TY  - CONF
AU  - Bačković, Dragana
AU  - Novković, Mirjana
AU  - Matić, Dragan
AU  - Antonijević, Nebojša
AU  - Strugarević, Evgenija
AU  - Kovač, Mirjana
AU  - Kušić-Tišma, Jelena
AU  - Rakićević, Ljiljana
AU  - Radojković, Dragica
PY  - 2021
UR  - https://www.uksrb.rs/en/magazine/archive/heart-and-blood-vessels-number-32021
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2344
AB  - Introduction. Despite proven clinical effect of clopidogrel, a
considerable number of patients do not have an adequate
response to this type of medication. Problems during therapy occur in the form of resistance, which is present in 11%
of patients or bleeding that occurs in about 9% of patients.
Pharmacogenomics studies demonstrated that variants of
the CYP2C19 gene significantly influence the interindividual heterogenity of the clopidogrel response. The American
Heart Association, US Food and Drug Administration and the
European Medicines Agency, cite the CYP2C19 gene as a significant factor which influences patients response to clopidogrel. Further, it has been shown that the contribution of
genetic and non-genetic factors affecting clopidogrel therapy
may vary between patients from different populations, which
justifies conducting population-specific studies.
The aim. The aim of our study was to examine the significance
of the CYP2C19*2 and the CYP2C19*17 variants in the individual response to clopidogrel, in Serbian patients.
Methods. The study involved 108 patients with carotid artery
stenosis who underwent endarterectomy and received clopidogrel for at least 30 days after the intervention. Also, 120
patients with myocardial infarction receiving clopidogrel after PCI (percutaneous coronary intervention) were included.
Commercial tests were used for standard laboratory testing.
Allelic discrimination was performed after Sanger sequencing.
Results were analysed using statistical tests.
Results. In patients undergoing endarterectomy CYP2C19*2
carriers had a higher risk for being clopidogrel low-responder
in comparison with non-carriers (1.250, 95% CI 1.695–1.658,
P<0.01). In the group of patients undergoing PCI, risk for reinfarction in patients who were carriers of CYP2C19*2 was higher
compared to patients with wild type genotype (OR 5.355, 95%
CI 0.955-31.08; P=0.038). Variant CYP2C19*17 showed no association with variations in response to clopidogrel therapy.
Conclusion. The CYP2C19*2 variant shows significant association with a poor response to clopidogrel and it should be
considered when planning therapy.
PB  - Beograd : Udruženje kardiologa Srbije
C3  - Heart and Blood Vessels
T1  - Analysis of the association of the CYP2C19 variants with the effects of clopidogrel therapy in patients underwent to carotid endarterectomy
IS  - 3
VL  - 40
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2344
ER  - 

@conference{
author = "Bačković, Dragana and Novković, Mirjana and Matić, Dragan and Antonijević, Nebojša and Strugarević, Evgenija and Kovač, Mirjana and Kušić-Tišma, Jelena and Rakićević, Ljiljana and Radojković, Dragica",
year = "2021",
abstract = "Introduction. Despite proven clinical effect of clopidogrel, a
considerable number of patients do not have an adequate
response to this type of medication. Problems during therapy occur in the form of resistance, which is present in 11%
of patients or bleeding that occurs in about 9% of patients.
Pharmacogenomics studies demonstrated that variants of
the CYP2C19 gene significantly influence the interindividual heterogenity of the clopidogrel response. The American
Heart Association, US Food and Drug Administration and the
European Medicines Agency, cite the CYP2C19 gene as a significant factor which influences patients response to clopidogrel. Further, it has been shown that the contribution of
genetic and non-genetic factors affecting clopidogrel therapy
may vary between patients from different populations, which
justifies conducting population-specific studies.
The aim. The aim of our study was to examine the significance
of the CYP2C19*2 and the CYP2C19*17 variants in the individual response to clopidogrel, in Serbian patients.
Methods. The study involved 108 patients with carotid artery
stenosis who underwent endarterectomy and received clopidogrel for at least 30 days after the intervention. Also, 120
patients with myocardial infarction receiving clopidogrel after PCI (percutaneous coronary intervention) were included.
Commercial tests were used for standard laboratory testing.
Allelic discrimination was performed after Sanger sequencing.
Results were analysed using statistical tests.
Results. In patients undergoing endarterectomy CYP2C19*2
carriers had a higher risk for being clopidogrel low-responder
in comparison with non-carriers (1.250, 95% CI 1.695–1.658,
P<0.01). In the group of patients undergoing PCI, risk for reinfarction in patients who were carriers of CYP2C19*2 was higher
compared to patients with wild type genotype (OR 5.355, 95%
CI 0.955-31.08; P=0.038). Variant CYP2C19*17 showed no association with variations in response to clopidogrel therapy.
Conclusion. The CYP2C19*2 variant shows significant association with a poor response to clopidogrel and it should be
considered when planning therapy.",
publisher = "Beograd : Udruženje kardiologa Srbije",
journal = "Heart and Blood Vessels",
title = "Analysis of the association of the CYP2C19 variants with the effects of clopidogrel therapy in patients underwent to carotid endarterectomy",
number = "3",
volume = "40",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2344"
}

Bačković, D., Novković, M., Matić, D., Antonijević, N., Strugarević, E., Kovač, M., Kušić-Tišma, J., Rakićević, L.,& Radojković, D.. (2021). Analysis of the association of the CYP2C19 variants with the effects of clopidogrel therapy in patients underwent to carotid endarterectomy. in Heart and Blood Vessels
Beograd : Udruženje kardiologa Srbije., 40(3).
https://hdl.handle.net/21.15107/rcub_imagine_2344

Bačković D, Novković M, Matić D, Antonijević N, Strugarević E, Kovač M, Kušić-Tišma J, Rakićević L, Radojković D. Analysis of the association of the CYP2C19 variants with the effects of clopidogrel therapy in patients underwent to carotid endarterectomy. in Heart and Blood Vessels. 2021;40(3).
https://hdl.handle.net/21.15107/rcub_imagine_2344 .

Bačković, Dragana, Novković, Mirjana, Matić, Dragan, Antonijević, Nebojša, Strugarević, Evgenija, Kovač, Mirjana, Kušić-Tišma, Jelena, Rakićević, Ljiljana, Radojković, Dragica, "Analysis of the association of the CYP2C19 variants with the effects of clopidogrel therapy in patients underwent to carotid endarterectomy" in Heart and Blood Vessels, 40, no. 3 (2021),
https://hdl.handle.net/21.15107/rcub_imagine_2344 .

TY  - JOUR
AU  - Novković, Mirjana
AU  - Matić, Dragan
AU  - Kušić-Tišma, Jelena
AU  - Antonijević, Nebojša
AU  - Radojković, Dragica
AU  - Rakićević, Ljiljana
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1187
AB  - Bleeding is one of the possible adverse events during clopidogrel therapy. The CYP2C19 gene is the most significant genetic factor which influences response to clopidogrel treatment. We aimed to examine the contribution of the CYP2C19 gene to bleeding occurrence during clopidogrel therapy in Serbian patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). This case-control study included 53 patients who experienced bleeding and 55 patients without bleeding. Bleeding events were defined and classified using the Bleeding Academic Research Consortium (BARC) criteria. All patients were prescribed daily doses of clopidogrel during the 1-year follow-up after PCI. The CYP2C19*17 (c.-806C  gt  T, rs12248560), rs11568732 (c.-889T  gt  G, CYP2C19*20), CYP2C19*2 (c.681G  gt  A; rs4244285) and CYP2C19*3 (c.636G  gt  A; rs4986893) variants were analysed in all 108 patients. Additionally, sequencing of all nine exons, 5'UTR and 3'UTR in the rs11568732 carriers was performed. Association between bleeding (BARC type ae lt yen gt  2) and the CYP2C19*17 variant was not observed [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.2-1.1; p = 0.107). The rs11568732 variant showed significant association with bleeding (OR, 3.7; 95% CI, 1.12-12.44; p = 0.025). Also, we found that the rs11568732 variant appears independently of haplotype CYP2C19*3B, which is contrary to the previous findings. Our results indicate the absence of CYP2C19*17 influence and turn the attention to the potential significance of the rs11568732 variant in terms of adverse effects of clopidogrel. However, it is necessary to conduct an independent conformation study in order to verify this finding. Also, an analysis of the functional implication of the rs11568732 variant is necessary in order to confirm the significance of this variant, both in relation to its influence on gene expression and in relation to its medical significance.
PB  - Springer Heidelberg, Heidelberg
T2  - European Journal of Clinical Pharmacology
T1  - Analysis of the CYP2C19 genotype associated with bleeding in Serbian STEMI patients who have undergone primary PCI and treatment with clopidogrel
EP  - 451
IS  - 4
SP  - 443
VL  - 74
DO  - 10.1007/s00228-017-2401-5
ER  - 

@article{
author = "Novković, Mirjana and Matić, Dragan and Kušić-Tišma, Jelena and Antonijević, Nebojša and Radojković, Dragica and Rakićević, Ljiljana",
year = "2018",
abstract = "Bleeding is one of the possible adverse events during clopidogrel therapy. The CYP2C19 gene is the most significant genetic factor which influences response to clopidogrel treatment. We aimed to examine the contribution of the CYP2C19 gene to bleeding occurrence during clopidogrel therapy in Serbian patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). This case-control study included 53 patients who experienced bleeding and 55 patients without bleeding. Bleeding events were defined and classified using the Bleeding Academic Research Consortium (BARC) criteria. All patients were prescribed daily doses of clopidogrel during the 1-year follow-up after PCI. The CYP2C19*17 (c.-806C  gt  T, rs12248560), rs11568732 (c.-889T  gt  G, CYP2C19*20), CYP2C19*2 (c.681G  gt  A; rs4244285) and CYP2C19*3 (c.636G  gt  A; rs4986893) variants were analysed in all 108 patients. Additionally, sequencing of all nine exons, 5'UTR and 3'UTR in the rs11568732 carriers was performed. Association between bleeding (BARC type ae lt yen gt  2) and the CYP2C19*17 variant was not observed [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.2-1.1; p = 0.107). The rs11568732 variant showed significant association with bleeding (OR, 3.7; 95% CI, 1.12-12.44; p = 0.025). Also, we found that the rs11568732 variant appears independently of haplotype CYP2C19*3B, which is contrary to the previous findings. Our results indicate the absence of CYP2C19*17 influence and turn the attention to the potential significance of the rs11568732 variant in terms of adverse effects of clopidogrel. However, it is necessary to conduct an independent conformation study in order to verify this finding. Also, an analysis of the functional implication of the rs11568732 variant is necessary in order to confirm the significance of this variant, both in relation to its influence on gene expression and in relation to its medical significance.",
publisher = "Springer Heidelberg, Heidelberg",
journal = "European Journal of Clinical Pharmacology",
title = "Analysis of the CYP2C19 genotype associated with bleeding in Serbian STEMI patients who have undergone primary PCI and treatment with clopidogrel",
pages = "451-443",
number = "4",
volume = "74",
doi = "10.1007/s00228-017-2401-5"
}

Novković, M., Matić, D., Kušić-Tišma, J., Antonijević, N., Radojković, D.,& Rakićević, L.. (2018). Analysis of the CYP2C19 genotype associated with bleeding in Serbian STEMI patients who have undergone primary PCI and treatment with clopidogrel. in European Journal of Clinical Pharmacology
Springer Heidelberg, Heidelberg., 74(4), 443-451.
https://doi.org/10.1007/s00228-017-2401-5

Novković M, Matić D, Kušić-Tišma J, Antonijević N, Radojković D, Rakićević L. Analysis of the CYP2C19 genotype associated with bleeding in Serbian STEMI patients who have undergone primary PCI and treatment with clopidogrel. in European Journal of Clinical Pharmacology. 2018;74(4):443-451.
doi:10.1007/s00228-017-2401-5 .

Novković, Mirjana, Matić, Dragan, Kušić-Tišma, Jelena, Antonijević, Nebojša, Radojković, Dragica, Rakićević, Ljiljana, "Analysis of the CYP2C19 genotype associated with bleeding in Serbian STEMI patients who have undergone primary PCI and treatment with clopidogrel" in European Journal of Clinical Pharmacology, 74, no. 4 (2018):443-451,
https://doi.org/10.1007/s00228-017-2401-5 . .

TY  - JOUR
AU  - Mitropoulou, Christina
AU  - Fragoulakis, Vasilios
AU  - Rakićević, Ljiljana
AU  - Novković, Mirjana
AU  - Vozikis, Athanassios
AU  - Matić, Dragan M.
AU  - Antonijević, Nebojša
AU  - Radojković, Dragica 
AU  - van Schaik, Ron H.
AU  - Patrinos, George P.
PY  - 2016
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/965
AB  - Introduction: Clopidogrel, which is activated by the CYP2C19 enzyme, is among the drugs for which all major regulatory agencies recommend genetic testing to be performed to identify a patient's CYP2C19 genotype in order to determine the optimal antiplatelet therapeutic scheme. The CYP2C19*2 and CYP2C19*3 variants are loss-of-function alleles, leading to abolished CYP2C19 function and thus have the risk of thrombotic events for carriers of these alleles on standard dosages, while the CYP2C19*17 allele results in CYP2C19 hyperactivity. Aims: Here, we report our findings from a retrospective study to assess whether genotyping for the CYP2C19*2 allele was cost effective for myocardial infarction patients receiving clopidogrel treatment in the Serbian population compared with the nongenotype-guided treatment. Results: We found that 59.3% of the CYP2C19*1/*1 patients had a minor or major bleeding event versus 42.85% of the CYP2C19*1/*2 and *2/*2, while a reinfarction event occurred only in 2.3% of the CYP21C9*1/*1 patients, compared with 11.2% of the CYP2C19*1/*2 and CYP2C19*2/*2 patients. There were subtle differences between the two patient groups, as far as the duration of hospitalization and rehabilitation is concerned, in favor of the CYP2C19*1/*1 group. The mean cost for the CYP2C19*1/*1 patients was estimated at (sic)2547 versus (sic)2799 in the CYP2C19*1/*2 and CYP2C19*2/*2 patients. Furthermore, based on the overall CYP2C19*1/*2 genotype frequencies in the Serbian population, a break-even point analysis indicated that performing the genetic test prior to drug prescription represents a cost-saving option, saving (sic)13 per person on average. Conclusion: Overall, our data demonstrate that pharmacogenomics-guided clopidogrel treatment may represent a cost-saving approach for the management of myocardial infarction patients undergoing primary percutaneous coronary intervention in Serbia.
PB  - Future Medicine Ltd, London
T2  - Pharmacogenomics
T1  - Economic analysis of pharmacogenomic-guided clopidogrel treatment in Serbian patients with myocardial infarction undergoing primary percutaneous coronary intervention
EP  - 1784
IS  - 16
SP  - 1775
VL  - 17
DO  - 10.2217/pgs-2016-0052
ER  - 

@article{
author = "Mitropoulou, Christina and Fragoulakis, Vasilios and Rakićević, Ljiljana and Novković, Mirjana and Vozikis, Athanassios and Matić, Dragan M. and Antonijević, Nebojša and Radojković, Dragica  and van Schaik, Ron H. and Patrinos, George P.",
year = "2016",
abstract = "Introduction: Clopidogrel, which is activated by the CYP2C19 enzyme, is among the drugs for which all major regulatory agencies recommend genetic testing to be performed to identify a patient's CYP2C19 genotype in order to determine the optimal antiplatelet therapeutic scheme. The CYP2C19*2 and CYP2C19*3 variants are loss-of-function alleles, leading to abolished CYP2C19 function and thus have the risk of thrombotic events for carriers of these alleles on standard dosages, while the CYP2C19*17 allele results in CYP2C19 hyperactivity. Aims: Here, we report our findings from a retrospective study to assess whether genotyping for the CYP2C19*2 allele was cost effective for myocardial infarction patients receiving clopidogrel treatment in the Serbian population compared with the nongenotype-guided treatment. Results: We found that 59.3% of the CYP2C19*1/*1 patients had a minor or major bleeding event versus 42.85% of the CYP2C19*1/*2 and *2/*2, while a reinfarction event occurred only in 2.3% of the CYP21C9*1/*1 patients, compared with 11.2% of the CYP2C19*1/*2 and CYP2C19*2/*2 patients. There were subtle differences between the two patient groups, as far as the duration of hospitalization and rehabilitation is concerned, in favor of the CYP2C19*1/*1 group. The mean cost for the CYP2C19*1/*1 patients was estimated at (sic)2547 versus (sic)2799 in the CYP2C19*1/*2 and CYP2C19*2/*2 patients. Furthermore, based on the overall CYP2C19*1/*2 genotype frequencies in the Serbian population, a break-even point analysis indicated that performing the genetic test prior to drug prescription represents a cost-saving option, saving (sic)13 per person on average. Conclusion: Overall, our data demonstrate that pharmacogenomics-guided clopidogrel treatment may represent a cost-saving approach for the management of myocardial infarction patients undergoing primary percutaneous coronary intervention in Serbia.",
publisher = "Future Medicine Ltd, London",
journal = "Pharmacogenomics",
title = "Economic analysis of pharmacogenomic-guided clopidogrel treatment in Serbian patients with myocardial infarction undergoing primary percutaneous coronary intervention",
pages = "1784-1775",
number = "16",
volume = "17",
doi = "10.2217/pgs-2016-0052"
}

Mitropoulou, C., Fragoulakis, V., Rakićević, L., Novković, M., Vozikis, A., Matić, D. M., Antonijević, N., Radojković, D., van Schaik, R. H.,& Patrinos, G. P.. (2016). Economic analysis of pharmacogenomic-guided clopidogrel treatment in Serbian patients with myocardial infarction undergoing primary percutaneous coronary intervention. in Pharmacogenomics
Future Medicine Ltd, London., 17(16), 1775-1784.
https://doi.org/10.2217/pgs-2016-0052

Mitropoulou C, Fragoulakis V, Rakićević L, Novković M, Vozikis A, Matić DM, Antonijević N, Radojković D, van Schaik RH, Patrinos GP. Economic analysis of pharmacogenomic-guided clopidogrel treatment in Serbian patients with myocardial infarction undergoing primary percutaneous coronary intervention. in Pharmacogenomics. 2016;17(16):1775-1784.
doi:10.2217/pgs-2016-0052 .

Mitropoulou, Christina, Fragoulakis, Vasilios, Rakićević, Ljiljana, Novković, Mirjana, Vozikis, Athanassios, Matić, Dragan M., Antonijević, Nebojša, Radojković, Dragica , van Schaik, Ron H., Patrinos, George P., "Economic analysis of pharmacogenomic-guided clopidogrel treatment in Serbian patients with myocardial infarction undergoing primary percutaneous coronary intervention" in Pharmacogenomics, 17, no. 16 (2016):1775-1784,
https://doi.org/10.2217/pgs-2016-0052 . .