54029/2022ppd.
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Background: Admission hyperglycemia is a predictor of poor prognosis after ischemic stroke (IS). Previous studies have found that admission hyperglycemia was related to clopidogrel high on-treatment platelet reactivity (HTPR) in diabetic patients with myocardial infarction. However, reports on associations between admission hyperglycemia and clopidogrel HTPR remain scarce in IS patients. In this study, we assessed the correlation between admission hyperglycemia and clopidogrel HTPR in patients with IS. Methods: In this retrospective study, we included IS patients who were treated with clopidogrel for at least 5 days. Thromboelastography (TEG) was used to evaluate the platelet function. Clopidogrel HTPR was defined if adenosine diphosphate (ADP)-induced platelet fibrin clot strength (MAADP)> 47 mm. Otherwise, it would be defined as clopidogrel normal on-treatment platelet reactivity (NTPR). Two groups were divided according to admission glucose of 7.8 mmol/L, consistent with previous studies on admission hyperglycemia. The independent risk factors of clopidogrel HTPR were assessed by multivariate logistic regression analysis. Results: A total of 147 patients were evaluated, and 42(28.57%) of patients were identified as clopidogrel HTPR. In the hyperglycemia group (admission glucose level ≥7.8mmol/L), 40.38% patients were defined as clopidogrel HTPR, which was significantly higher than in the normoglycemia group (22.11%, admission glucose level<7.8mmol/L) (P=0.019). According to multivariate analysis, hyperglycemia was independently associated with clopidogrel HTPR (OR=8.36, 1.47-47.55, P=0.017). Admission glucose level was linearly correlated with MAADP (r=0.29, P=0.005). Furthermore, with the increase of admission glucose level tertiles, the incidence of clopidogrel HTPR increased gradually (P for trend=0.008). Conclusions: Admission hyperglycemia is an independent predictor of clopidogrel HTPR and the glucose level is linearly correlated with MAADP in IS patients. Besides, with the increase of glucose level tertiles, the incidence of clopidogrel HTPR increases gradually.
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Dhillon, Ashwat S., Jorge Caro, Han Tun, David G. Armstrong, Vincent Rowe, David M. Shavelle, and Leonardo C. Clavijo. "Therapeutic Window of Clopidogrel and Ticagrelor in Patients With Critical Limb-Threatening Ischemia." Journal of Cardiovascular Pharmacology and Therapeutics 25, no. 2 (September 24, 2019): 158–63. http://dx.doi.org/10.1177/1074248419877411.
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Background: Critical limb-threatening ischemia (CLTI) is associated with an increased risk of major adverse limb events and mortality. High on-treatment platelet reactivity (HPR) is associated with an increased risk of ischemic events, while low on-treatment platelet reactivity (LPR) is associated with an increased risk of bleeding. This study investigates the frequency with which patients with CLTI on clopidogrel or ticagrelor achieve a “therapeutic window” (TW) of platelet inhibition. Methods: Data from the “Switch To Ticagrelor in Critical Limb Ischemia Anti-Platelet Study” were assessed retrospectively to determine the incidence of TW of on-treatment platelet reactivity in 50 consecutive patients with CLTI (mean age: 65.2 ± 10.5 years, 54% male). The data included 4 measurements of patients’ platelet reactivity using the VerifyNow P2Y12 Assay: baseline and steady state platelet reactivity on clopidogrel 75 mg daily and on ticagrelor 90 mg twice daily. Results: At baseline, 46% of patients on clopidogrel were within TW of on-treatment platelet reactivity compared to 10% of patients on ticagrelor ( P < .0001). At steady state, 42% of patients on clopidogrel were within the TW compared to 10% of patients on ticagrelor ( P < .0001). Patients on ticagrelor exhibited higher rates of LPR compared to those on clopidogrel at baseline as well as at steady state (baseline 88% vs 18%, steady state 88% vs 28%; P < .0001). Conclusion: Although ticagrelor has been proposed as an alternative for patients with HPR on clopidogrel, the current study observes an excess of platelet inhibition with ticagrelor in most patients with CLTI at a dose of 90 mg twice daily.
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Wiśniewski, Adam, Joanna Sikora, Aleksandra Karczmarska-Wódzka, Przemysław Sobczak, Adam Lemanowicz, Elżbieta Zawada, Rytis Masiliūnas, and Dalius Jatužis. "Unfavorable Changes of Platelet Reactivity on Clopidogrel Therapy Assessed by Impedance Aggregometry Affect a Larger Volume of Acute Ischemic Lesions in Stroke." Diagnostics 11, no. 3 (February 27, 2021): 405. http://dx.doi.org/10.3390/diagnostics11030405.
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Background: High on-treatment platelet reactivity or its equivalent—resistance to the antiplatelet agent—significantly reduces the efficacy of the therapy, contributing to a negative impact on stroke course. Previous studies demonstrated that aspirin resistance is associated with a larger size of acute ischemic infarct. Due to the increasing use of clopidogrel in the secondary prevention of stroke, we aimed to assess the impact of clopidogrel resistance on the size and extent of ischemic lesions, both acute and chronic. Methods: This prospective, single-center and observational study involved 74 ischemic stroke subjects, treated with 75 mg of clopidogrel. We used impedance aggregometry to determine platelet reactivity 6–12 h after a dose of clopidogrel as a first assessment and 48 h later as the second measurement. A favorable dynamics of platelet reactivity over time was the decrease in the minimum value equal to the median in the entire study. The volume of acute ischemic infarct was estimated within 48 h after onset in diffusion-weighted imaging and fluid-attenuated inversion recovery sequences of magnetic resonance and the severity of chronic vascular lesions by Fazekas scale. Results: Subjects with mild severity of chronic vascular lesions (Fazekas 1) exhibited a significant decrease of platelet reactivity over time (p = 0.035). Dynamics of platelet reactivity over time differed between subjects with large, moderate, mild and insignificant size of acute ischemic lesion (Kruskall-Wallis H = 3.2576; p = 0.048). In multivariate regression models, we reported unfavorable dynamics of platelet reactivity alone and combined with a high initial value of platelet reactivity as independent predictors of higher risk of a significant ischemic infarct volume (OR 7.16 95%CI 1.69–30.31, p = 0.008 and 26.49 95%CI 1.88–372.4, p = 0.015, respectively). Conclusions: We emphasized that unfavorable dynamics of platelet reactivity over time during clopidogrel therapy in acute phase of stroke affect the volume of acute infarct and the severity of chronic vascular lesions.
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Park, Yongwhi, Udaya Tantry, Jong-Hwa Ahn, Kye Hwan Kim, Jin-Sin Koh, Jeong-Rang Park, Seok-Jae Hwang, et al. "Effect of adjunctive dipyridamole to DAPT on platelet function profiles in stented patients with high platelet reactivity." Thrombosis and Haemostasis 112, no. 12 (2014): 1198–208. http://dx.doi.org/10.1160/th14-01-0040.
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SummaryAdjunctive use of phosphodiesterase (PDE) inhibitor can enhance antiplatelet and vasoprotective properties in patients with cardiovascular disease. The aim of this study was to evaluate the impact of PDE5 inhibitor dipyridamole on platelet function in stented patients with high platelet reactivity (HPR) during dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. Patients with HPR after 600-mg clopidogrel loading were randomly assigned to adjunctive dipyridamole 75 mg twice daily to standard DAPT (DIP group; n = 45) or double-dose clopidogrel of 150 mg daily (DOUBLE group; n = 46) for 30 days. Platelet function was assessed at baseline and 30-day follow-up with platelet reactivity index (PRI) by vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) assay and platelet aggregation (PA) by light transmittance aggregometry (LTA). Primary endpoint was PRI at 30-day follow-up. HPR was defined as PRI > 50%. Baseline platelet function did not differ between the groups. Following 30-day therapy, platelet function was significantly reduced in the DIP and DOUBLE groups (all p-values ≤ 0.004 and ≤ 0.068, respectively). PRI values were not significantly different between the two groups (mean difference: 3.1%; 95% confidence interval: –2.8% to 9.0%: p = 0.295). PA values and prevalence of HPR were similar between the groups. However, a significant number of patients still exhibited HPR in the DIP (75.6%) and DOUBLE (67.4%) groups. In conclusion, among stented HPR patients, adding dipyridamole to DAPT does not reduce platelet reactivity and prevalence of HPR compared with double-dose clopidogrel therapy, and therefore both strategies are inadequate to overcome HPR.
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Bonello, Laurent. "Personalised Antiplatelet Therapy – Whether to Choose Genotype or Phenotype." European Cardiology Review 6, no. 4 (2010): 45. http://dx.doi.org/10.15420/ecr.2010.8.2.45.
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A significant proportion of patients do not achieve optimal platelet reactivity inhibition after a loading dose of clopidogrel. The large interindividual variability in clopidogrel responsiveness is related to several factors, including the genetic polymorphism of hepatic cytochromes 2C19 2*, which has recently been highlighted by a US Food and Drug Administration (FDA) warning. In fact, patients exhibiting reduced clopidogrel metabolism and/or low clopidogrel responsiveness (i.e. high on-treatment platelet reactivity) have an increased rate of thrombotic events following percutaneous coronary intervention. In this article, current knowledge on this important clinical issue is summarised. While the future of genetic testing remains undetermined, several trials are under way to demonstrate the potential utility of platelet reactivity testing with P2Y12-ADP receptor antagonists.
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Stratz, Christian, Stefan Leggewie, Willibald Hochholzer, Christian M. Valina, Michael Gick, Ajay J. Kirtane, Gregg W. Stone, Franz-Josef Neumann, Dietmar Trenk, and Thomas G. Nührenberg. "Temporal variability in the antiplatelet effects of clopidogrel and aspirin after elective drug-eluting stent implantation." Thrombosis and Haemostasis 114, no. 11 (2015): 1020–27. http://dx.doi.org/10.1160/th15-03-0257.
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SummaryGiven conflicting data on temporal variability in pharmacodynamic platelet responses to clopidogrel, we investigated platelet reactivity on clopidogrel and aspirin for up to six months after elective percutaneous coronary intervention (PCI) with drug-eluting stents. Platelet reactivity was determined in 102 patients before loading with clopidogrel and aspirin, and on maintenance therapy after PCI on day 1, at one month and six months by VerifyNow™ P2Y12 and Aspirin assays and by residual platelet aggregation (RPA) on light transmission aggregometry using adenosine diphosphate and arachidonic acid. By VerifyNow testing, median (interquartile range) P2Y12 reaction units (PRU) on clopidogrel were 166 (90–234), 195 (124–257), and 198 (141–252) on day 1, one month and six months after PCI, respectively (p=0.005 day 1 to 1 month, and p=0.86 1 month to 6 months). Using a cut-off of > 208 PRU, 35% of patients had high platelet reactivity (HPR) to clopidogrel on day 1, 43% at one month, and 46% at six months after PCI. Between day 1 and six months after PCI, 38.2% of patients changed clopidogrel responder status at least once. Other cut-offs and RPA yielded similar results. Platelet inhibition by aspirin was consistent over time with only five patients being characterised as having HPR. Considerable variation in individual on-clopidogrel platelet reactivity was present during both the subacute and the late phases of maintenance therapy after elective PCI. Hence, the utility of contemporary platelet function testing to guide antiplatelet therapy may be limited.
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Alexopoulos, Dimitrios, Theodora-Eleni Plakomyti, and Ioanna Xanthopoulou. "Variability and treatment of high on-prasugrel platelet reactivity in patients with initial high on-clopidogrel platelet reactivity." International Journal of Cardiology 154, no. 3 (February 2012): 333–34. http://dx.doi.org/10.1016/j.ijcard.2011.10.031.
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Aradi, Dániel, Orsolya Rideg, András Vorobcsuk, Tamás Magyarlaki, Balázs Magyari, Attila Kónyi, Tünde Pintér, Iván G. Horváth, and András Komócsi. "Justification of 150 mg clopidogrel in patients with high on-clopidogrel platelet reactivity." European Journal of Clinical Investigation 42, no. 4 (September 9, 2011): 384–92. http://dx.doi.org/10.1111/j.1365-2362.2011.02594.x.
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Wang, Yilong, Yi Lin, Xia Meng, Weiqi Chen, Guohua Chen, Zhimin Wang, Jialing Wu, et al. "Effect of ticagrelor with clopidogrel on high on-treatment platelet reactivity in acute stroke or transient ischemic attack (PRINCE) trial: Rationale and design." International Journal of Stroke 12, no. 3 (February 23, 2017): 321–25. http://dx.doi.org/10.1177/1747493017694390.
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Rationale and aim Little is known about the safety and efficacy of the combination of ticagrelor and aspirin in acute ischemic stroke. This study aimed to evaluate whether the combination of ticagrelor and aspirin was superior to that of clopidogrel and aspirin in reducing the 90-day high on-treatment platelet reactivity for acute minor stroke or transient ischemic attack, especially for carriers of cytochrome P450 2C19 loss-of-function allele. Sample size and design This study was designed as a prospective, multicenter, randomized, open-label, active-controlled, and blind-endpoint, phase II b trial. The required sample size was 952 patients. It was registered with ClinicalTrials.gov (NCT02506140). Study outcomes The primary outcome was the proportion of patients with high on-treatment platelet reactivity at 90 days. High on-treatment platelet reactivity is defined as the P2Y12 reaction unit >208 measured using the VerifyNow P2Y12 assay. Conclusion The Platelet Reactivity in Acute Non-disabling Cerebrovascular Events study explored whether ticagrelor combined with aspirin could reduce further the proportion of patients with high on-treatment platelet reactivity at 90 days after acute minor stroke or transient ischemic attack compared with clopidogrel and aspirin.
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Wiśniewski, Adam, Joanna Sikora, Aleksandra Karczmarska-Wódzka, Joanna Bugieda, Karolina Filipska, and Robert Ślusarz. "Unfavorable Dynamics of Platelet Reactivity during Clopidogrel Treatment Predict Severe Course and Poor Clinical Outcome of Ischemic Stroke." Brain Sciences 11, no. 2 (February 18, 2021): 257. http://dx.doi.org/10.3390/brainsci11020257.
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Background: Previous studies have revealed that high platelet reactivity while on clopidogrel may affect the severe course and worse prognosis of ischemic stroke. However, the above findings were based on a single measurement of platelet function. We aimed to investigate whether the dynamics of platelet reactivity over time would more accurately determine its actual impact on clinical outcome. Methods: We enrolled 74 ischemic stroke subjects, taking a dose of 75 mg a day of clopidogrel to this prospective, single-center, and observational study. The determination of platelet function was based on the impedance aggregometry 6–12 h after the first dose of clopidogrel and 48 h later. We defined a favorable dynamics of platelet reactivity as a decrease in values at least equal to the median obtained in the entire study. The clinical condition was assessed by the National Institutes of Health Stroke Scale on the first, third, and ninetieth days and the functional status by modified Rankin Scale, respectively. Results: A favorable dynamics of platelet reactivity was associated with the mild clinical condition and favorable functional status, both early and late. Early neurological deterioration was related to unfavorable dynamics of platelet reactivity over time. In multivariate regression models, we found that unfavorable dynamics of platelet reactivity, alone and combined with a high baseline value of platelet reactivity, is an independent predictor of a severe clinical condition, the risk of deterioration, and poor early and late prognosis. Conclusion: We highlighted that dynamics of platelet reactivity over time predict the clinical course and prognosis of stroke better than a single value.
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Rada, Feryal Hashim. "ANTIPLATELET ADEQUACY OF CYCLOPENTYL TRIAZOLOPYRIMIDINE VERSUS CLOPIDOGREL IN-PATIENTS WITH CORONARY HEART DISEASE." Asian Journal of Pharmaceutical and Clinical Research 11, no. 12 (December 7, 2018): 536. http://dx.doi.org/10.22159/ajpcr.2018.v11i12.29703.
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Objective: Ticagrelor, cyclopentyl triazolopyrimidine drug, and Clopidogrel, second-generation thienopyridine drug are antiplatelet drugs indicated for the prevention of thrombotic events in patients with acute or chronic coronary syndromes. The aim of this study is to assess efficacy and safety outcomes of ticagrelor treatment versus Clopidogrel treatment in patients with stable coronary artery disease (stable angina) using maximal platelet aggregation percent (MPAP) method and platelet reactivity index percent (PRIP) method.Methods: A total of 42 patients (27 male and 15 female), their ages ranging (48±8) years with stable angina enrolled from Ibn Albitar Center for Cardiac Surgery for this crossover study. After satisfying, the properties of inclusion criteria they screened for clopidogrel treatment 75 mg daily for 2 weeks than after 2 weeks periods of wash off they treated with ticagrelor 90 mg twice daily for another 2 weeks. Platelet reactivity was tested at baseline (before treatment), after 2 weeks treatment with clopidogrel and after another 2 weeks treatment with ticagrelor. Platelet reactivity measured by light transmittance aggregometry test and by vasodilator-stimulated phosphoprotein (VASP) phosphorylation test.Results: The results of MPAP after 2 weeks treatment with clopidogrel or ticagrelor showed high significant reduction in platelet aggregation in patients with ticagrelor treatment as compared to clopidogrel treatment (30±6% vs. 44±8%). As well, the results of PRIP using VASP-phosphorylation after 2 weeks treatment with clopidogrel or ticagrelor showed high significant reduction in platelet aggregation in patients with ticagrelor treatment as compared to clopidogrel treatment (22±5% vs. 36±7%).Conclusion: Treatment with ticagrelor produced a reduction in platelet reactivity consistent with the reduction in major adverse cardiovascular events and improved survival without increasing major bleeding.
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Boinska, Joanna, Marek Koziński, Michał Kasprzak, Michał Ziołkowski, Jacek Kubica, and Danuta Rość. "Diurnal Oscillations of Fibrinolytic Parameters in Patients with Acute Myocardial Infarction and Their Relation to Platelet Reactivity: Preliminary Insights." Journal of Clinical Medicine 11, no. 23 (November 30, 2022): 7105. http://dx.doi.org/10.3390/jcm11237105.
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There is limited information about diurnal changes in fibrinolysis parameters after acute myocardial infarction (AMI) and their relationship with on-treatment platelet reactivity. The aim of this study was to assess tissue plasminogen activator (t-PA), plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin (α2-AP) activity, and plasmin–antiplasmin (PAP) complexes in 30 AMI patients taking dual antiplatelet therapy (DAPT), i.e., acetylsalicylic acid and clopidogrel. Fibrinolytic parameters were assessed at four time points (6 a.m., 10 a.m., 2 p.m., and 7 p.m.) on the third day after AMI using immunoenzymatic methods. Moreover, platelet reactivity was measured using multiple-electrode aggregometry, to assess potential differences in fibrinolytic parameters in low/high on-aspirin platelet reactivity and low/high on-clopidogrel platelet reactivity subgroups of patients. We detected significant diurnal oscillations in t-PA and PAI-1 levels in the whole study group. However, PAP complexes and α2-AP activity were similar at the analyzed time points. Our study reveals a potential impact of DAPT on the time course of fibrinolytic parameters, especially regarding clopidogrel. We suggest the presence of diurnal variations in t-PA and PAI-1 concentrations in AMI patients, with the highest levels midmorning, regardless of platelet reactivity. Significantly elevated levels of PAI-1 during the evening hours in clopidogrel-resistant patients may increase the risk of thrombosis.
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Collet, Jean-Philippe, Mathieu Kerneis, Jean-Sebastien Hulot, Stephen A. O’Connor, Johanne Silvain, Nicolas Mansencal, Delphine Brugier, et al. "Point-of-care genetic profiling and/or platelet function testing in acute coronary syndrome." Thrombosis and Haemostasis 115, no. 02 (March 2016): 382–91. http://dx.doi.org/10.1160/th15-05-0394.
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SummaryOur aim was to demonstrate that the sequential use of the Verigene® rapid CYP2C19 test for genetic profiling and the VerifyNowTM bedside test for platelet function measurement in ACS patients may optimise P2Y12 inhibition. “Rapid” (CYP2C19*1/*1 or CYP2C19*17 carriers, n=211) and “slow” metabolisers (CYP2C19*2 carriers, n=58) were first put on clopidogrel and prasugrel for ≥ 2 weeks, respectively. Patients with low platelet reactivity (PRU< 30) on prasugrel or high platelet reactivity (> 208 PRU) on clopidogrel were then switched to clopidogrel and prasugrel, respectively. Our objectives were (i) to demonstrate that the proportion of “rapid” metabolisers on 75 mg of clopidogrel within 30–208 (PRU) of P2Y12 inhibition is non-inferior to “slow” metabolisers on prasugrel 10 mg and (ii) to evaluate the same end-point after switching drugs. The proportion of “rapid” and “slow” metabolisers within 30–208 PRU of P2Y12 inhibition was 71 % and 56.9 %, respectively, an absolute difference of +14.1 % (95 % CI, –0.05 % to 28.28 %) with a non-inferiority margin greater than the predefined margin of –10 %. Among patients out of target, all but one “slow” metabolisers displayed low-on prasugrel platelet reactivity while the majority of “rapid” metabolisers (68 %) displayed high-on clopidogrel platelet reactivity. After switching, the proportion of patients within 30–208 PRU of P2Y12 inhibition was 83.6 % and 79.3 % in “rapid” and “slow” metabolisers, respectively (+4.3 %, 95 % CI –7.3 % to 15.9 %). In conclusion, this study demonstrates a loose relationship between genotype and platelet function phenotype approaches but that they are complementary to select prasugrel or clopidogrel MD in stented ACS patients.
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Bath, Philip M., Jane May, Katie Flaherty, Lisa J. Woodhouse, Natalia Dovlatova, Sue C. Fox, Timothy J. England, et al. "Remote Assessment of Platelet Function in Patients with Acute Stroke or Transient Ischaemic Attack." Stroke Research and Treatment 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/7365684.
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Background. The TARDIS trial assessed the safety and efficacy of intensive versus guideline antiplatelet agents given for one month in patients with acute stroke or TIA. The aim of this substudy was to assess the effect of antiplatelet agents taken at baseline on platelet function reactivity and activation.Methods. Platelet function, assessed by remotely measured surface expression of P-selectin, was assessed in patients at their time of randomisation. Data are median fluorescence values.Results. The aspirin P-selectin test demonstrated that platelet expression was lower in 494 patients taking aspirin than in 162 patients not: mean 210 (SD 188) versus 570 (435), difference 360.3 (95% CI 312.2–408.4) (2p<0.001). Aspirin did not suppress P-selectin levels below 500 units in 23 (4.7%) patients. The clopidogrel test showed that platelet reactivity was lower in 97 patients taking clopidogrel than in 585 patients not: 655 (296) versus 969 (315), difference 314.5 (95% CI 247.3–381.7) (2p<0.001). Clopidogrel did not suppress P-selectin level below 860 units in 24 (24.7%) patients.Conclusions. Aspirin and clopidogrel suppress stimulated platelet P-selectin, although one-quarter of patients on clopidogrel have high on-treatment platelet reactivity. Platelet function testing may be performed remotely in the context of a large multicentre trial. Trial registrationISRCTN47823388.
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Bernlochner, Isabell, Steven Steinhubl, Siegmund Braun, Tanja Morath, Juliane Jaitner, Julia Stegherr, Julinda Mehilli, et al. "Association between inflammatory biomarkers and platelet aggregation in patients under chronic clopidogrel treatment." Thrombosis and Haemostasis 104, no. 12 (2010): 1193–200. http://dx.doi.org/10.1160/th10-05-0266.
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SummaryInflammatory processes in the vessel wall are associated with progression of atherosclerosis and myocardial infarction. Both high levels of C-reactive protein (CRP) and high on-clopidogrel treatment platelet reactivity (HPR) have been linked to an increased risk of ischaemic events after percutaneous coronary intervention (PCI). The aim of this study was to explore the association between biomarker levels of inflammation and platelet reactivity. Stable patients (n=1,223) eligible for this study were under chronic antiplatelet treatment with aspirin and clopidogrel due to prior coronary stent placement. ADP-induced platelet aggregation (in AU*min) was measured on a Multiplate analyser. The primary outcome measure of this retrospective study was the ADP-induced platelet aggregation in patients with versus those without elevated CRP levels. Of the patients 15.5% (n=189) showed elevated CRP levels (≥5 mg/l). Platelet aggregation (median [interquartile range]) was significantly higher in patients with elevated CRP levels compared to patients with normal (<5 mg/l) CRP levels (305 [202–504] AU*min vs. 218 [144–384] AU*min; p<0.001). A multivariable linear regression model that adjusted for known predictors of HPR confirmed a significant independent association between elevated CRP levels and high ADP-induced platelet aggregation values (p=0.0002). Elevated WBC count and fibrinogen levels were also associated with higher platelet aggregation values (p<0.001 for both). In conclusion, elevated levels of CRP, WBC count and fibrinogen were significantly associated with high platelet reactivity in patients under chronic clopidogrel treatment. Whether a direct relation between platelets and inflammation exists, as well as the clinical impact of our results, warrants further investigations.
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Jaitner, Juliane, Julia Stegherr, Tanja Morath, Siegmund Braun, Isabell Bernlochner, Albert Schömig, Adnan Kastrati, and Sibbing Dirk. "Stability of the high on-treatment platelet reactivity phenotype over time in clopidogrel-treated patients." Thrombosis and Haemostasis 105, no. 01 (2011): 107–12. http://dx.doi.org/10.1160/th10-07-0440.
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SummaryInterindividual response variability to clopidogrel treatment is a well established phenomenon. In recent studies and ongoing large-scale trials where patients with high on-treatment platelet reactivity (HPR) to clopidogrel are being randomised to an intensified antiplatelet treatment, confirmation of the HPR phenotype is based on one single platelet function assessment. The stability of the HPR phenotype over time has never been investigated but should be considered crucial for justification of intensified antiplatelet treatment regimens beyond clinical trials. The goal of this study was to test for the stability of the HPR phenotype over time in clopidogrel-treated patients. Patients (n=31) under chronic clopidogrel treatment (75 mg/day) were investigated by serial adenosine diphosphate (ADP)-induced platelet aggregation assessment with multiple electrode aggregometry (MEA) on a Multiplate analyser and light transmission aggregometry (LTA) at three different time points (once per week) during monitored antiplatelet treatment. On the basis of a cut-off level approach (468 AU*min for MEA, 53% for LTA) patients were classified into patients with (n=27) or without (n=4) HPR. For MEA, the phenotype was stable in 93.5% (n=29) of patients whereas 6.5% (n=2) crossed the cut-off level. For LTA, the phenotype was stable in 68% (n=21) of patients whereas 32% (n=10) patients crossed the cut-off level (chi-square P=0.01 for comparison of pheno-type stability between both assays). In conclusion, the HPR phenotype is stable over time in the majority of clopidogrel-treated patients. Comparative assessment of phenotype stability across available platelet function assays warrants further investigation.
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Malý, Martin, Ivana Hadačová, Petr Hájek, David Zemánek, and Josef Veselka. "High-residual platelet activity despite dual antiplatelet treatment associated with subacute stent thrombosis." Open Medicine 4, no. 1 (March 1, 2009): 119–24. http://dx.doi.org/10.2478/s11536-009-0007-8.
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AbstractHigh-residual platelet activity despite the dual antiplatelet treatment with aspirin and clopidogrel is associated with major adverse cardiac events, including stent thrombosis. Acute and subacute stent thrombosis is rare, but presents itself with serious complications including high mortality and morbidity rates. Light transmittance aggregometry with specific agonists — arachidonic acid and 5-adenosin diphosphate — is still considered a standard for the assessment of platelet reactivity, besides novel methods like vasodilator-stimulated phosphoprotein phosphorylation. In our case study, we report the coincidence of high-residual platelet activity with subacute stent thrombosis despite the recommended doses of antiplatelet agents — aspirin and clopidogrel. Stent thrombosis was treated by aspiration thrombectomy, and antiplatelet treatment was modified by increasing the dose of aspirin and substituting clopidogrel with a firstgeneration thienopyridin — ticlopidin. The effect of the treatment was documented by reaching the optimal inhibition of platelet reactivity. In the 6- and 12-month follow-up, the patient presented no ischemic events.
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Shi, Rui, Lan Ge, Xin Zhou, Wen-Jie Ji, Rui-Yi Lu, Ying-Ying Zhang, Shan Zeng, et al. "Decreased platelet miR-223 expression is associated with high on-clopidogrel platelet reactivity." Thrombosis Research 131, no. 6 (June 2013): 508–13. http://dx.doi.org/10.1016/j.thromres.2013.02.015.
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Liu, Guang Zhong, Song Zhang, Dang Hui Sun, Jing Shi, Wan Lan Bo, Wen Nan Wang, Chong Yang Zhang, et al. "Half-dose ticagrelor versus high-dose clopidogrel in reducing platelet reactivity in acute coronary syndrome patients with high on-clopidogrel platelet reactivity (divide study)." European Journal of Clinical Pharmacology 75, no. 8 (May 12, 2019): 1059–68. http://dx.doi.org/10.1007/s00228-019-02687-0.
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Sibbing, Dirk, Robert A. Byrne, Isabell Bernlochner, and Adnan Kastrati. "High platelet reactivity and clinical outcome – Fact and fiction." Thrombosis and Haemostasis 106, no. 08 (2011): 191–202. http://dx.doi.org/10.1160/th11-01-0040.
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SummaryIn patients suffering from acute coronary syndromes or undergoing percutaneous coronary intervention, oral antiplatelet treatment is routinely administered with the primary aim of inhibiting platelet-mediated thrombus formation and subsequent abrupt vessel occlusion. Simultaneous inhibition of blood platelet cyclooxygenase-1 by aspirin and of the P2Y12 receptor by clopidogrel or prasugrel is currently recommended in this setting. Inter-individual response variability to aspirin and especially to clopidogrel is the subject of much debate as evidence has grown over the years linking an attenuated response to treatment with the occurrence of ischaemic events. Consequently, the clinical entity of high (on-treatment) platelet reactivity (HPR) was born and subsequently characterised in numerous studies over the last decade. Until recently, alternative treatment options were limited in patients exhibiting HPR. At present the antiplatelet therapy landscape is changing with the advent of prasugrel and ticagrelor as alternative and more potent treatment options. Different tests for monitoring platelet function are available and are being increasingly employed in research projects and clinical routine. These tests may prove useful for achieving optimal platelet inhibition for the individual patient, and several centres now incorporate such testing in day-to-day practice. Widespread adoption of this practice and incorporation into clinical guidelines awaits the results of ongoing trials in which treatment is changed based on platelet function monitoring. This review aims to summarise available facts and fiction in relation to platelet function testing and reactivity with a particular focus on P2Y12 receptor inhibition in patients undergoing coronary stent placement.
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Gremmel, Thomas, and Simon Panzer. "Clinical, genetic and confounding factors determine the dynamics of the in vitro response/non response to clopidogrel." Thrombosis and Haemostasis 106, no. 08 (2011): 211–18. http://dx.doi.org/10.1160/th11-03-0137.
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SummaryPlatelet inhibition by clopidogrel varies from one individual to the next. Further, in vitro high on-treatment residual adenosine-diphosphate inducible platelet reactivity (HRPR) is associated with an increased risk for major adverse cardiovascular events after percutaneous coronary intervention (PCI) with stent implantation. Recent studies identified numerous influencing factors for the antiplatelet effect of clopidogrel. Besides genetic predispositions, diverse clinical conditions as well as pharmacological interactions were shown to significantly impair clopidogrel-mediated platelet inhibition. Consequently, these influencing factors may affect clinical outcome after PCI and it is therefore desirable to identify cofounders of HRPR by platelet reactivity testing. It is apparent, that not all assays are sensitive to the same variables, and only cofounders of HRPR that are repeatedly identified by more than one test system may be clinically meaningful. However, treatment adjustment based on platelet function testing has not been associated with improved patients’ outcome. This summary shall provide an overview over current knowledge on influencing factors for clopidogrel-mediated platelet inhibition and aid guidance for critical interpretation of in vitro obtained data on HRPR.
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Wadowski, Patricia P., Silvia Lee, Christoph W. Kopp, Renate Koppensteiner, Simon Panzer, and Thomas Gremmel. "Low Levels of High-Density Lipoprotein Cholesterol Are Linked to Impaired Clopidogrel-Mediated Platelet Inhibition." Angiology 69, no. 9 (February 26, 2018): 786–94. http://dx.doi.org/10.1177/0003319718760074.
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Low high-density lipoprotein cholesterol (HDL-C) levels are an independent predictor of ischemic events in patients with atherosclerotic cardiovascular disease. This may in part be due to decreased clopidogrel-mediated platelet inhibition in patients with low HDL-C. We investigated the association of HDL-C with on-treatment platelet reactivity to adenosine diphosphate (ADP) in 314 patients on dual antiplatelet therapy with clopidogrel and aspirin undergoing angioplasty and stenting. Platelet P-selectin expression was assessed by flow cytometry, and platelet aggregation was determined by the VerifyNow P2Y12 assay and the Impact-R. High-density lipoprotein cholesterol levels were inversely associated with P-selectin expression and the VerifyNow P2Y12 assay (both P ≤ .01). Moreover, we found a positive correlation of HDL-C with surface coverage by the Impact-R ( P = .003). Patients with low HDL-C (≤35 mg/dL) exhibited a significantly higher P-selectin expression in response to ADP and higher platelet aggregation by the VerifyNow P2Y12 assay and the Impact-R than patients with normal HDL-C (>35 mg/dL; all P < .05). High on-treatment residual platelet reactivity by the VerifyNow P2Y12 assay occurred significantly more frequently in patients with low HDL-C levels than in those with normal HDL-C (47.4% vs 30.1%, P = .01). In conclusion, low HDL-C is linked to impaired clopidogrel-mediated platelet inhibition after angioplasty and stenting.
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Akram, Nabila, Ghulam Mustafa, Anum A. Hanif, Shahzad Tawwab, Shabbir Hussain, Haiba Kaul, and Shahida Mohsin. "Cytochrome 2C19 and paraoxonase-1 polymorphisms and clopidogrel resistance in ischemic heart disease patients." Personalized Medicine 16, no. 5 (September 2019): 379–86. http://dx.doi.org/10.2217/pme-2018-0030.
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Aim: Polymorphisms in cytochrome P450 (CYP) 2C19 and paraoxonase-1 (PON-1) genes are thought to be involved in clopidogrel high on treatment reactivity in ischemic heart disease (IHD) patients. Methods: A total of 240 patients with IHD were screened for CYP2C19 loss-of-function alleles (LOF; *2, *3) and PON-1 Q192R. Patients were classified as responders and nonresponders to clopidogrel based upon platelet aggregation studies. Genotyping of the CYP2C19 and PON-1 allele was carried out by PCR-RFLP. Results: Results showed that 14.3% of the patients were nonresponders, whereas 85.7% were responders to the clopidogrel therapy. CYP2C19*3 allele showed significant association with clopidogrel high on treatment reactivity in IHD patients. Conclusion: Result of our study demonstrate that IHD patients with CYP2C19*3 allele can face the problem of clopidogrel high on treatment reactivity in Punjabi Pakistani population.
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Cattaneo, Marco. "Diagnosis and Management of High Platelet Reactivity on Treatment with Clopidogrel." Seminars in Thrombosis and Hemostasis 38, no. 07 (October 3, 2012): 645–51. http://dx.doi.org/10.1055/s-0032-1326785.
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Meves, Saskia H., Kay D. Schröder, Heinz G. Endres, Christos Krogias, Jan C. Krüger, and Horst Neubauer. "Clopidogrel High-on-Treatment Platelet Reactivity in Acute Ischemic Stroke Patients." Thrombosis Research 133, no. 3 (March 2014): 396–401. http://dx.doi.org/10.1016/j.thromres.2013.12.002.
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Angiolillo, Dominick, Roger DeRaad, Andrew Frelinger, Paul Gurbel, Timothy Costigan, Joseph Jakubowski, Clement Ojeh, Suman Duvvuru, Mark Effron, and Jorge Saucedo. "Decrease in high on-treatment platelet reactivity (HPR) prevalence on switching from clopidogrel to prasugrel: Insights from the switching anti-platelet (SWAP) study." Thrombosis and Haemostasis 109, no. 02 (2013): 347–55. http://dx.doi.org/10.1160/th12-06-0378.
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SummaryThe prevalence of high platelet reactivity (HPR) in patients who have switched from clopidogrel to prasugrel during maintenance phase after an acute coronary syndrome (ACS) event is unknown. Therefore, the effect of switching from clopidogrel to prasugrel on the prevalence of HPR was evaluated. This analysis from the previously reported SWAP (SWitching Anti Platelet) study assessed HPR at baseline, 2 and 24 hours, and seven days after switching from clopidogrel to prasugrel maintenance dose (MD), with or without a prasugrel loading dose (LD) using four definitions: maximum platelet aggregation (MPA) >65% (primary endpoint), MPA >50%, P2Y12 reaction units (PRU) >235, and platelet reactivity index (PRI) ≥50%. A total of 95 patients were available for analysis; 56 patients provided DNA for genetic assessments of cytochrome P450 (CYP) 2C19. There were 26 (27.4%) patients with HPR at the end of the clopidogrel run-in (defined as MPA >65%). The HPR prevalence varied by each definition and ranged from 19% (PRU >235) to 68% (PRI ≥50%). A significantly higher HPR prevalence was observed during clopidogrel versus the combined prasugrel therapy groups at seven days as measured by MPA >65% (21.2% vs. 4.5%, p>0.05), PRU >235 (18.8% vs. 0%, p=0.001), and PRI ≥50% (66.7% vs. 7.9%, p<0.0001). There was a significantly higher percentage of subjects carrying at least one reduced function allele with HPR measured by MPA >65% (p=0.02) or PRU >235 (p=0.05) than non-carriers with HPR. Switching ACS patients during maintenance clopidogrel therapy to prasugrel with or without an LD is associated with a reduced HPR prevalence and may provide an alternative strategy to treat patients with HPR, independent of CYP2C19 genotype.
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Ramotowski, Bogumił, Paul A. Gurbel, Udaya Tantry, Jan S. Bracha, Marta Karaźniewicz-Łada, Zbigniew Lewandowski, and Andrzej Budaj. "Effect of Smoking Cessation on the Pharmacokinetics and Pharmacodynamics of Clopidogrel after PCI: The Smoking Cessation Paradox Study." Thrombosis and Haemostasis 120, no. 03 (January 15, 2020): 449–56. http://dx.doi.org/10.1055/s-0039-3402758.
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Abstract Background Cigarette smoking is associated with enhanced clopidogrel effect and platelet inhibition. However, the effect of smoking cessation on clopidogrel pharmacokinetics (PK) and pharmacodynamics (PD) is unknown. We aimed to determine the effect of smoking cessation, confirmed by cotinine measurement, on clopidogrel PK and PD after percutaneous coronary intervention (PCI). Methods and Results Following successful PCI, patients treated with 75 mg/day clopidogrel who reported smoking ≥10 cigarettes/day with NicAlert urine cotinine level 6 were enrolled. Clopidogrel and its metabolite concentrations, VerifyNow P2Y12 reaction units (PRUs), and NicAlert levels were measured in the study group before and at 30 days after smoking cessation and in a control group. CYP1A2 and CYP2C19 genotypes were determined. At 30-day visit (n = 87), 45 patients continued smoking, whereas 42 patients stopped smoking. Baseline PRUs were similar between groups. At 30 days, the smoking cessation group had higher PRUs (150.5 ± 68.6 vs. 118.4 ± 65.9, p = 0.03), greater absolute PRU change (27.7 ± 39.8 vs. −12.9 ± 55.4, p = 0.0002), greater change of PRUs adjusted for baseline platelet reactivity (38.6 ± 10.0, p < 0.01), greater risk of high platelet reactivity (HPR) (odds ratio: 10.14 [1.52–67.5], p = 0.017), and a trend towards decreased H3 clopidogrel metabolite levels (−3.41 ng/mL [−11.00 to 0.54 ng/mL], p = 0.072). CYP2C19 LoF carriers who stopped smoking had the highest PRUs, whereas those with the wild type who continued smoking had the lowest PRUs (p < 0.008). Conclusion Smoking cessation in clopidogrel-treated patients after PCI is associated with increased platelet reactivity and greater risk of HPR. Alternative P2Y12 inhibitors may be considered in selected patients who stop smoking after PCI.
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Jean-Philippe, Collet. "Current Concepts in the Clinical Utility of Platelet Reactivity Testing." Interventional Cardiology Review 8, no. 2 (2013): 100. http://dx.doi.org/10.15420/icr.2013.8.2.100.
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The pharmacodynamic effect of clopidogrel varies among individuals; approximately a third will have high on-treatment platelet reactivity (HTPR) to adenosine diphosphate and may benefit from more intensive antiplatelet therapy. Platelet reactivity testing has an important role in monitoring the therapeutic efficiency of clopidogrel and the safety of more potent drugs that confer an increased bleeding risk, because it provides a direct measure of the biological effect of these drugs. Numerous studies have demonstrated an association between HTPR and the risk of cardiac events in acute coronary syndrome (ACS) or after percutaneous coronary intervention (PCI). While the prognostic value of platelet reactivity testing following PCI has been demonstrated repeatedly in cohort studies and meta-analyses, randomised controlled studies investigating the clinical utility of the technique to guide treatment decisions failed to improve clinical outcomes of clopidogrel-treated patients undergoing stent implantation. Available data suggest that platelet function monitoring may be carried out in clopidogrel-treated patients with a higher risk of thrombotic events. These include patient risk factors such as body mass index (BMI), type 2 diabetes, and those prior unexpected ischemic events such as stent thrombosis, as well as procedural risk factors. As we move towards conclusively defining a therapeutic window associated with both cardiovascular (upper threshold) and bleeding risk (lower threshold) for antiplatelet agents, platelet reactivity testing will become a central tool in the practice of personalised strategies.
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Kastrati, Adnan, Steffi Harlfinger, Olga Gorchakova, Andreas Lazar, Nicolas von Beckerath, Albert Schömig, Edgar Schömig, and Dirk Taubert. "Pharmacokinetics of clopidogrel after administration of a high loading dose." Thrombosis and Haemostasis 92, no. 08 (2004): 311–16. http://dx.doi.org/10.1160/th04-02-0105.
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SummaryThe adenosine diphosphate (ADP) receptor P2Y12 blocking agent clopidogrel is clinically proven to be efficient in preventing thrombotic events. However, its therapeutic value is limited by an, as yet poorly explained, interindividual heterogeneity in platelet inhibition. To evaluate possible pharmacokinetic determinants of this response variability, we developed a sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for quantification of unmodified inactive clopidogrel, its inactive carboxyl metabolite, and its active thiol metabolite in plasma. Analyte concentrations and platelet aggregation were assessed in ten healthy volunteers receiving an oral load of 600 mg clopidogrel. Subjects showed marked inter-individual differences in maximal platelet inhibition and in plasma pharmacokinetics. Univariate regression revealed linear correlations between maximal antiplatelet effect and peak plasma concentrations (cmax) of unchanged clopidogrel (r=0.76; p=0.01), of the carboxyl metabolite (r=0.70; p=0.03), and of the thiol metabolite (r=0.73; p=0.02), as well as linear correlations between cmax values of clopidogrel and its metabolites. This indicates that the response variability is predominantly caused by individual differences in clopidogrel absorption and that other factors, such as ADP receptor reactivity or differences in bioactivation of clopidogrel, do not play a major role.
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Samoš, Matej, Marián Fedor, František Kovář, Michal Mokáň, Tomáš Bolek, Peter Galajda, Peter Kubisz, and Marián Mokáň. "Type 2 Diabetes and ADP Receptor Blocker Therapy." Journal of Diabetes Research 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/6760710.
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Type 2 diabetes (T2D) is associated with several abnormalities in haemostasispredisposingto thrombosis. Moreover, T2D was recently connected with a failure in antiplatelet response to clopidogrel, the most commonly used ADP receptor blocker in clinical practice. Clopidogrel high on-treatment platelet reactivity (HTPR) was repeatedly associated with the risk of ischemic adverse events. Patients with T2D show significantly higher residual platelet reactivity on ADP receptor blocker therapy and are more frequently represented in the group of patients with HTPR. This paper reviews the current knowledge about possible interactions between T2D and ADP receptor blocker therapy.
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Suarez, Dagmar Fredy Hernandez, Kyle Melin, Angel Lopez-Candales, and Jorge Duconge. "2529." Journal of Clinical and Translational Science 1, S1 (September 2017): 67. http://dx.doi.org/10.1017/cts.2017.239.
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OBJECTIVES/SPECIFIC AIMS: To determine the association between clinical characteristics and platelet reactivity in Hispanic patients on clopidogrel therapy. METHODS/STUDY POPULATION: A cross-sectional pilot study was performed in 58 Puerto Rican patients diagnosed with any type of vascular disease and actively receiving a maintenance dose of clopidogrel for at least 7 days. The study population was divided into 2 groups: Group I with non-high on-treatment platelet reactivity (TPR); Group II with high TPR. To determine the platelet function, P2Y12 reaction units (PRU) were obtained by VerifyNow® P2Y12 assay (Accumetrics, USA). RESULTS/ANTICIPATED RESULTS: We studied a heterogeneous cohort of patients with coronary artery disease (57%), peripheral artery disease (30%), carotid artery stenosis (7%), cerebral artery aneurysm (3%), and stroke (3%) on clopidogrel therapy for secondary prevention of thromboembolic events. The mean TPR was 205±49 PRU (range: 61–304), with a prevalence of 28% patients with high TPR (PRU≥230). No significant clinical differences were found between the non-high TPR and high-TPR groups (p>0.05). However, multivariable logistic regression analysis showed that both diabetes mellitus (OR=7.5; CI: 1.01–51.9) and proton-pump inhibitors (OR=13.6; CI: 1.3–142.0) were independently correlated with high TPR (p<0.05) after adjusting for other clinical variables. DISCUSSION/SIGNIFICANCE OF IMPACT: These results provide new insight into the importance of clinical characteristics on platelet reactivity in this Caribbean population. Further studies are warranted to determine whether important clopidogrel pharmacogenes are related with platelet function in Hispanics, as well as the role of TPR in guiding antiplatelet therapy and predicting future adverse cardiovascular events in this population.
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Alexopoulos, Dimitrios, Gerasimos Dimitropoulos, Periklis Davlouros, Ioanna Xanthopoulou, George Kassimis, Eleana F. Stavrou, George Hahalis, and Aglaia Athanassiadou. "Prasugrel Overcomes High On-Clopidogrel Platelet Reactivity Post-Stenting More Effectively Than High-Dose (150-mg) Clopidogrel." JACC: Cardiovascular Interventions 4, no. 4 (April 2011): 403–10. http://dx.doi.org/10.1016/j.jcin.2010.12.011.
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Ding, Peng, Yujie Wei, Nana Chen, and Huiliang Liu. "Validation of a New ELISA-Based Vasodilator-Associated Stimulated Phosphoprotein Phosphorylation Assay to Assess Platelet Reactivity Index in a Chinese Population." Clinical and Applied Thrombosis/Hemostasis 24, no. 3 (January 23, 2017): 452–61. http://dx.doi.org/10.1177/1076029616689300.
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The level of platelet reactivity during P2Y12-adenosine diphosphate receptor antagonist is associated with ischemic and bleeding risks following percutaneous coronary intervention in acute coronary syndrome. Determining platelet reactivity inhibition may be valuable for confirming effective platelet inhibition for individual patients and identifying patients at risk of bleeding. The enzyme-linked immunosorbent assay (ELISA)-based vasodilator-stimulated phosphoprotein (VASP) assay offers unique advantages over other methods and has not been used in the Chinese population. We enrolled 10 healthy volunteers and 54 patients with acute coronary syndrome. The volunteers received no treatment, and patients were administered a loading dose of clopidogrel or ticagrelor. The platelet reactivity index (PRI) was measured using flow cytometry (FC)-VASP and ELISA-VASP at baseline and 8-hour postloading dose. Blood samples of healthy volunteers and clopidogrel- or ticagrelor-treated patients were frozen and stored for 1, 2, and 4 weeks after initial activation. All frozen samples were tested using ELISA-VASP. The PRI assessed by FC-VASP and ELISA-VASP correlated well showing a high degree of consistency in identifying high or low on-treatment platelet reactivity. No significant time-dependent changes in PRI results were observed in frozen samples stored up to 4 weeks compared to nonfrozen samples. The PRI of ticagrelor-treated patients was lower than that of clopidogrel-treated patients. The ELISA-VASP effectively assesses the PRI, and results obtained from frozen specimens are unaffected by storage and shipment prior to assay. Ticagrelor was superior to clopidogrel in decreasing the PRI.
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Kim, In-Suk, Young-Hoon Jeong, and Gyeong-Won Lee. "CYP2C19*2 and *3 Polymorphisms Are Associated with High Post- Treatment Platelet Reactivity in Korean Patients with Acute Coronary Syndrome Undergoing Percutanous Coronary Intervention." Blood 112, no. 11 (November 16, 2008): 982. http://dx.doi.org/10.1182/blood.v112.11.982.982.
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Abstract Background: Cytochrome P450 (CYP) 2C19 is an enzyme showing genetic polymorphism that may cause marked interindividual and interethnic variation in the metabolism and disposition of its substrates. CYP2C19*2 and CYP2C19*3 are the most common of CYP2C19 polymorphisms, and show phenotypic poor metabolism. Recent data have shown that the CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet response to clopidogrel in healthy controls and Caucasian patients with acute coronary syndrome. However, It is unknown whether CYP2C19 *3, which is frequently noted in Asian, is also associated with platelet response to clopidogrel. Therefore, this study was conducted to analyze the effect of CYP2C19 *2 and *3 polymorphisms on high post-treatment platelet reactivity (HPPR) on clopidogrel in Korean patients with acute coronary syndrome, as a representative of Asian populations. Methods: The study included 136 consecutive patients undergoing percutanous coronary intervention (PCI). Adenosine diphosphate (ADP)-induced platelet aggregation by light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay (Ultegra rapid platelet function assay; Accumetrics Inc., USA) were assessed after a loading dose and after the maintenance dose of clopidogrel before discharge. CYP2C19 genotype was analyzed by Snapshot method. Results: The genotypic distributions of CYP2C19*1/*1, *1/*2, *1/*3, *2/*2, and *2/*3 were 57 (41.9%), 47 (34.6%), 12 (8.8%), 14 (10.3%), 6 (4.4%), and 6(4.4%), respectively. The frequencies of CYP2C19 mutant alleles in Korean were higher than Caucasians. The CYP2C19*2 and CYP2C19*3 polymorphisms were significantly associated with persistent higher platelet aggregation by LTA, and lower inhibition of platelet reactivity by VerifyNow P2Y12 assay after clopidogrel than CYP2C19*1 genotype. The CYP2C19*2 and *3 alleles were more frequent in clopidogrel hyporesponsiveness, defined by persistent HPPR (5 uM ADP-induced platelet aggregation >50%; p = 0.01). Conclusions: This study suggests that the CYPC19*2 and *3 alleles influence clopidogrel hyporesponsiveness after clopidogrel in Asian patients with acute coronary syndromes undergoing PCI. These findings can have a significant impact on the future design of pharmacognetic antiaggregant strategies for acute coronary syndrome on antiplatelet treatment.
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Berdejo, Javier, Gerard Roura, Josep Gómez-Lara, Rafael Romaguera, Luis Teruel, Guillermo Sánchez-Elvira, Ana Marcano, et al. "Clopidogrel pretreatment in primary percutaneous coronary intervention: Prevalence of high on-treatment platelet reactivity and impact on preprocedural patency of the infarct-related artery." Thrombosis and Haemostasis 110, no. 07 (2013): 110–17. http://dx.doi.org/10.1160/th13-01-0057.
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SummaryTo date, there is limited data on levels of platelet inhibition achieved in patients with ST-elevation myocardial infarction (STEMI) who are loaded with clopidogrel and aspirin (ASA) prior to undergoing primary percutaneous coronary intervention (P-PCI). The aim of this investigation was to evaluate the percentage of STEMI patients with high on-treatment platelet reactivity (HPR) to clopidogrel at the time of initiating P-PCI and its association with the initial patency of the infarct-related artery (IRA). This prospective pharmacodynamic study included 50 STEMI patients, previously naïve to oral antiplatelet agents, who received 500-mg ASA and 600-mg clopidogrel loading doses prior to P-PCI. Platelet function assessment was performed at the beginning of the procedure using various assays, including VerifyNow™ system (primary endpoint), light transmission aggregometry and multiple electrode aggregometry. The percentage of patients with suboptimal response to clopidogrel and ASA assessed with the VerifyNow™ system was 88.0% and 28.6%, respectively. Similar results were obtained with the other assays used. A higher percentage of patients with initial patency of the IRA was observed among those patients without HPR compared with those with HPR to clopidogrel (66.7% vs 15.9%; p=0.013), while no differences were observed regarding postprocedural angiographic or electrocardiographic outcomes. In conclusion, this study shows that a high percentage of STEMI patients have inadequate levels of clopidogrel-induced and, to a lesser extent, aspirin-mediated platelet inhibition when starting a P-PCI procedure, and suggests that a poor response to clopidogrel might be associated with impaired initial TIMI flow in the IRA.
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Aradi, Dániel, Lisa Gross, Dietmar Trenk, Tobias Geisler, Béla Merkely, Róbert Gábor Kiss, András Komócsi, et al. "Platelet reactivity and clinical outcomes in acute coronary syndrome patients treated with prasugrel and clopidogrel: a pre-specified exploratory analysis from the TROPICAL-ACS trial." European Heart Journal 40, no. 24 (April 24, 2019): 1942–51. http://dx.doi.org/10.1093/eurheartj/ehz202.
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Abstract Aims The value of platelet function testing (PFT) in predicting clinical outcomes and guiding P2Y12-inhibitor treatment is uncertain. In a pre-specified sub-study of the TROPICAL-ACS trial, we assessed ischaemic and bleeding risks according to high platelet reactivity (HPR) and low platelet reactivity (LPR) to ADP in patients receiving uniform prasugrel vs. PFT-guided clopidogrel or prasugrel. Methods and results Acute coronary syndrome patients with PFT done 14 days after hospital discharge were included with prior randomization to uniform prasugrel for 12 months (control group, no treatment modification) vs. early de-escalation from prasugrel to clopidogrel and PFT-guided maintenance treatment (HPR: switch-back to prasugrel, non-HPR: clopidogrel). The composite ischaemic endpoint included cardiovascular death, myocardial infarction, or stroke, while key safety outcome was Bleeding Academic Research Consortium (BARC) 2–5 bleeding, from PFT until 12 months. We identified 2527 patients with PFT results available: 1266 were randomized to the guided and 1261 to the control group. Before treatment adjustment, HPR was more prevalent in the guided group (40% vs. 15%), while LPR was more common in control patients (27% vs. 11%). Compared to control patients without HPR on prasugrel (n = 1073), similar outcomes were observed in guided patients kept on clopidogrel [n = 755, hazard ratio (HR): 1.06 (0.57–1.95), P = 0.86] and also in patients with HPR on clopidogrel switched to prasugrel [n = 511, HR: 0.96 (0.47–1.96), P = 0.91]. In contrast, HPR on prasugrel was associated with a higher risk for ischaemic events in control patients [n = 188, HR: 2.16 (1.01–4.65), P = 0.049]. Low platelet reactivity was an independent predictor of bleeding [HR: 1.74 (1.18–2.56), P = 0.005], without interaction (Pint = 0.76) between study groups. Conclusion Based on this substudy of a randomized trial, selecting prasugrel or clopidogrel based on PFT resulted in similar ischaemic outcomes as uniform prasugrel therapy without HPR. Although infrequent, HPR on prasugrel was associated with increased risk of ischaemic events. Low platelet reactivity was a strong and independent predictor of bleeding both on prasugrel and clopidogrel.
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Tsujimoto, Masanori, Yukiko Enomoto, Jouji Kokuzawa, and Toru Iwama. "Diabetes mellitus and carotid artery plaques exhibiting high-intensity signals on MR angiography are related to increased platelet reactivity after carotid artery stenting." Journal of NeuroInterventional Surgery 9, no. 1 (July 1, 2016): 106–10. http://dx.doi.org/10.1136/neurintsurg-2016-012419.
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BackgroundIncreased platelet reactivity after carotid artery stenting (CAS) may cause thromboembolic complications.ObjectiveThis study aimed to investigate the incidence of increased platelet reactivity after CAS and to determine the factors related to it.MethodsPatients who underwent CAS were recruited prospectively. They received pre-procedural antiplatelet therapy comprising some combination of aspirin (100 mg/day), clopidogrel (75 mg/day), and/or cilostazol (200 mg/day) for a minimum of 7 days. ADP- and collagen-induced platelet aggregation were measured before and 4 days after CAS. Changes in platelet reactivity were reported as changes in the categorized platelet reactivity grade based on the effective dose 50%. Clinical characteristics of patients with and without increased platelet reactivity were compared.ResultsAmong 38 consecutive patients who underwent CAS, 18 (47%) exhibited increased platelet reactivity. Diabetes mellitus (OR 15.0; 95% CI 2.1 to 106.5; p=0.007) and carotid artery plaques exhibiting high-intensity signals (HIS) on time-of-flight MR angiography (TOF-MRA) (OR 25.2; 95% CI 2.0 to 316.2; p=0.013) were independently associated with increased platelet reactivity in a multivariate analysis.ConclusionsIncreased platelet reactivity occurred in nearly half of the studied patients subjected to CAS and was independently associated with diabetes mellitus and carotid artery plaques exhibiting HIS on TOF-MRA.