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Pharmacogenomics, the study of genetic variations in drug transporters, drug-metabolizing enzymes, and drug receptors that cause variable drug responses, is eventually been applied in all fields of medicine [29, 50]. In the field of cardiology, however, the clinical application of pharmacogenomics has lagged behind in the 90's. However, in the last 10 years, the firm discoveries of the implication of gene polymorphisms in the therapeutic response of the anticoagulant drug warfarin and its analogs and the antiplatelet agent clopidogrel have boosted cardiology pharmacogenomics [33]. Personalized medicine of anticoagulant and antiplatelet therapy is a challenging field that holds promise of individualizing therapy based on the genetic information of the patients. Nowadays, accumulated evidence point towards to the implementation of established pharmacogenomic applications for these two drug categories in cardiovascular medicine that may ultimately become daily routine clinical practice in the near future.
Anticoagulant pharmacogenomics: coumarinic oral anticoagulants
The most mature pharmacogenomic application in cardiology concerns the anticoagulant therapy [30]. The coumarinic oral anticoagulants (COAs) warfarin, acenocoumarol, and phenprocoumon are the cornerstone of anticoagulant therapy. They constitute the standard world-wide oral anticoagulant treatment for the treatment of thromboembolic disorders and for stroke prophylaxis in patients with atrial fibrillation. Despite their undisputable effectiveness, COAs have narrow therapeutic window and their anticoagulant effect needs to be carefully and frequently monitored in order to maintain adequate anticoagulation during therapy. Furthermore, COAs are associated with a high risk of major bleeding, especially during the initial phase of treatment. Coumarin-induced bleeding, partly caused by overdosing, is a leading cause of hospital admission and drug related death. In COAs therapy a great inter- and intra-patient variability exists in the response that leads to often dose adjustments of therapy [35]. Several factors are known to contribute to interindividual COA dose variability including age, sex, BMI, smoking, vitamin K intake, and concomitant drug therapy [25].
However, the greatest proportion of interindividual COAs therapy is attributed to genetic factors. Evidence accumulated during the last decade has revealed variations in the genes of two enzymes, cytochrome P450 2C9 (CYP2C9), the enzyme that metabolizes COAs, and vitamin K epoxide reductase (VKORC1), the pharmacologic target enzyme of these drugs as the main genetic predictors of COAs dose requirements [5, 42, 59]. The variant alleles CYP2C9*2 and *3 result in decreased CYP2C9 enzymatic activity affecting coumarin pharmacokinetics, while VKORC1 -1639G>A polymorphism influ-
ences the pharmacodynamic response to coumarins [51]. It is more than a decade since, in 1999, the first evidence that CYP2C9*2 and *3 alleles affect in vivo warfarin dose requirements appeared [2] whereas information on the VKORC1 gene polymorphisms and their importance in warfarin resistance became available in 2004 when it was shown that mutations in VKORC1 cause warfarin resistance [40]. Since then, polymorphisms in these two genes, VKORC1 and CYP2C9, have been extensively studied in combination in regard to the response to anticoagulant therapy and it is now established that they are the major genetic determinants of COAs response variability [5].
The correlation between COAs dose requirements and polymorphisms in CYP2C9 and VKORC1 genes is true for each of the three coumarins, however, warfarin is by far the most studied from the three [5, 42, 59]. Validation of CYP2C9 and VKORC1 gene polymorphisms in retrospective pharmacogenet-ic studies for all three coumarins shows that carriers of CYP2C9*2 and *3 alleles and VKORC1 -1639G>A polymorphism are at increased bleeding risk and require lower mean daily doses. The significant association of VKORC1 gene polymorphisms with interindividual variation of warfarin dose requirements was confirmed in a recent meta-analysis of studies on the impact of VKORC 1 genetic variation on warfarin dose requirements [61]. Furthermore, the results of three different genome-wide association studies in patients treated with either warfarin or acenocoumarol, showed that CYP2C9 and VKORC1 polymorphisms are highly associated with coumarins dose, replicating this way the results of retrospective studies [8, 52, 53].
It has been estimated that polymorphisms in CYP2C9 and VKORC1 genes together account for up to 40% of the variability in COAs initiation and maintainance dose requirements. To apply this knowledge in clinical practice, efforts are focusing in incorporating genetic information to currently used dosing regiments [5, 15]. Several pharmacogenetic-based dosing algorithms incorporating CYP2C9 and VKORC1 genotype information have been proposed for warfarin, including those by Sconce et al in 2005 and Gage et al in 2008 [16, 44]. The latter algorithm is available on line and can be freely used [101]. Recently, the International Warfarin Pharmacogenetics Consortium used clinical and genetic data from 4043 patients to create a dosing algorithm that was based on both clinical variables and genetic information [28, 34]. This pharmacogenetic algorithm was validated in a validation cohort of over 1000 patients. They found that initial doses of warfarin estimated by the pharmacogenetic algorithm were significantly closer to the required stable therapeutic doses than those derived from a non-pharmacogenetic clinical
algorithm or fixed dose approach [28, 34]. To the best of our knowledge, information on validated pharmacogenetic-based clinical algorithms for acenocoumarol and phenprocoumon is still lacking.
Additionally to retrospective and genome-wide association studies, results from four small scale prospective trials of genotype-guided warfarin dosing are available. These prospective trials showed a tendency to improvement during warfarin therapy initiation when genotypic information was taken into account, but have not convincingly demonstrated the potential benefit on pharmacogenetic-guided dosing on treatment outcomes [3, 7, 23, 43]. Furthermore, VKORC 1 gene polymorphisms were included in only two of these studies in the dosing algorithm [3, 43]. The first study found that genotype-guided algorithm predicted more accurately the stable maintenance dose of warfarin and led to fewer dose adjustments compared to standard clinical care [3]. The second study, in 297 patients starting warfarin therapy, reported that genetic polymorphisms of both CYP2C9 and VKORC 1 have a significant influence on the required warfarin dose after the first two weeks of therapy [43]. Additional randomized trials are on the way. The clinical trial registry site of U.S. National Institutes of Health, lists three small clinical trials currently recruiting patients to assess the clinical benefits of pharmacogenetic-guided dosing of warfarin in Singapore, Turkey, and USA [102]. In addition, one large randomized trial in USA (Clarification of Optimal Anticoagulant through Genetics - COAG) is currently recruiting patients [103]. These studies are expected to further elucidate the clinical utility of pharmacogenetic-guided dosing of warfarin.
For acenocoumarol and phenprocoumon, the two other COAs prescribed in Europe in addition to warfarin, no data from prospective pharmacogenetic clinical trials are available. To fill this gap, a trial is currently recruiting patients in Europe, supported by the European Commission FP7 Programme. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial takes place in six countries in Europe and has started recruiting patients in early 2011 [58]. EU-PACT trial will assess the safety, clinical utility and cost-effectiveness of newly developed phar-macogenetic-guided dosing algorithms for warfarin, acenocoumarol, and phenprocoumon in 3,000 patients, with a follow-up period of three months. Another critical element for the successful implementation of COAs pharmacogenetics in the clinic is the availability of rapid and validated genotyping procedures for CYP2C9 and VKORC1 gene polymorphisms so that genotyping can be performed prior to anticoagulant prescription in a non-laboratory environment. The EU-PACT trial will use such a validated procedure [58].
In 2005, the Clinical Pharmacology Subcommittee of the US Food and Drug Administration (FDA) Advisor Committee for Pharmaceutical Science recommended that the FDA relabel warfarin indicating that CYP2C9 and VKORC1 genotyping can assist in optimizing warfarin dosing. The FDA relabeled warfarin with genomic information in August 2007. In the revised label for warfarin it is stated that lower doses may be best for patients with variations in one or both of these genes [104]. On January of 2010, the FDA moved to a last warfarin relabeling and this time a table indicating the range of expected therapeutic warfarin doses based on CYP2C9 and VKORC1 genotypes was provided [104]. Despite this change, genotyping is not yet a part of daily routine practice and guidelines by specialist societies such as the American College of Chest Physicians have not been adapted due to the lack of sufficient randomized data from prospective studies [4].
While all the efforts are focusing on the implementation of a CYP2C9/VKORC1 genotype-based dosing algorithm in COAs therapy, research continues to seek for novel clinically significant polymorphisms or rare variants in CYP2C9/VKORC1 genes and other genes and gene polymorphisms that can eventually improve the predictive accuracy of the genotype-based algorithms. Such candidate genes are CYP4F2, which catalyzes the oxidation of Vitamin K and gamma-glutamyl carboxylase (GGCX), a component of Vitamin K cycle [27, 41, 60]. Though gene polymorphisms in these two genes predict a low proportion of COAs response variability, it is obvious that genetic factors govern a great proportion of the unknown causality percentage of interindividual response.
Antiplatelet pharmacogenomics: clopidogrel
Another promising field in cardiology medicine where pharmacogenomics is near to be implemented is the antiplatelet therapy with clopidogrel. Clopidogrel is the standard of care of acute coronary syndromes and the number 2 selling drug in the world. It is indicated in patients undergoing percutaneous coronary interventions (PCI) with or without stenting, and also for the reduction of atherothrom-botic events in patients with recent myocardial infarction, recent stroke or established peripheral arterial disease [38, 54]. Clopidogrel is a specific and irreversible inhibitor of the platelet P2Y12 adenosine diphosphate (ADP) receptor. Clopidogrel is an inactive prodrug that requires several biotransformation steps to become active. After intestinal absorption, which is dependent on the transporter protein P-glycoprotein, the biotransformation to the active metabolite is mainly mediated by the hepatic cytochrome P450 (CYP) system [36]. The main CYP enzyme involved in hepatic bioactivation of clopidogrel is CYP2C19.
Non-responsiveness to clopidogrel is widely recognized and is related to recurrent ischemic events. Approximately 25% of patients receiving clopidogrel experience a subtherapeutic antiplatelet response. This poor response to clopidogrel is associated with an increased risk of recurrent ischemic events and is known as clopidogrel resistance [19, 20, 21, 49]. In addition to lack of compliance, clinical factors such as obesity, insulin resistance, and the nature of the coronary event may contribute to the variability of the clopidogrel response [12, 17]. There is growing evidence that the response to clopidogrel may be influenced by pharmacokinetic variables such as intestinal absorption and metabolic activation in the liver, both of which are affected by genetic polymorphisms. In particular CYP2C19 genotype has emerged as a major determinant of the variability of pharmacodynamic response to clopidogrel [9, 17, 39].
In 2006, Hulot et al conducted a prospective pharmacogenetic study in healthy white male volunteers treated for 7 days with clopidogrel 75 mg/d [24]. In this seminal study, response to clopidogrel was found to be significantly associated with the CYP2C19 genotype. Specifically, it was shown that CYP2C19*2 allele that leads to impaired CYP2C19 function is associated with a marked decrease in platelet responsiveness to clopidogrel [24]. Further studies replicated these results and added more evidence on the idea that genetic variations in CYP2C19 gene leading to decreased activity of the enzyme are associated with decreased exposure of the patient to the active metabolite of clopidogrel. The presence of the CYP2C19*2 loss of function variant is significantly associated with lower exposure to clopidogrel active metabolite, lower inhibition of platelet aggregation, poor-responder status and adverse cardiovascular outcomes [19, 20, 26, 56, 57]. The year 2009 was the breakthrough of clopidogrel pharmacogenetics. The results of post-hoc clinical trial analyses (substudies of CLARITY-TIMI 28 (465 participants) and TRITON-TIMI 38 (1477 participants) [31, 32] and of cohort studies (6489 participants) [10, 18, 45,
46, 47, 56] independently showed that carriers of a reduced-function CYP2C19 allele not-only had significantly lower levels of the active metabolite of clopidogrel and diminished platelet inhibition, but also they experience a higher rate of major adverse cardiovascular events, including stent thrombosis, compared to homozygous wild type individuals.
Consequently, in May 2009, FDA changed drug label information of clopidogrel to highlight the impact of CYP2C19 genotype on the drug's pharmacokinetics, pharmacodynamics and clinical response [11, 105]. In the revised label of the drug, pharmaco-genetic information was included, notifying that pharmacogenetic testing can identify genotypes asso-
ciated with variability in CYP2C19 activity and that patients with genetically reduced CYP2C19 function have diminished antiplatelet responses and generally exhibit higher cardiovascular event rates following myocardial infarction than do patients with normal CYP2C19 function. Though FDA recommended the pharmacogenetic CYP2C19 analysis, the new drug label does not include genotype-guided dose recommendations but states that optimal dose for CYP2C19 PMs needs to be determined [11, 105].
A different aspect of diminished antiplatelet response even in individuals with normal CYP2C19 enzyme activity includes the concominant prescription of CYP2C19 inhibitors, such as proton pump inhibitors (PPIs) [13]. FDA has added a black box warning in clopidogrel label notifying that several PPIs should be avoided in patients receiving clopidogrel due to their CYP2C19 inhibitory effect [105]. Despite this warning, in the most recent document on the concomitant use of PPIs and thieno-pyridines developed by the American College of Cardiology Foundation (ACCF), the American College of Gastroenterology (ACG), and the American Heart Association (AHA) there is no action recommended regarding co-prescription of these drugs as no definitive conclusions were drawn comparing the pharmacokinetics and potential for drug interaction of the various PPIs with clopidogrel [1]. However, in case of polypharmacy, clinicians should be aware that other prescribed drugs, such as several antidepressants, are strong CYP2C19 inhibitors and can abolish antiplatelet response to clopidogrel [22].
The field of clopidogrel pharmacogenetics keeps evolving. A novel allelic variant, CYP2C19*17, has been discovered recently that results in increased transcriptional activity of CYP2C19 and increased enzymatic activity of the enzyme [48]. This allele is quite common in Caucasian populations (prevalence up to 30%) [37]. Carriers of CYP2C19*17 metabolize rapidly CYP2C19 substrates, and this may lead to enhanced response to antiplatelet treatment with clopidogrel. Results from current studies suggest that although the presence of CYP2C19*17 allele may improve the prevention of thrombotic events and lead to better response to clopidogrel, it also may increase the risk of bleeding [14, 45, 46, 55]. A recent study in 1524 patients undergoing percutaneous coronary intervention after pretreatment with 600 mg clopidogrel revealed that CY2C19*17 allele carriage is associated with a significant increase in risk of bleeding [45, 46]. It thus appears that FDA may soon need to change clopidogrel label again to include information on CYP2C19*17 allele.
Research focuses to the identification of additional polymorphisms in genes that influence responsiveness to clopidogrel independently or in synergism with CYP2C19 polymorphism. Most recent data on
clopidogrel response genes, debate on paraoxonase-1 (PON-1), an esterase proposed to be associated with the formation of the thiol active metabolite from clopidogrel and the common functional PON-1 Q192R polymorphism. Bouman et al have recently showed that PON-1 192R allele results in a more efficient clopidogrel bioactivation and that carriers of 192Q allele are at higher risk of stent thrombosis compared to non-carriers due to lower clopidogrel bioactivation [6]. These results, however, were not confirmed in a consequent study conducted by Sib-bing and colleagues. In the latter study, CYP2C19*2 allele remained the sole significant determinant of both antiplatelet effect of clopidogrel and risk of coronary stent thrombosis [47]. While waiting for further studies to solidify the association or noassociation of PON-1 gene polymorphisms with clopidogrel response, CYP2C19 loss of function alleles remain the core of clopidogrel pharmacogenomics.
In view of all knowledge on COAs and clopidogrel pharmacogenomics, it appears that individualized therapy for these major drug classes in cardiology is a step prior of daily routine clinical practice. Near future holds promise on the implementation of genotyping prior to therapy initiation. It is expected that adverse reactions caused by COAs and clopidogrel will significantly be reduced, relieving this way the burden from health system. Hopefully, incorporating COAs and clopidogrel phar-macogenomics in cardiology will encourage application of pharmacogenomic knowledge on other medicines used in cardiology such as statins.
REFERENCES
1. Abraham NS, Hlatky MA et al. (2010). "ACCF/ACG/ AHA 20І0 expert consensus document on the concomitant use of proton pump inhibitors and thieno-pyridines: a focused update of the ACCF/ACG/AHA 200S expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents."
J Am Coll Cardiol 56(24): 205І-66.
2. Aithal GP, Day CP et al. (І999). "Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications." Lancet 353(9І54): 7І7-9.
3. Anderson JL, Horne BD et al. (2007). "Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation." Circulation 116(22): 2563-70.
4. Ansell J, Hirsh J et al. (200S). "Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)." Chest 133(6 Suppl): 160S-198S.
5. Bodin L, Verstuyft C et al. (2005). "Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocouma-rol sensitivity." Blood 106(1): І35-40.
6. Bouman HJ, Schomig E et al. (20ІІ). "Paraoxonase-1 is a major determinant of clopidogrel efficacy." Nat Med 17(1): ІІ0-6.
7. Caraco Y, Blotnick S et al. (200S). "CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study." Clin Pharmacol Ther 83(3): 460-70.
S. Cha PC, Mushiroda T et al. (20І0). "Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese." Hum Mol Genet 19(23): 4735-44.
9. Chen BL, Zhang W et al. (200S). "Inhibition of ADP-induced platelet aggregation by clopidogrel is related to CYP2C19 genetic polymorphisms." Clin Exp Pharmacol Physiol 35(8): 904-8.
10. Collet JP, Hulot JS et al. (2009). "Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study." Lancet 373(9660): 309-І7.
11. Ellis KJ, Stouffer GA et al. (2009). "Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations." Pharmacogenomics 10(11): 1799-817.
12. Feher G, Koltai K et al. (2007). "Clopidogrel resistance: role of body mass and concomitant medications." Int J Cardiol 120(2): 188-92.
13. Fernando H, Dart AM et al. (20ІІ). "Proton pump inhibitors, genetic polymorphisms and response to clopidogrel therapy." Thromb Haemost 105(6).
14. Frere C, Cuisset T et al. (2009). "The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome." J Thromb Haemost 7(8): І409-ІІ.
15. Gage BF, Eby C et al. (2008). "Use of pharmacogenet-ic and clinical factors to predict the therapeutic dose of warfarin." Clin Pharmacol Ther 84(3): 326-3І.
16. Gage BF, Eby C et al. (2004). "Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin." Thromb Haemost 91(1): 87-94.
17. Geisler T, Schaeffeler E et al. (2008). "CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation." Pharmacogenomics 9(9): І25І-9.
18. Giusti B, Gori AM et al. (2009). "Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis." Am J Cardiol 103(6): 806-ІІ.
19. Gladding P, Webster M et al. (2008). "Antiplatelet drug nonresponsiveness." Am Heart J 155(4): 59І-9.
20. Gladding P, Webster M, et al. (2008). "The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial." JACC Cardiovasc Interv 1(6): 620-7.
21. Gurbel PA and Tantry US (2006). "Aspirin and clopidogrel resistance: consideration and management."
J Interv Cardiol І9(5): 439-48.
22. Hemeryck A and Belpaire FM (2002). "Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update." Curr Drug Metab 3(1): 13-37.
23. Hillman MA, Wilke RA et al. (2005). "A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data." Clin Med Res 3(3): 137-45.
24. Hulot JS, Bura A et al. (2006). "Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects." Blood 108(7): 2244-7.
25. James AH, Britt RP et al. (1992). "Factors affecting the maintenance dose of warfarin." J Clin Pathol 45(8): 704-6.
26. Kim KA, Park PW et al. (2008). "The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance." Clin Pharmacol Ther 84(2): 236-42.
27. King CR, Deych E et al. (2010). "Gamma-glutamyl carboxylase and its influence on warfarin dose." Thromb Haemost 104(4): 750-4.
28. Klein TE, Altman RB et al. (2009). "Estimation of the warfarin dose with clinical and pharmacogenetic data." N Engl J Med 360(8): 753-64.
29. Manolopoulos VG (2007). "Pharmacogenomics and adverse drug reactions in diagnostic and clinical practice." Clin Chem Lab Med 45(7): 801-14.
30. Manolopoulos VG, Ragia G et al. (2010). "Pharmacogenetics of coumarinic oral anticoagulants." Pharmacogenomics 11(4): 493-6.
31. Mega JL, Close SL et al. (2009). "Cytochrome p-450 polymorphisms and response to clopidogrel." N Engl J Med 360(4): 354-62.
32. Mega JL, Close SL et al. (2009). "Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes." Circulation 119(19): 2553-60.
33. Musunuru K (2011). "Current Role of Pharmacogenomics in Cardiovascular Medicine." Curr Treat Options Cardiovasc Med DOI10.1007/s11936-0ІІ-0І29-6.
34. Nunnelee JD (2009). "Review of an Article: The international Warfarin Pharmacogenetics Consortium (2009). Estimation of the warfarin dose with clinical and pharmacogenetic data. NEJM 360 (8): 753-64." J Vasc Nurs 27(4): 109.
35. Pirmohamed M (2006). "Warfarin: almost 60 years old and still causing problems." Br J Clin Pharmacol 62(5): 509-11.
36. Price MJ (2009). "Bedside evaluation of thieno-pyridine antiplatelet therapy." Circulation 119(19): 2625-32.
37. Ragia G, Arvanitidis KI et al. (2009). "Need for reassessment of reported CYP2C19 allele frequencies in various populations in view of CYP2C19*17 discovery: the case of Greece." Pharmacogenomics 10(1): 43-9.
38. Reaume KT, Regal RE et al. (2008). "Indications for dual antiplatelet therapy with aspirin and clopidogrel: evidence-based recommendations for use." Ann Pharmacother 42(4): 550-7.
39. Rocca B and Patrono C (2005). "Determinants of the interindividual variability in response to antiplatelet drugs." J Thromb Haemost 3(8): 1597-602.
40. Rost S, Fregin A et al. (2004). "Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2." Nature 427(6974): 537-41.
41. Sagreiya H, Berube C et al. (2010). "Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9." Pharmacogenet Genomics 20(7): 407-13.
42. Schalekamp T, Brasse BP et al. (2007). "VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement." Clin Pharmacol Ther 81(2): 185-93.
43. Schwarz UI, Ritchie MD et al. (2008). "Genetic determinants of response to warfarin during initial anticoagulation." N Engl J Med 358(10): 999-1008.
44. Sconce EA, Khan TI et al. (2005). "The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen." Blood 106(7): 2329-33.
45. Sibbing D, Koch W et al. "Cytochrome 2C19*17 Allelic Variant, Platelet Aggregation, Bleeding Events, and Stent Thrombosis in Clopidogrel-Treated Patients With Coronary Stent Placement." Circulation 121(4): 512-8.
46. Sibbing D, Koch W et al. (2010). "Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement." Circulation 121(4): 512-8.
47. Sibbing D, Koch W et al. (2011). "No association of
paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting." Eur Heart J
DOI:10.1093/eurheartj/ehr155
48. Sim SC, Risinger C et al. (2006). "A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants." Clin Pharmacol Ther 79(1): 103-13.
49. Simon DI and Jozic J (2008). "Drug-eluting stents and antiplatelet resistance." Am J Cardiol 102(9 Suppl): 29J-37J.
50. Squassina A, Manchia M et al. (2010). "Realities and expectations of pharmacogenomics and personalized medicine: impact of translating genetic knowledge into clinical practice." Pharmacogenomics 11(8): 1149-67.
51. Stehle S, Kirchheiner J et al. (2008). "Pharmacogenetics of oral anticoagulants: a basis for dose individualization." Clin Pharmacokinet 47(9): 565-94.
52. Takeuchi F, McGinnis R et al. (2009). "A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose." PLoS Genet 5(3): e1000433.
53. Teichert M, Eijgelsheim M et al. (2009). "A genome-wide association study of acenocoumarol maintenance dosage." Hum Mol Genet 18(19): 3758-68.
54. Thomas D and Giugliano RP (2008). "Antiplatelet therapy in early management of non-ST-segment elevation acute coronary syndrome: the 2002 and 2007 guidelines from North America and Europe." J Cardiovasc Pharmacol 51(5): 425-33.
