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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.
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