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STATE-OF-THE-ART PAPER

Pharmacogenetics in Cardiovascular Antithrombotic Therapy

Francisco Marín, MD, PhD^_*, Rocío González-Conejero, PhD, Piera Capranzano, MD, Theodore A. Bass, MD, Vanessa Roldán, MD, PhD and Dominick J. Angiolillo, MD, PhD^,_*

^_* Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
Centro de Hemodonación, Universidad de Murcia, Murcia, Spain
Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida

Manuscript received December 23, 2008; revised manuscript received March 25, 2009, accepted April 14, 2009.

^_* Reprint requests and correspondence: Dr. Dominick J. Angiolillo, Division of Cardiology, University of Florida College of Medicine-Jacksonville, 655 West 8th Street, Jacksonville, Florida 32209 (Email: Dominick.angiolillo{at}jax.ufl.edu).

	Abstract

Top Abstract Search Strategy and Selection... Pharmacogenetics: A Brief... Antiplatelet Agents Anticoagulants Fibrinolytic Drugs Conclusions References

 
Thrombosis is the most important underlying mechanism of coronary artery disease and embolic stroke. Hence, antithrombotic therapy is widely used in these scenarios. However, not all patients achieve the same degree of benefit from antithrombotic agents, and a considerable number of treated patients will continue to experience a new thrombotic event. Such lack of clinical benefit may be related to a wide variability of responses to antithrombotic treatment among individuals (i.e., interindividual heterogeneity). Several factors have been identified in this interindividual heterogeneity in response to antithrombotic treatment. Pharmacogenetics has emerged as a field that identifies specific gene variants able to explain the variability in patient response to a given drug. Polymorphisms affecting the disposition, metabolism, transporters, or targets of a drug all can be implicated in the modification of an individual's antithrombotic drug response and therefore the safety and efficacy of the aforementioned drug. The present paper reviews the modulating role of different polymorphisms on individuals' responses to antithrombotic drugs commonly used in clinical practice.

Key Words: pharmacogenetics • polymorphism • antithrombotic therapy

Abbreviations and Acronyms   ACS = acute coronary syndrome   ADP = adenosine diphosphate   COX = cyclooxygenase   CYP = cytochrome P450   FXIII = factor XIII   GP = glycoprotein   HIT = heparin-induced thrombocytopenia   HR = hazard ratio   INR = international normalized ratio   LMWH = low molecular weight heparin   MDR = multidrug resistance-associated protein   MI = myocardial infarction   PCI = percutaneous coronary intervention   VKA = vitamin K antagonist   VKOR = vitamin K epoxide reductase   VKORC1 = vitamin K epoxide reductase subunit 1

Pharmacogenetics has emerged as a field that tries to identify specific gene variants that are able to explain the variability in patient response to a given drug. This variability may explain the efficacy of a specific drug in a given patient as well as its adverse side effects (9). Polymorphisms affecting genes that encode disposition, metabolism, transporters, or targets of the drug can all potentially modify an individual's response to one therapy and thus explain its efficacy and safety profiles (10). Because such interindividual heterogeneity in antithrombotic drug response is less complex than the risk of developing cardiovascular diseases, the role of a single functional polymorphism affecting any step modulating the pharmacokinetics or pharmacodynamics of a drug could potentially be more relevant.

Thrombosis is the most important underlying mechanism of coronary artery disease and embolic stroke. Hence, numerous agents with antithrombotic properties, including platelet inhibitors, antithrombins, oral anticoagulants, and fibrinolytics, are commonly used in the treatment of cardiovascular disease (11–13). Clinical outcomes associated with antithrombotic drug usage are not homogeneous, and an important proportion of treated patients will continue to experience a new thrombotic event. Several factors (age, renal and liver function, metabolic disorders such as diabetes mellitus, and lifestyle variables such as smoking) have been identified as being involved in this interindividual heterogeneity. However, these factors cannot fully explain the variable interindividual response profiles, suggesting that factors intrinsic to the patient, such as his or her genetic makeup, may be involved. This paper reviews the influence of genetic polymorphisms on antithrombotic drug efficacy.

	Search Strategy and Selection Criteria

Top Abstract Search Strategy and Selection... Pharmacogenetics: A Brief... Antiplatelet Agents Anticoagulants Fibrinolytic Drugs Conclusions References

 
Published data for this review were identified by searches in MEDLINE and reference lists from relevant articles. Searches were concentrated on the following key words: pharmacogenetic, pharmacogenomic, antiplatelet agents, aspirin, clopidogrel, ticlopidine, GP IIb/IIIa inhibitors, heparin, oral anticoagulants, dicoumarins, warfarin, fibrinolytic drugs, genetic, genes, and polymorphism. Representative studies of various reviews about pharmacogenomics, pharmacogenetics, and antithrombotic drugs also were included.

	Pharmacogenetics: A Brief Overview

Top Abstract Search Strategy and Selection... Pharmacogenetics: A Brief... Antiplatelet Agents Anticoagulants Fibrinolytic Drugs Conclusions References

 
Pharmacogenetics is the study of how genetic differences influence the variability in patients' responses to drugs (14). Most genetic changes involved in pharmacogenetics are common polymorphisms. Certainly, genetic polymorphism could also explain the individual risk of developing an adverse drug reaction or drug inefficacy (9,15).

Candidate genes encode proteins involved in different pathways of a given treatment (16). Therefore, polymorphisms can influence drug metabolism by modifying the function of drug-metabolizing enzymes (17). In this case, candidate polymorphisms shall determine the extent of the metabolism and, as a consequence, the same administered dose may reach therapeutic levels in some individuals but not in others. In the latter case, this may either be responsible for supratherapeutic levels of a given drug (thus exceeding safety margins and increasing the risk of adverse effects or toxicity) or infratherapeutic levels (thus patients continue to be exposed to the risks related to the disease process for which a given drug was prescribed). However, polymorphisms also could modify the pharmacokinetics of a given drug by affecting its binding capacity to target proteins as carriers or receptors (18).

Absorption, distribution, excretion, and targeting to the site of action also can be influenced, thus modulating the ultimate pharmacological response to the drug (19). Finally, polymorphisms that affect the level or function of the target of the treatment might also influence the effectiveness of such therapy. The study of pharmacogenetics encompasses the search for answers to the hereditary basis for interindividual differences in drug response with the ultimate goal of personalized therapy selection to reduce the incidence of adverse drugs reactions and improve treatment efficacy (10,20).

	Antiplatelet Agents

Top Abstract Search Strategy and Selection... Pharmacogenetics: A Brief... Antiplatelet Agents Anticoagulants Fibrinolytic Drugs Conclusions References

 
The pivotal role of the platelets in the pathogenesis of atherothrombosis emphasizes the importance of early and sustained antiplatelet therapy. Unfortunately, there are limitations to currently approved antiplatelet agents, and a considerable number of treated patients will experience a new thrombotic event despite being on recommended treatment regimens, giving rise to the concept of antiplatelet drug resistance (21). The definition of antiplatelet drug resistance is controversial; thus, the reported prevalence varies widely, depending on laboratory methods used and/or the population studied (22). Several clinical (age, other underlying comorbidities such as diabetes, lifestyle variables such as smoking, and importantly compliance) and cellular (increased platelet turnover, up-regulation of platelet-signaling pathways, drug–drug interactions) factors have been involved in this interindividual response heterogeneity. Genetic factors also have been implicated as having an important role in patient response to antiplatelet drugs (23,24). Importantly, the majority of candidate genes in antiplatelet drug resistance are also implicated in the pre-existent variability in platelet function (25). Although it has been proposed that antiplatelet resistance confers a worse prognosis, perhaps it may indicate pre-existing greater risk (26).

The most relevant proteins involved in platelet function and platelet hyper-reactivity are those expressed on the platelet surface. These proteins play a key role in the steps of platelet adhesion, activation, and aggregation. The glycoprotein (GP) IIb/IIIa receptor is among the most important platelet complexes, as demonstrated by the severe bleeding associated with deficiency of these proteins (27). The platelet GP IIb/IIIa receptor plays a pivotal role in platelet activation and aggregation by binding fibrinogen and von Willebrand factor. Many antiplatelet therapies have this complex directly or indirectly as their main target. The GP IIb/IIIa complex is highly polymorphic. The most studied polymorphism affecting this complex is the Pl^A polymorphism of the GP IIIa subunit, which is responsible for the Pro33Leu amino acid change. It has been suggested that this polymorphism modulates platelet function and, in particular, the Pl^A2 allele is associated with increased platelet reactivity (28).

A second complex in the platelet surface that plays a key role in platelet adhesion is the high-affinity receptor for collagen, the GP Ia/IIa complex. Some polymorphisms have been identified that affect the structure and density of this complex on the platelet surface. The most relevant is C807T (Phe 224), which, albeit being a silent polymorphism affecting the Ia subunit, is associated with variations in expression of the whole receptor on the platelet surface (29). Thus, the 807T allele, which is associated with up to 10 times more expression of this receptor, might affect platelet function and could modify the effect of antiplatelet drugs. Finally, other antiplatelet therapies target platelet receptors such as the adenosine diphosphate (ADP) receptor or the generation of compounds relevant for secondary activation pathways. Table 1 summarizes pharmacogenetic studies on antiplatelet agents.

Unfortunately, the definition of aspirin resistance remains controversial (37), and the reported range of aspirin resistance varies broadly, from 5% to 40%, depending on the assay used for identification and the population studied (38,39). However, strictly speaking the term "resistance" refers to the inability of an antiplatelet agent to block its target. Thus, aspirin resistance should be defined as the failure of aspirin to block arachidonic acid-induced platelet aggregation, inhibiting platelet thromboxane A₂ production mediated by COX-1 (40).

Several laboratory assays are available to test for aspirin effects: light transmittance aggregometry, Platelet Function Analyzer (PFA)-100 (Dade Behring, Deerfield, Illinois), VerifyNow-ASA assay (Accumetrics, San Diego, California), thromboelastography, or the determinations of serum thromboxane B₂ levels or its urinary metabolite 11-dehydro-thromboxane B₂ (22,41). Controversial data have been recently published regarding the real prevalence of aspirin resistance when it is assessed by methods that directly indicate the degree of platelet COX-1 inhibition (42). In fact, studies (43–45) in which the authors used COX-1–specific assays have shown that the prevalence of aspirin resistance is extremely low (<5%).

Importantly, poor compliance of the patient to treatment has been identified as a primary cause of resistance (42). Nevertheless, the authors of several studies (36,46–48) have shown a relationship between markers of residual platelet activation determined by assays that are not highly COX-1–specific and the risk of new ischemic events or cardiovascular death. Aspirin in fact has been suggested to have COX-1–independent effects, which may be subject to more interindividual variability and may explain the adverse outcomes among patients with high platelet reactivity (22,44).

Many mechanisms could be related to aspirin resistance (49). Clinical factors, including poor patient compliance, drug-absorption abnormalities, or drug–drug interactions, play a role (50). Importantly, ibuprofen blocks the inhibition of serum thromboxane B₂ formation and platelet aggregation by aspirin (51). Other conditions and entities associated with enhanced platelet reactivity can modify responsiveness (i.e., acute coronary syndrome, congestive heart failure, dyslipidemia, or exercise) (23). Different cellular factors have been proposed to influence aspirin efficacy, such as inadequate suppression of platelet COX-1 due to increased platelet turnover, overexpression of COX-2 mRNA, erythrocyte–platelet interaction, catecholamine levels, or the generation of 8-iso-PGF₂ (23).

Genetic background also could play a role in interindividual response to antiplatelet drugs, which raises the putative number of candidate polymorphisms that could be involved in the aspirin resistance phenomenon. Several of these have been investigated, as summarized in Table 1. The authors of different studies (28,52–56) support that the Pl^A polymorphism may account for differences in aspirin-induced effects. Apparently, carriers of the Pl^A2 allele would require a greater dose of aspirin to experience the same antiaggregant effect as do subjects with a Pl^A1 homozygous genotype and have an increased risk of cardiovascular thrombosis (49,52,56–58). It is also interesting to point out that some reports found a significant association between the Pl^A2 allele and aspirin resistance in complications after coronary angioplasty (59,60) or after coronary stent implantation (61–63).

The authors of one study (29) investigated the relevance of the GP Ia C807T polymorphism, which is associated with the expression of this collagen receptor on the platelet surface. However, in most studies (45,53,64,65) performed either in patients or healthy control subjects, the authors did not find an association with aspirin resistance. However, it has been observed that the C807T polymorphism and another polymorphism of GP Ia, G873A, could be independently related with greater platelet reactivity in patients under dual antiplatelet therapy (66,67).

Understanding the role of polymorphisms affecting the target of aspirin, the COX-1 enzyme, is also of importance. Interestingly, some polymorphisms of the COX-1 gene could modify the activity of the enzyme, having an influence on aspirin dose requirements (68,69). Hence, our group has found that the COX-1 C50T polymorphism is associated with thromboxane B₂ levels before and after aspirin treatment in healthy subjects (44). Importantly, high levels of this metabolite have shown to be a good marker of thrombotic risk in patients treated with aspirin (70). The potential influence of polymorphisms of the COX-2 enzyme on aspirin response was evaluated. A recent Japanese study (71) did not find any influence of COX-1 or -2 polymorphisms on platelet responsiveness, but the authors did not find any patients with the C50T polymorphism. This polymorphism also was not found in a Chinese population (72).

These findings underscore the importance of defining ethnicity in pharmacogenetic analyses. Moreover, a functional polymorphism of the COX-2 (G-765C) enzyme also might be relevant in aspirin resistance (73). We found a significant association between the COX-2 G-765C polymorphism and the efficiency of reduction of thromboxane B₂ after aspirin treatment (45). Additional studies should be performed to confirm such associations and to evaluate the role of these polymorphisms in thromboembolic disease of patients treated with aspirin.

Other polymorphisms investigated include a C893T polymorphism in the ADP subtype P2Y₁ receptor, but without a clear mechanism involved (74). More recently, the presence of the P2Y₁ 893CC genotype appears to confer an attenuated antiplatelet effect during aspirin treatment in healthy Chinese volunteers (72). However, these findings have not been confirmed in other studies (64,75).

Ultimately, it is important to note that factors extrinsic to the platelet, such as hemostatic factors, may affect platelet function. Therefore, aspirin also may have different degrees of efficacy according to hemostatic polymorphisms. The Val34Leu polymorphism is a functional genetic change affecting the activation of factor XIII (FXIII), its transglutaminase activity, and the structure of the clot. It has been shown that inhibition of FXIII activation by aspirin is enhanced in the Leu34 carriers, suggesting that these subjects might benefit more than the Leu34-negative subjects from the reduction in risk for MI with low-dose aspirin (76).

In conclusion, several genetic polymorphisms have been proposed to influence aspirin response and contribute to poor prognosis. Of these, the Pl^A polymorphism appears to have the most robust evidence, whereas this is not as sound with other COX-1, COX-2, and GP Ia polymorphisms.

Thienopyridine derivates.   Ticlopidine and clopidogrel are thienopyridine derivates that irreversibly inhibit the ADP P2Y₁₂ receptor on the platelet surface (77,78). Although ticlopidine has been prescribed in different cardiovascular disease manifestations, it has been mainly assessed in combination with aspirin in patients undergoing percutaneous coronary intervention (PCI) (79). However, the more favorable safety profile of clopidogrel (80) has made it the thienopyridine of choice, mainly as an adjunctive antithrombotic treatment with aspirin to prevent thrombotic events after an acute coronary syndrome (ACS) and after coronary stent implantation, in particular with drug-eluting stents (81–84). Accumulating data have shown that there is a wide variability in response profiles among clopidogrel-treated individuals (85). Similarly to aspirin, several methods have been used to assess clopidogrel-induced antiplatelet effects (85). Unfortunately, standardized definitions of antiplatelet drug responsiveness are lacking. Nevertheless, there are consistent data that patients who persist with increased platelet reactivity despite clopidogrel, also coined as suboptimal clopidogrel responders or clopidogrel-resistant patients, have an increased risk of ischemic events, including stent thrombosis (86). Recent findings (87,88) have shown that a considerable number of patients who are resistant to clopidogrel also may be resistant to aspirin, which further increases their risk of thrombotic complications.

There are no specific pharmacogenetic studies on ticlopidine. Most studies were developed under other antiplatelet agents, and the results are certainly conflicting (60,61), as shown in Table 1. Interestingly, nonresponders to clopidogrel and ticlopidine are relatively infrequent, suggesting that poor response to thienopyridines may be related to a drug-specific mechanism (89).

Clopidogrel is a pro-drug requiring oxidation by the hepatic cytochrome P450 (CYP) system to generate an active metabolite (85). In particular, approximately 85% of a clopidogrel dose is hydrolyzed by esterases into an inactive metabolite, whereas the remaining dose is converted into the active metabolite in a process, which requires 2 sequential CYP-dependent steps. CYP3A4, CYP3A5, CYP2C9, and CYP1A2 are involved in one step; CYP2B6 and CYP2C19 are involved in both steps (90). Therefore, it was hypothesized (85) that genetic variations of one or more of these enzymes influences clopidogrel's antiplatelet effects (Fig. 1).

View larger version (62K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Genetic Targets Potentially Modulating Clopidogrel-Induced Antiplatelet Effects Clopidogrel is a pro-drug that, after intestinal absorption, is metabolized in the liver by cytochrome (P450 CYP) system to generate an active metabolite. The active metabolite then irreversibly inhibits the platelet P2Y12 receptor, which in turn blocks platelet activation and subsequent aggregation ultimately mediated by the glycoprotein (GP) IIb/IIIa receptor. Genetic polymorphisms of targets in this metabolic pathway may all potentially influence clopidogrel-induced antiplatelet effects. Of these, the genetic variations of CYP enzymes, in particular 2C19, which is involved in both metabolic steps and strongly modulates the generation of clopidogrel's active metabolite, seem to be the most important. MDR = multidrug resistance-associated protein.

Fontana et al. (93) confirmed these findings in a healthy volunteer population but failed to find any influence of this polymorphism on clopidogrel response when studied in patients with coronary artery disease (94). However, the latter was performed in a relatively small cohort of patients, and numerous cohort studies (95–100) confirmed the modulating effect of the CYP2C19*2 loss-of-function allele on clopidogrel response as assessed by various pharmacodynamic measurements.

The greater prevalence of the CYP2C19*2 loss-of-function allele among Asian subjects may explain why the prevalence of suboptimal clopidogrel responders is greater in Japanese patients than in Caucasian ones (96). Geisler et al. (97) showed that prediction of responsiveness after clopidogrel loading dose may substantially be improved by adding CYP2C19*2 genotype to nongenetic risk factors. In addition to pharmacodynamic studies, pharmacokinetic analyses (98) have confirmed the role of the CYP2C19 gene on clopidogrel response and have shown it to be associated with variations in the plasmatic levels of clopidogrel's active metabolite. The latter study failed to show an impact of this polymorphism on the plasmatic levels of prasugrel, a third-generation thienopyridine with more efficient pharmacokinetic, and consequently pharmacodynamic, profiles (98,99). In a recent study, Trenk et al. (100) showed that patients carrying at least one CYP2C19*2 allele are more prone to high-on clopidogrel platelet reactivity, which was associated with poor clinical outcome after coronary stent placement.

More recently, 4 large-scale studies (101–104) have confirmed the prognostic implications of the CYP2C19 polymorphism in clopidogrel-treated patients. In a predefined subgroup analysis of the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38) trial (101,105), which showed significantly improved clinical outcomes in patients (n = 13,608) with moderate- to high-risk ACS undergoing PCI who were administered prasugrel compared with clopidogrel, a subgroup underwent genetic testing (n = 1,477) (101). Carriers of the CYP2C19 reduced function allele, which is present in 30% of the study population, had a 53% relative increased risk of the composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke (12.1% vs. 8.0%; hazard ratio [HR]: 1.53, 95% confidence interval: 1.07 to 2.19; p = 0.014). These patients also had a >3-fold risk of stent thrombosis.

These outcomes are attributed to the markedly diminished pharmacokinetic and pharmacodynamic responses to clopidogrel associated with CYP2C19 polymorphisms (101). Pharmacokinetic and pharmacodynamic responses to prasugrel as well as clinical outcomes were not affected by CYP2C19 polymorphisms associated with reduced clopidogrel metabolism (101). Authors examining a French registry of MI (102) showed an increased event rate (adjusted HR: 1.98) that was more pronounced in the subgroup that underwent PCI (adjusted HR: 3.58). In another study (103), the influence of CYP2C19 polymorphisms was assessed in a selected population of young patients who survived a first MI; results showed an independent association with cardiovascular events. Finally, another recent study (104) demonstrated an association between CYP2C19 and stent thrombosis.

CYP3A4 plays a pivotal role in CYP system; therefore, the role of genetic variants of this enzyme on clopidogrel response was the first to evaluated (106). In particular, 5 CYP3A4 polymorphisms were studied in patients with coronary artery disease before and after a 300-mg loading dose as well as in the chronic phase of clopidogrel therapy. Of the 5 polymorphisms, only 1 (IVS10+12G>A) was associated with variable degrees of clopidogrel response, as assessed by measures of platelet activation but not aggregation (106). However, a lack of modulation effects of the IVS10+12G>A polymorphism on platelet aggregation was observed by others (107). The possible influence of CYP3A5 on prognosis has been assessed, without showing any significant influence (102).

The absorption of clopidogrel and thereby active metabolite formation have shown to be diminished by P-GP–mediated efflux and to be influenced by the multidrug resistance-associated protein (MDR)-1 C3435T genotype (108). Interestingly, this polymorphism has been associated with a greater rate of cardiovascular events at 1 year (102). Pharmacodynamic differences have shown to be associated with the MDR1 C1236T (rs1128503) genotype after a high (600-mg) but not standard (300-mg) clopidogrel loading dose regimen, suggesting that the capacity to absorb greater concentrations of clopidogrel varies among individuals and may be genetically determined (109).

However, changes in genes encoding platelet glycoprotein also have been explored. Indeed, the first study to evaluate the presence of a pharmacogenetic modulation of clopidogrel response was performed by Angiolillo et al. (110), in which the Pl^A polymorphism was considered as the genetic target. Platelet activation before and after a 300-mg loading dose of clopidogrel was assessed in aspirin-treated patients undergoing PCI. The study confirmed the modulating effects of this polymorphism on aspirin-induced effects and showed that platelet activation was significantly attenuated (35% less inhibition) in Pl^A2 carriers compared with the Pl^A1/A1 genotype (110). At 24 h, GP IIb/IIIa activation persisted significantly greater in Pl^A1/A2 patients (110). However, the modulating effects of the Pl^A polymorphism on clopidogrel response are limited to the acute phase of treatment, as no differences were observed in patients on maintenance therapy (111). The latter finding was also confirmed by Cooke et al. (54).

The effect of polymorphisms of other platelet membrane receptors on clopidogrel response has also been evaluated. The role of the GP Ia C807T polymorphism on modulating platelet function in patients undergoing coronary stenting receiving a 300-mg clopidogrel loading dose was also analyzed by our group (112). The T allele of the GP Ia gene was shown to modulate platelet aggregation and clopidogrel antiplatelet effects. These findings were confirmed in a larger cohort of stable patients in the chronic maintenance phase of clopidogrel therapy (66) as well as those presenting with an ACS (67). Overall, these findings suggest an enhanced reactivity to fibrillar collagens, typically exposed during coronary stenting, in T-allele carriers and might contribute to the increased thrombotic risk observed in these patients (113,114). However, the modulating effects of the GP Ia C807T polymorphism on clopidogrel response were not confirmed by Cuisset et al. (65). Another potential target modulating the effects of clopidogrel is the protease-activated receptor-1, the receptor for thrombin on the platelet surface. Smith et al. (115) showed the intervening sequence-14 A>T dimorphism of protease-activated receptor-1 to be associated with greater platelet reactivity before and after clopidogrel administration.

Because the ADP P2Y₁₂ receptor is the target for the active metabolite of clopidogrel, the authors of several studies have investigated the potential role of gene sequence variations of this receptor on clopidogrel responsiveness. Fontana et al. (116) identified 5 frequent polymorphisms, of which 4 were in total linkage disequilibrium leading to 2 haplotypes (H1 and H2). The H2 haplotype was associated with enhanced ADP-induced platelet aggregation in a cohort of nonmedicated, healthy volunteers. In case-control studies in which platelet aggregation was not assessed, this haplotype was associated with the presence of coronary artery disease (117) and peripheral arterial disease (118). Numerous other investigations (87,102,107,119–121) have therefore evaluated the functional implications of gene sequence variations of the P2Y₁₂ receptor in patients with coronary artery disease treated with clopidogrel in both the acute (i.e., after a loading dose) and chronic (i.e., during maintenance therapy) phases of treatment. However, none of these studies showed any functional impact of genetic variations of the P2Y₁₂ receptor on clopidogrel response or impact on clinical outcomes.

In conclusion, there are consistent data that relate clopidogrel variability response to hepatic CYP polymorphisms, mainly, the CYP2C19 loss-of function polymorphism. Importantly, in addition to modulation of pharmacodynamic and pharmacokinetic profiles, this polymorphism has also been associated with greater ischemic event rates, including stent thrombosis. These findings have led many to suggest genetic testing for this polymorphism as a screening measure for clopidogrel response. Point-of-care assays are currently under development to allow rapid genetic testing for this polymorphism.

The GP IIb/IIIa receptor inhibitors.   The relevance of the GP IIb/IIIa complex in platelet activation and aggregation supports the development of intravenous GP IIb/IIIa receptor inhibitors as potent antiplatelet drugs (122). These drugs have consistently demonstrated their utility in high-risk patients with ACS, especially those who undergo early PCI (123). The role of polymorphisms, specifically affecting the target of these agents, has been investigated in this setting (Table 1). Most studies have evaluated the role of the Pl^A polymorphism on the antiplatelet effects of GP IIb/IIIa agents and have obtained controversial results. Some reports (28,124) suggest that GP IIb/IIIa antagonists have lower platelet-inhibiting effects in carriers of the Pl^A2 allele. These findings are in line with the worse clinical outcomes and the greatest rates of in-stent restenosis observed in Pl^A2 carrier patients treated with these agents (62). In contrast, other studies (125–128) found no significant effect of Pl^A genotype in platelet inhibition or in myocardial reperfusion (129).

Oral GP IIb/IIIa inhibitors have not demonstrated any beneficial effect in ACS (130,131). A significant interaction with the Pl^A polymorphism has been suggested to be one of the causes leading to failure of these drugs (132,133). An adverse interaction was observed between Pl^A2 allele and orbofiban therapy (133). In particular, this finding suggests that slight differences in receptor structure, a change of a proline in place of a leucine at position 33 of GP IIIa, may influence the response to specific GP IIb/IIIa inhibitors, not only attenuating any beneficial effect but also contributing to the increase of deleterious responses.

	Anticoagulants

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Unfractionated heparin and low molecular weight heparin (LMWH).   Most pharmacogenetic analyses on heparin (134) have been related to heparin-induced thrombocitopenia (HIT) and its thromboembolic complications (Table 2). Recently, it has been proposed that the Pl^A2 polymorphism of the GPIIIa gene may modulate the pro-thrombotic effects of HIT (135). However, data on this association are not consistent (136). There are also controversial data regarding the association between platelet FcRIIA H131R and platelet factor 4 polymorphisms with HIT (137–140), whereas the association of hemostatic polymorphisms with thromboembolic complications is certainly weak (136).

Oral anticoagulants.   In 2003, 21.2 million people were prescribed warfarin for various indications (MI, atrial fibrillation, stroke, prosthetic heart valve replacement, venous thrombosis, and major surgery). However, major bleeding remains a feared adverse effect, especially during the first weeks of treatment. Vitamin K antagonists (VKAs) in general are characterized by a marked interpatient and intrapatient variability, which makes it difficult to determine the effective dosage. It is well known that the maintenance dose of VKAs is influenced by different acquired factors, such as race, dietary vitamin K intake, comorbid conditions, acute illness, or comedications (142). Recent advances in pharmacogenetics have been made, and pharmacogenetic-based VKA therapy could potentially improve the safety and effectiveness of these drugs (143).

The final objective of VKAs consists of decreasing the amount of reduced vitamin K available for the carboxylation of clotting factors II, VII, IX, and X (144). This is the reason that the administration of vitamin K is the antidote for coumarinics toxicity. Vitamin K-dependent proteins require carboxylation of key glutamic acid residues for exerting their activity (145). As a result of the overall scarcity of vitamin K in cells, vitamin K epoxide, generated as a product of gamma-carboxylation, must be rapidly recycled to reduced form (KH₂) to sustain further gamma-carboxylation reactions. The set of sequential reactions that guarantees vitamin K recycling is known as the vitamin K cycle (Fig. 2) (146). The enzyme that usually catalyzes the carboxylation reaction is a vitamin K-dependent gamma-glutamil carboxylase, and the enzyme responsible for the regeneration of vitamin K from vitamin K epoxide is vitamin K epoxide reductase (VKOR). The identification of the VKOR gene remained elusive until 2004, when 2 laboratories using different approaches (147,148) cloned it. Thus, they found that mutations in VKOR occurred in 2 families with defective vitamin K-dependent clotting factors, in 4 families with hereditary warfarin resistance, and in several rat strains with resistance to warfarin-like poisons. These studies discovered VKOR to be the target of VKAs.

View larger version (64K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Vitamin K Cycle The vitamin K cycle regenerates the reduced form of vitamin K from its epoxide form through the vitamin K epoxide reductase (VKOR). Reduced vitamin K is necessary for post-translational gamma-carboxylation of glutamic acid residues of the vitamin K-dependent coagulation factors FII, FVII, FIX, and FX and proteins C, S, and Z. Gamma-carboxylation is catalyzed by a gamma-glutamyl carboxylase and requires the reduced form of vitamin K, molecular oxygen, and carbon dioxide. Vitamin K antagonists (VKAs) produce their anticoagulant effect, interfering with VKOR activity.

It is well established that the in vivo elimination of VKAs is largely influenced by the CYP2C9 genotype. Of note, the decreased clearance caused by CYP2C9*2 and *3 alleles also has a significant clinical impact (151), so that these 2 polymorphisms have been associated with increased responsiveness to warfarin. Aithal et al. (152) compared control patients requiring a typical dose of warfarin with those who take 10.5 mg weekly. This second group showed a high risk of reaching a supratherapeutic international normalized ratio (INR) during the induction phase and a 4-fold risk of bleeding. Also, the presence of *2 and *3 variants in these patients was 6-fold more frequent. Similarly, the relationship of CYP2C9 genotype with bleeding complications, with the time to achieve the maintenance dose, and with overanticoagulation also has been established (153–155). Therefore, it has been shown that patients with at least 1 variant allele had not only an increased risk of a supratherapeutic INR, with the consequently increased risk of bleeding, but they also required more time to achieve a stable dose (153). This increased risk of bleeding appears during the warfarin initial treatment period but not during long-term therapy (156). Similar results have been obtained concerning other coumarin derivatives (157).

Target of VKAs: vitamin K epoxide reductase subunit 1 (VKORC1) genotype and interpatient variability.   Understanding why patients with the same CYP2C9 genotype have such a great standard deviation to the mean maintenance dose was critical. This was partly elucidated with the posterior discovery of the VKOR gene. It is now well established that common polymorphisms in regulatory regions of the VKOR gene correlate strongly with VKA response (Table 2). Rieder et al. (158) resequenced the VKOR gene in almost 200 European-American warfarin patients and identified 5 haplotypes in the VKOR subunit 1 (VKORC1) associated with warfarin dose requirements (Table 2). Among possible variations, a single allelic site, C1173T in intron 1, assigns European-American subjects to a high- or low-dose group 95% of the time. The molecular mechanism of this warfarin dose-response appears to be regulated at the transcriptional level.

Rieder et al. (158) found that VKORC1 mRNA levels varied according to the haplotype. This highly useful single polymorphism has been repeatedly shown to be associated with optimal coumarin anticoagulant dose in both European and Asian patients (159–162). There are 2 types of patients exhibiting a clinical phenotype that is compatible with partial-to-complete warfarin (or other coumarins) resistance; the most frequent corresponds to patients carrying the combination of VKORC1 haplotypes for high dose and CYP2C9*1*1 genotype, whose incidence has been calculated as 20% for Caucasian patients (163). Other less-frequent polymorphisms in VKOR, such as R98W, also can reduce VKORC1 activity (164). The second type of warfarin resistance is caused by single amino acid mutations like R58G, V29L, V45A, and L128R (164). These cases range from a very high dose of therapeutic warfarin (>40 mg/day) to complete failure to respond to therapy (147).

Toward personalized oral anticoagulation.   In a study including 297 patients with stable anticoagulation genotyped for both CYP2C9 and VKORC1 polymorphisms, a multivariate regression model including age and height produced a model for estimating warfarin dose of R² 55% (165). The performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose and modeling stable dose requirements based on clinical, physiologic, environmental, and genetic factors represents a promising strategic approach to predict individualized stable warfarin dose requirements (166,167). The initiation of VKA is associated with one of the highest adverse event rates for any single drug, and physicians often are reluctant to initiate therapy in elderly patients or patients at risk of bleeding (168). Up to one-half of patients with atrial fibrillation and no contraindication to warfarin therapy who are at high risk of stroke (annual risk >4%) are currently not receiving anticoagulant therapy because of the risk perceived to be associated with such therapy by both patients and health care providers (169).

The first month of anticoagulant therapy is especially problematic because the therapeutic dose is empirically assessed, and further adjustment is made on the basis of a trial-and-error strategy. This adjustment leads to the risk of overanticoagulation with potential bleeding complications or underanticoagulation with potential thrombotic events. In a study of approximately 300 patients starting warfarin therapy, the authors assessed the relationship between CYP2C9 genotypes and VKORC1 haplotypes to the INR responses that are used to adjust doses. Conversely to previous published data, the authors showed that VKORC1 haplotypes modulate the early response to warfarin and not CYP2C9 genotypes. VKORC1 haplotypes predict the time to reach a first therapeutic INR and the time to an INR >4. CYP2C9 genotypes only predict the time to a supratherapeutic INR (>4) (170).

As previously described, in extensively studied Caucasian populations, the CYP2C9 genotype predicts 10% of the interpatient variability in warfarin dose. Similarly, in Caucasian and Asian populations, the VKORC1 genotype predicts 25% of such variability. The importance of these strong genetic effects was recognized by recent relabeling of warfarin by the Food and Drug Administration to increase awareness in the clinical community (171). However, it is important to note that patient demographics, clinical factors, and established genetic variants combined only explain 45% to 55% of the total dose variation (Table 3 ) (171). Recently published studies in which the authors use a genome-wide scan strategy for common genetic variants potentially modulating warfarin response concluded that none of the other candidate genes (besides VKORC1 and CYP2C9) substantially influence such response (172,173).

The controversy about the relationship between these new genetic factors and the pharmacogenetics of VKA deserves further evaluation. New models will be forthcoming and will continue to evolve with data from large genome association studies and with the inclusion of acquired or environmental factors not considered to date. Importantly, it must be kept in mind that important pharmacogenetic differences also exist among VKAs (177). A recent study shows how clinical and genetic data from 4,043 patients were used to create a dose algorithm where genetic data were added to clinical variables (178). This pharmacogenetic approach produces recommendations that are significantly closer to the required therapeutic dose than if only clinical data or a fixed-dose were used, although the greatest benefits were observed in the approximately 50% of the population that required a greater or lesser warfarin dose than the mean. In any case, randomized, controlled trials are necessary to determine whether pharmacogenetic testing is worthwhile or which patients would better benefit by this strategy (178). In conclusion, pharmacogenetic studies can explain the heterogeneity to VKA response and may be potentially useful, particularly in patients at the 2 extremes of dose requirements.

	Fibrinolytic Drugs

Top Abstract Search Strategy and Selection... Pharmacogenetics: A Brief... Antiplatelet Agents Anticoagulants Fibrinolytic Drugs Conclusions References

 
Fibrinolytic therapy is used to achieve pharmacological reperfusion and restoration of flow of an acute coronary occlusion in patients with an acute ST-segment elevation MI (179), acute ischemic stroke (180), and pulmonary embolism (181). Indeed, fibrinolytic therapy leads to better survival, recovery of left ventricular function, and remodeling after acute MI (182–184). Thrombolytic therapy within 3 h of the onset of symptoms of ischemic stroke significantly reduced the number of patients experiencing the combined end point of death or dependency (185), and there is good evidence that thrombolytic therapy accelerates resolution of pulmonary embolism and results in more rapid hemodynamic improvement. The evidence that thrombolytic therapy improves clinical outcome is less evident (181).

Unfortunately, up to 40% of treated patients do not achieve optimal tissue perfusion (186), and the potential benefits are limited by early (thrombotic) reocclusion of the infarct-related artery (187). However, a few factors have been identified to be involved in this interindividual heterogeneity. They include age, delay between symptom onset and fibrinolytic therapy, smoking habits, and infarct size or site (188,189). During the last few years, interest has increased regarding initiatives that could improve the efficacy of fibrinolytic therapy, including pre-hospital fibrinolysis programs, the administration of new drugs (e.g., tenecteplase), or new pharmacological reperfusion strategies (e.g., half-dose fibrinolytic plus GP IIb/IIIa receptor blockade or adjunctive clopidogrel therapy) (190).

Only a few studies have analyzed the influence of genetic factors on the efficacy of fibrinolytic therapy (Table 2). One study (191) analyzed the role of the C-1562T polymorphism affecting the promoter region of the matrix metalloproteinase-9 gene in the hemorrhagic transformation of stroke after fibrinolytic therapy in 61 patients; the authors found no significant effect. Similarly, negative results were found when authors analyzed the relationship between Pl^A polymorphism and myocardial salvage after fibrinolysis (127,129). Again, negative findings were found when authors analyzed plasminogen activator inhibitor-1 4G/5G polymorphism (192,193).

The FXIII Val34Leu polymorphism is among the most relevant functional polymorphisms identified in the hemostatic system; thus, it plays a key role in the stability and structure of the fibrin clot. Therefore, polymorphisms of this gene have been evaluated in understanding variations in individual response to fibrinolytic therapy. Activated FXIII catalyses the formation of covalent gamma-glutamyl-gamma-lysine bonds between fibrin monomers, increasing the resistance of fibrin to degradation by plasmin (194,195). The Val34Leu polymorphism affects the function of FXIII by increasing the rate of FXIII activation by thrombin, which results in an increased and faster rate of fibrin stabilization (196,197). Moreover, interesting reports clearly demonstrated a different fibrin structure associated with the FXIII Val34Leu genotype (198). However, the thrombotic role of this polymorphism is controversial and might be population specific (198–201). The faster activation rate of the Leu34 variant and the different structure and resistance of the fibrin-bound clot observed in subjects carrying this allele encouraged the study of this polymorphism on fibrinolytic therapy (197).

In a small and retrospective cohort of patients after a premature MI, our group (202) observed that Leu34 allele carriers could show more "resistance" to fibrinolytic therapy. Afterward, we prospectively studied a cohort of patients from 2 different European populations undergoing fibrinolytic treatment. Evaluation of the efficacy of fibrinolytic therapy was assessed noninvasively (203). In a multivariate analysis, fibrinolysis in patients who carried the Leu34 allele was significantly less efficient. Re-evaluation at 24 h revealed that the FXIII Val34Leu polymorphism was the only factor displaying a significant role.

Additionally, we showed that the simultaneous combination of Leu34 allele and nonsmokers significantly increases the risk of poorer efficacy of fibrinolysis and had the worst 24-h outcome. Accordingly, our study supports that the combination of genetic and environmental factors may explain the heterogeneity in the efficacy of fibrinolytic therapy. Overall, these findings may have implications in clinical practice, as demonstrated by a study from our group evaluating the role in the efficacy and side-adverse effects of thrombolytic therapy in stroke in which patients with the FXIII V/V genotype and low fibrinogen (<3.6 g/l) displayed the best clinical outcome (204). In contrast, carriers of the L34 variant and high fibrinogen levels showed almost no clinical response. The FXIII V34L polymorphism was also associated with mortality (204).

During the past few years, it has been shown that several polymorphisms can influence the efficacy of fibrinolytic therapy. Therefore, thrombin-activable fibrinolysis inhibitor, TAFI, Thr325Ile (193), and the ACE gene I/D polymorphism (205) were associated with recanalization resistance by the end of tissue plasminogen activator infusion in acute ischemic stroke, assessed by transcranial Doppler, whereas no association was found between PAI-1 4 G/5 G polymorphism and recanalization rate (193). Methylenetetrahydrofolate reductase C677T polymorphism was independently associated with the presence of persistently occluded infarct-related artery after thrombolysis (206). Newer studies are warranted to better elucidate the role of genetic modulation on the efficacy of pharmacological recanalization therapy with fibrinolytic agents. In conclusion, promising results suggest that an underlying genetic background could explain the heterogeneity in response to fibrinolytic drugs.

	Conclusions

Top Abstract Search Strategy and Selection... Pharmacogenetics: A Brief... Antiplatelet Agents Anticoagulants Fibrinolytic Drugs Conclusions References

 
Despite being a relatively young field in medicine, pharmacogenetics has emerged as a relevant discipline that will help find the most appropriate treatment for each patient, increasing the efficacy (improving outcomes) and safety (reducing the side effects) of a given drug. Here, we have reviewed the most important polymorphisms that have been associated with antithrombotic therapies used in cardiovascular diseases. The present review emphasizes the importance of identifying individuals in whom their potential clinical benefits may be limited as the result of an inadequate response based on a specific genetic profile. Titrating antithrombotic drug regimens according to antithrombotic function may overcome this phenomenon. In clinical practice, all patients are different, and the identification of the genetic basis of such heterogeneity will help replace general protocols with specific and individualized treatment regimens. Pharmacogenetics will help the development of such personalized medicine.

	Acknowledgments

 
The authors thank Drs. J. Corral, J. Pineda, J. Caturla, J. Rivera, K. W. Lee, E. Bernardo, A. Fernandez-Ortiz, and E. Trabetti, and Profs. G. Y. H. Lip, C. Macaya, P. F. Pignatti, M. Valdés, and V. Vicente, who have been involved in the research studies of our groups.

	Footnotes

 
Dr. Angiolillo has received honoraria for lectures from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly & Co., and Daiichi Sankyo, Inc.; honoraria from the advisory board of Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly & Co., Daiichi Sankyo, Inc., The Medicines Company, Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, and AstraZeneca; and has received research grants from GlaxoSmithKline, Otsuka, Eli Lilly & Co., Daiichi Sankyo, Inc., The Medicines Company, Portola, Accumetrics, Schering-Plough, AstraZeneca, and Eisai. Dr. Bass has received honoraria for lectures from Eli Lilly & Co. and Daiichi Sankyo, Inc., and research grants from Baxter.

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