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• W2894047368 abstract "HomeStrokeVol. 49, No. 10Pharmacogenetics of Stroke Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBPharmacogenetics of Stroke Stephanie Ross, MSc, PhD and Guillaume Paré, MD, MSc Stephanie RossStephanie Ross Search for more papers by this author and Guillaume ParéGuillaume Paré Correspondence to Guillaume Paré, MD, MSc, Departments of Pathology & Molecular Medicine, McMaster University, 37 Barton St E Rm. C3-103, Hamilton, Ontario, Canada, L8L 2X2. Email E-mail Address: [email protected] Search for more papers by this author Originally published24 Aug 2018https://doi.org/10.1161/STROKEAHA.118.020369Stroke. 2018;49:2541–2548Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 24, 2018: Ahead of Print In the United States, it is expected that >690 000 patients will have an ischemic stroke, whereas 240 000 patients will have a transient ischemic attack in each year.1,2 The use of antiplatelet and anticoagulant therapies has lowered the risk of recurrent strokes, but there is still variation in response to these agents.3 There has also been an increased understanding of stroke pharmacogenetics which has been driven by advances in genotyping technology and increased interest in developing targeted pharmaceutical treatments. The primary goal of pharmacogenetics is to treat patients who are more likely to benefit from a particular intervention by using their genetic information to select appropriate treatments. Thus, a better understanding of the genetic determinants that influence treatment response to stroke therapies will help to improve their safety and effectiveness, as well as reducing costs.4The purpose of this review was to summarize the pharmacogenetics of stroke by providing an overview of the genetic variants that contribute to the individual responses to aspirin, clopidogrel, warfarin, and dabigatran.AspirinAspirin is the most commonly used antiplatelet in the primary and secondary prevention of stroke.5 Aspirin reduces platelet activation by irreversibly acetylating COX (cyclooxygenase)-1, which in turn, inhibits production of thromboxane A2 from arachidonic acid.6 Although there is strong evidence to support the use of aspirin, several patients may still experience treatment failure and an increased risk in recurrent events.7,8 Aspirin resistance occurs when aspirin fails to suppress the production of thromboxane A2, which leads to the subsequent activation and aggregation of platelets. Aspirin resistance can result in laboratory resistance (ie, aspirin fails to inhibit a test of platelet function) or clinical resistance (ie, aspirin does not reduce the risk of atherothromboembolic ischemic events).6 The causes of aspirin resistance are complex and may result from alternative pathways not inhibited by aspirin, patient compliance, or genetic factors.Several genes have been associated with aspirin resistance. The effect of these common genetic variants was assessed in a systematic review by Goodman et al9. The authors reported that the most well studied genetic variants were the PlA1/A2 of the GPIIIa (glycoprotein IIIa) gene, which encodes for a fibrinogen receptor and von Willebrand factor that aids in the platelet aggregation activation.10 Goodman et al9 reported that there was no difference between carriers of the P1A1/A2 allele who were aspirin resistant or aspirin sensitive (odds ratio (OR), 1.14; 95% CI, 0.84–1.54; P value=0.40; N=968), but there was significant heterogeneity in the pooled estimate (P for heterogeneity (Het P)=0.004). The authors stratified the analysis and observed that healthy carriers of the P1A1/A2 allele were more likely to be aspirin resistant as compared to those who were aspirin sensitive (OR, 2.36; 95% CI, 1.24–4.49; P=0.009; N=240; Het P=0.03), whereas the effect was attenuated in P1A1/A2 allele carriers with cardiovascular disease (OR, 0.92; 95% CI, 0.65–1.30; P=0.64; N=728; Het P=0.05).9 The authors noted that the observed heterogeneity may result from the methods in which aspirin resistance was measured. The authors also commented that the effect of P1A1/A2 carrier status on aspirin resistance was null in patients with cardiovascular disease because they may be treated with statins, which would impair platelet function. The authors also observed that the GPIIIa, COX-1, COX-2, and P2Y12 had no effect on aspirin resistance, but this has not been reported consistently across studies.11–16 The lack of consistency may be because of limited sample sizes and differences in vascular outcomes or patient populations. Thus, more large-scale randomized controlled trials (RCTs) in healthy individuals and patients with cardiovascular disease are required to truly understand the effect of aspirin resistance.The COX enzymes are involved in the formation of prostaglandins, prostacyclin, and thromboxane.6 Studies have indicated that the variability in aspirin response may be influenced by COX-1 (PTGS1 [prostaglandin-endoperoxide synthase]) genetic variants. For instance, the rs10306114 and rs3842787 (COX-1) polymorphisms were associated with greater inhibition of prostaglandin in healthy individuals,12 as well as in 2 cardiovascular disease patient cohorts treated with aspirin.15,17 Thus, it would seem that genetic variation in COX-1 is associated with changes in platelet function and aspirin response; however, there is a lack of well-powered studies assessing the effect of COX-1 polymorphisms on stroke outcomes.In contrast to the COX-1 enzyme, the COX-2 is an inducible enzyme that is expressed by inflammation cells, and it is thought to have protective effects because it facilitates the production of prostacyclin.18 However, the role of COX-2 is controversial. Some RCTs have shown that selective COX-2 inhibitors are associated with adverse events,19,20 whereas animal models suggest that genetic inhibition of the COX-2 enzyme decreases the risk of atherosclerosis21 while increasing the risk of thrombosis.22 For instance, the rs20417 (COX-2/PTGS2) genetic variant has been associated with a decrease in COX-2 activity in atherosclerotic plaque and a reduced risk of myocardial infarction and stroke,23,24 but these results have not been observed consistently, which may be a result of small sample sizes. Moreover, an interaction between aspirin use and rs20417 carrier status was reported, where rs20417 carriers treated with aspirin had a reduced risk of vascular events as compared to nonaspirin users.25,26 Thus, Ross et al27 tested the association of rs20417 carrier status with the risk of vascular outcomes using a meta-analysis of 49,232 patients from 6 prospective RCTs. The authors showed that rs20417 carrier status was associated with a reduced risk of cardiovascular outcomes (OR, 0.78; 95% CI, 0.70–0.87; Figure 1)27. The authors also observed that aspirin use (P for interaction=0.004) and previous coronary artery disease (P for interaction=0.015) appeared to modify the association between rs20417 carrier status and the risk of vascular outcomes.27 Moreover, rs20417 carriers had significantly lower levels of urinary thromboxane and prostacyclin metabolites as compared to rs20417 noncarriers (P=0.01 and P=0.01, respectively).27 In addition, Brænne et al28 conducted a genetic analysis where they identified common variants that represent targets for COX-2 inhibitors to narrow down the potential mechanisms affecting coronary artery disease risk. The authors identified several genetic variants that influenced the effect of COX-2 inhibitors, such as rs7270354 (MMP9 [matrix metallopeptidase 9]) and rs4888383 (BCAR1 [breast cancer antiestrogen resistance protein 1]), which points to further mechanisms (other than COX-2) that might be responsible for the COX-2 inhibitor–associated coronary artery disease risk.Download figureDownload PowerPointFigure 1. Association of rs20417 carrier status with major cardiovascular events in 6 prospective patient populations. Analyses were adjusted for age, sex, randomization status (when appropriate), and self-reported ethnicity. ACTIVE-A (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events), CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events), epiDREAM/DREAM (Epidemiological Arm of the DREAM Study/Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication), ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial), RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), and WGHS (Women’s Genome Health Study) data were included in the meta-analysis. DREAM represents epiDREAM/DREAM. Hetero. P indicates heterogeneity P value; and OR, odds ratio. Reprinted from Ross et al27 with permission. Copyright © 2018, European Society of Cardiology.ClopidogrelClopidogrel is a prodrug that inhibits the P2Y12 receptor on the surface of platelets.29 Dual antiplatelet therapy with clopidogrel and aspirin is used in the management of recurrent stroke in patients with acute ischemic stroke or transient ischemic attack.30–32 However, there is variability in response to clopidogrel, where some patients have an increased risk of recurrent ischemic vascular events.33The majority of genetic studies exploring the effect of clopidogrel responsiveness have focused on the hepatic CYP2C19 (cytochrome P450 2C19) enzyme because it is involved in the biotransformation of clopidogrel into its active metabolite.34 Studies have demonstrated that carriers of the loss-of-function alleles (CYP2C19*2 or CYP2C19*3) have poorer response to clopidogrel, decreased platelet inhibition, and an increased risk of vascular events.35 However, carriers of the gain-of-function allele (CYP2C19*17) have increased levels of clopidogrel metabolite higher inhibition of ADP-induced platelet aggregation and an increased risk of bleeds.36 In light of the variability in clopidogrel response, the Food and Drug Administration issued a box warning on the clopidogrel label, which suggests that loss-of-function CYP2C19 carriers should be treated with a higher dose of clopidogrel or with an alternative antiplatelet agent.Pan et al37 conducted a meta-analysis that assessed the effect of loss-of-function (CYP2C9*2, *3, and *8) and gain-of-function (CYP2C19*17) alleles on clopidogrel in 4762 patients with acute ischemic stroke or transient ischemic attack. The authors reported that loss-of-function carriers had an increased risk of stroke as compared to noncarriers (relative risk, 1.92; 95% CI, 1.57–2.35; P<0.001).7 However, in this analysis, the authors included observational studies and studies without control groups, which makes it difficult to determine whether the risk of stroke is because of CYP2C19 carrier status or mechanisms that are independent of clopidogrel. Thus, Paré et al38 explored the effect of loss and gain-of-function alleles using a subset of 1156 patients from the ACTIVE-A trial (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events). The authors reported that there was no interaction between the beneficial effect of clopidogrel and loss-of-function carrier status on a composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or stroke (hazard ratio (HR), 0.74; 95% CI, 0.58–0.94; Het P=0.73) or bleeds (HR, 1.49; 95% CI, 0.88–2.55; Het P=0.16). Similar results were also observed for gain-of-function carriers on vascular events.38 Furthermore, Holmes et al39 showed that loss-of-function carrier status did not modify the association between clopidogrel and risk of vascular events or bleeds (P for interaction >0.05 for all) in a meta-analysis of 4 placebo-controlled RCTs (N=11 477).The transition of CYP2C19 testing in clinical practice to guide clopidogrel therapy has been slow because of the uncertainty in the benefit of treating patients based on their CYP2C19 carrier status. Furthermore, other therapeutic agents can be used to overcome the increased risk of vascular events that are associated with clopidogrel treatment.40 For instance, prasugrel and ticagrelor provide enhanced platelet P2Y12 receptor inhibition in patients who are poorly responsive to standard doses of clopidogrel41,42 and improved clinical outcomes irrespective of genotype.43,44 Conversely, clopidogrel is now off-patent, and it may be more cost effective to treat patients who are more likely to respond to clopidogrel while treating nonresponders with an alternative nonpatent therapy. Thus, CYP2C19 testing may be beneficial in clinical practice if the choice of therapy differs depending on genotype because of improved outcomes or cost (Figure 2).Download figureDownload PowerPointFigure 2. Two hypothetical scenarios illustrating situations in which pharmacogenetic testing is or is not of clinical utility. LOF indicates loss of function; and Tx, treatment. Reprinted from Paré et al40 with permission. Copyright © 2018, American Heart Association, Inc.Currently, no RCTs have assessed the efficacy and safety of CYP2C19 testing using clinical outcomes in patients with stroke. However, the IGNITE (Implementing Genomics in Practice) Network, funded by National Institutes of Health, was designed to support the integration of genomic data into patient’s records to help guide point of care decision making.45 Patients enrolled in the study were tested for their CYP2C19 genotype carrier status, and those who were identified as loss-of-function carriers were provided an alternative antiplatelet therapy (ie, prasugrel or ticagrelor) post percutaneous coronary intervention (PCI). The study showed that CYP2C19 loss-of-function carriers treated with clopidogrel had a higher risk of a major cardiovascular event as compared to those loss-of-function carriers treated with alternative antiplatelet therapy (HR, 2.30; 95% CI, 1.20–4.50; P=0.015; N=1815).46 In addition, there are several ongoing, well-designed prospective trials that explore the effect of CYP2C19 testing in patients undergoing primary percutaneous coronary intervention, such as TAILOR-PCI (Tailored Antiplatelet Therapy Following PCI; http://www.clinicaltrials.gov. Unique identifier: NCT01742117), GIANT (Genotyping Infarct Patients to Adjust and Normalize Thienopyridine Treatment; http://www.clinicaltrials.gov. Unique identifier: NCT01134380), and ADAPT (Assessment of Prospective CYP2C19 Genotype-Guided Dosing of Anti-Platelet Therapy in Percutaneous Coronary Intervention; http://www.clinicaltrials.gov. Unique identifier: NCT02508116), respectively. However, there is still a need for large, well-designed trials conducted in patients with stroke.WarfarinWarfarin is a vitamin K antagonist that is used in the primary and secondary prevention of patients with atrial fibrillation (AF).47 Warfarin metabolism is dependent on CYP2C9,48 and it targets the VKORC1 (vitamin K epoxide reductase complex subunit 1) enzyme to inhibit vitamin K metabolism.49 In addition, the CYP4F2 gene encodes for an enzyme that is involved in vitamin K metabolism.50 The variability in response to warfarin requires regular monitoring using the international normalized ratio (INR) to ensure optimal warfarin efficacy and a reduced risk in bleeds.47 However, studies have shown that genetic variants account for more of the variability in warfarin response (30% to 35%) as compared to clinical variables.51 Thus, a better understanding of how genetic variants contribute to the management of inadequate or excessive anticoagulation may decrease in the risk of stroke events.The common variants involved in the metabolism of warfarin are the VKORC1, the CYP2C9, and the CYP4F2 polymorphisms. Carriers of the minor allele of rs9923231 (VKORC1) variant have reduced liver expression of VKORC1, require a lower dose of warfarin, and have an increased risk of adverse events, and those who carry the rare VKORC1 mutation have warfarin resistance and an increased risk of adverse ischemic events.52,53 Loss-of-function CYP2C9 alleles (CYP2C9*2 and CYP2C9*3) have been associated with reductions in warfarin metabolism, overanticoagulation, and an increased risk of bleeding.54 Finally, carriers of the rs2108622 (CYP4F2) variant are associated with elevated vitamin K concentrations and require an increased warfarin dose.50Recent trials have explored the effect of genotype-guided dosing as compared to standard dosing in patients treated with warfarin. The COAG trial (Clarification of Optimal Anticoagulation Through Genetics) compared the effect of treating 1015 patients with a target INR of 2 to 3 with a genotype-guided dosing algorithm during the first 5 days of therapy.55 The authors reported that there was no difference between the mean percentage of time in the therapeutic range at 4 weeks for patients in the genotype-guided (45.2%) or the clinically-guided (45.4%) treatment groups (P=0.91). However, conflicting estimates were reported in the EU-PACT trial (European Pharmacogenetics of Anticoagulant Therapy).56 Similar to COAG, the trial compared the effect of genotype-guided dosing to standard dosing on anticoagulation control in 455 patients starting warfarin therapy for the first 5 days. The authors reported that the mean percentage of time in the therapeutic range at 4 weeks was higher for patients in the genotype-guided group (67.4%) versus the standard dosing group (60.3%; P<0.001). Finally, Mega et al57 conducted a prespecified subgroup analysis using data from the ENGAGE-AF trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction). The authors sought to determine whether carriers of rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), and rs9923231 (VKORC1) treated with warfarin had higher rates of bleeding as compared to those treated with edoxaban. Among the 4833 patients, a higher proportion of sensitive and highly sensitive responders to warfarin had more time overanticoagulated in the first 90 days of treatment than normal responders to warfarin (P-trend<0.0001). These 2 patient groups also had an increased risk of bleeding with warfarin as compared to normal responders (OR, 1.31; 95% CI, 1.05–1.64; P=0.0179 and OR, 2.66; 95% CI, 1.69–4.19; P<0.0001, respectively). In contrast, sensitive and highly sensitive responders treated with higher or lower doses of edoxaban had a reduced risk of bleeds as compared to those treated with warfarin (P for interaction in high dose edoxaban=0.0066 and P for interaction in low dose edoxaban=0.0036).Based on results, it is uncertain whether the use of pharmacogenetic testing in patients treated with warfarin is effective. But the lack of consistency among these trials may be because of differences in the patient populations or the trial designs. For instance, the EU-PACT trial consisted of European patients, whereas the COAG and the ENGAGE-AF trials were composed of North American patients with European and African ancestry. Thus, the observed estimates among the trials may be biased because of differences in allelic frequencies across ancestry groups or other lifestyle factors. The trials also used different dosing algorithms and provided different standards of care for the control groups. First, the dose algorithms may not be generalizable across studies because they were developed in European patient populations. Second, in the control arm, patients were treated with intensive INR measurements and frequent dose adjustments, which may not represent clinical practice and the frequent monitoring may have underestimated effect sizes. There were also differences in the length of follow-up among the 3 trials, which ranged from 28 to 90 days. This suggests that dosing algorithms could have a greater clinical impact over time, or it could reflect differences in clinical care across the 3 studies. Finally, all of the trials used a surrogate outcome to assess the efficacy of genetically-guided dosing algorithms.In light of these trials, the GIFT (Genetics Informatics Trial) was conducted to assess whether genotype-guided dosing improves the safety of warfarin initiation in 1650 patients undergoing elective hip or knee arthroplasty.58 Patients in the trial were randomized to receive a clinical and genetic-based algorithm or a clinical algorithm of warfarin dosing on days 1 to 11 targeting an INR of 1.8 or 2.5. Patients were genotyped for the following genetic variants: rs9923231 (VKORC1), rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), and rs2108622 (CYP4F2*3). The authors measured the effect of primary outcome, which was a composite of major bleeding within 30 days, INR of 4 or greater within 30 days, death within 30 days, and symptomatic or asymptomatic venous thromboembolism confirmed by objective testing within 60 days of arthroplasty. The authors reported that the genetic algorithm was more protective than the clinical algorithm (relative risk, 0.73; 95% CI, 0.56–0.95).58 Unlike the other genotype-guided RCTs, this trial incorporated the CYP4F2*3 genotype into the dosing algorithm, and the algorithm was used for the first 11 days of warfarin dosing, which is longer than the other trials. Although the results demonstrate that genetically-guided dosing reduces the risk of adverse events, the only significant outcome in the composite was INR of ≥4, which represents an extreme deviation in INR (relative risk, 0.71; 95% CI, 0.51–0.99). Despite the fact that an INR of ≥4 is a strong risk factor for vascular events, it does not always predict hard clinical outcomes, such as bleeds or death. Indeed, the study showed that genetically-guided dosing was not associated with major bleeding within 30 days (relative risk, 0.24; 95% CI, 0.05–1.15) or death within 30 days (no deaths occurred). Based on these discrepancies, it is important that future trials testing the effectiveness of warfarin pharmacogenetic algorithms in stroke patients select appropriate patient populations, outcomes, and trial designs.DabigatranDabigatran etexilate is an oral prodrug that is rapidly converted by CES1 (carboxylesterase 1) to the thrombin inhibitor, dabigatran. Dabigatran is a new anticoagulant that is as safe and as effective as warfarin but does not require periodic blood tests. The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy) was a noninferiority RCT that compared fixed doses of dabigatran (110 or 150 mg) to dose-adjusted warfarin on stroke or systemic embolism in 18 113 patients with AF and a risk of stroke.59 The parent trial showed that both the 110 mg and the 150 mg dose of dabigatran were noninferior to warfarin (P<0.05), whereas the 150 mg dose of dabigatran was superior to warfarin (P<0.001) but the 110 mg dose was not (P=0.34).59 In addition, the safety profiles of dabigatran were more favorable. However, there is interindividual variability in the blood concentration of dabigatran active metabolite among patients, which may impact the efficacy and safety of the drug.To explain the variability in response to dabigatran, Paré et al60 conducted a genome-wide association study to explore the genetic variants that influence dabigatran metabolism on efficacy and safety outcomes using 2944 patients from the RE-LY trial. The authors reported that the rs2244613 (CES1) genetic variant was associated with trough concentrations, whereas the rs4148738 (ABCB1[ATP-binding cassette transporters]) and the rs8192935 (CES1) genetic variants were associated with peak concentrations of dabigatran etexilate (P<9×10-8 for all). In addition, the minor allele of the rs2244613 genetic variant was associated with a reduced risk of any bleeds (OR, 0.67; 95% CI, 0.55–0.82; P=7×10-5) or minor bleeds (OR, 0.70; 95% CI, 0.57–0.85; P=7×10-5). The rs4148738 and the rs8192935 genetic variants were not associated with efficacy or safety outcomes (P>0.05 for all). Likewise, Paré et al60 also showed that rs2244613 carrier status appeared to modify the risk of bleeds among those treated with dabigatran or warfarin (P for interaction=0.0015). For instance, rs2244613 carriers treated with dabigatran had a reduced risk of bleeds as compared to noncarriers (HR, 0.70; 95% CI, 0.58–0.84; P=0.00016); however, this association was null in those treated with warfarin (HR, 1.13; 95% CI, 0.90–1.42; P=0.29), as expected, given the lack of involvement of carboxylesterase in warfarin metabolism. Table shows the association between the lead genetic variants with bleeding and ischemic events in dabigatran-treated participants from the RE-LY trial. These results demonstrate the importance of using pharmacogenetics to guide the treatment effect drugs with a narrow therapeutic index; however, they also highlight the decreasing likelihood of identifying clinically relevant polymorphisms for newer, safer drugs because they may not have enough power to detect infrequent ischemic events.Table. Association of Lead Genetic Variants With Bleeding and Ischemic Events in Dabigatran-Treated ParticipantsEventrs4148738* (ABCB1; Peak Concentration)rs8192935* (CES1; Peak Concentration)rs2244613* (CES1; Trough Concentration)OR (95% CI)†P ValueOR (95% CI)†P ValueOR (95% CI)†P ValueIschemic stroke of system embolism0.88(0.53–1.46)0.620.76 (0.43–1.34)0.340.70 (0.33–1.47)0.34Any ischemic event0.98 (0.69–1.40)0.921.04 (0.72–1.51)0.840.95 (0.59–1.51)0.82Any bleeding0.94 (0.82–1.09)0.440.89 (0.76–1.03)0.130.67 (0.55–0.82)7×10−5‡Major bleeding1.14 (0.85–1.52)0.400.88 (0.64–1.21)0.440.66 (0.43–1.01)0.06Minor bleeding0.94 (0.81–1.09)0.380.89 (0.76–1.05)0.170.70 (0.57–0.85)4×10−4‡Association of SNPs with events was performed with logistic regression assuming an additive genetic model. Logistic regression models included age, sex, dabigatran dose, CHADS2 score, use of aspirin, log(Cockcroft-Gault creatinine clearance), and the first 10 genetic principal components as independent variables. ABCB1 indicates ATP-binding cassette transporters; CES1, carboxylesterase 1; OR, odds ratio; and SNP, single nucleotide polymorphism.*SNP (candidate locus; original association with dabigatran concentration).†OR per minor allele.‡Significant (P<0.05) results.Reprinted from Paré et al60 with permission. Copyright © 2018, American Heart Association, Inc.Although the previous results demonstrated a practical application of using pharmacogenetics, there are other clinical characteristics that may impact dabigatran response. For instance, patients with chronic kidney disease (CKD) have an increased risk of AF, as well as a subsequent risk of stroke.61,62 CKD patients with AF have limited treatment options because CKD has been shown to increase the risk of bleeds in warfarin-treated patients.63 Therefore, dabigatran and other new oral anticoagulants may provide a viable option for this patient group because these agents reduce the risk of stroke or systemic embolic events as compared to warfarin in patients with AF.59,64–66 However, it has been reported that 80 to 85% of dabigatran is excreted by the kidneys.67 Thus, CKD patients with AF who are treated with dabigatran have a higher risk of bleeds because of increased drug accumulation.68 There is also a lack of clinical data to support the efficacy and safety of dabigatran in patients with CKD and AF because these patients are typically excluded from RCTs. One meta-analysis showed that new oral anticoagulants may reduce the risk of stroke and systemic embolism as compared to warfarin in AF patients with CKD but the majority of patients in this study had CKD stage G3 (N=12,155) or stage G4 (N=390) and, thus, these results cannot be generalized to patients with CKD stage G4 or greater.69 Although there is limited evidence to support the use of dabigatran in this patient population, nongenetic factors, such as CKD contribute to response to dabigatran regardless of genotype. Additional studies will be needed to delineate the role of pharmacogenetics, if any, in this patient population.ConclusionsPharmacogenetics promises the use of safer, better, and cheaper drugs by providing stroke patients with the right drug at the right dose. There are clear examples of treating patients with an appropriate drug or dose based on their genotype carrier status, which will help to improve treatment benefit or reduce adverse events. For instance, major histocompatibility complex, class I, B (HLA-B)*57:01 carriers status is associated with hypersensitivity in patients with HIV who are treated with abacavir.70 However, UDP-glucuronosyltransferase 1-1 (UGT1A1) carriers with colon cancer can be treated with a lower dose of irinotecan to reduce the risk of neutropenia.71 These examples support the use of pharmacogenetics because they demonstrate a strong genetic association that leads to improved treatment efficacy or a reduction in adverse events.Although the aforementioned examples highlight the role of genetic testing, there is limited evidence to support the use of pharmacogenetics in stroke patients because it is a complex disorder. We hypothesize that some stroke subgroups may derive a greater benefit from pharmacogenetics than others. For instance, pharmacogenetic associations with anticoagulants and antiplatelets may be more pertinent in patients at risk of intracerebral hemorrhage than those with ischemic small vessel disease, but there is limited evidence. Thus, a better understanding of stroke genetics will be key to derive the full benefit from pharmacogenetic testing.The adoption of pharmacogenetics in clinical practice has been slow, which may be because of gaps in evidence or other barriers, such as awareness and cost-effectiveness. First, there is a need for more rigorous evidence-based approaches to assess the effect of genetic testing in stroke patients. For instance, there is limited evidence to su" @default.
• W2894047368 created "2018-10-05" @default.
• W2894047368 creator A5054423486 @default.
• W2894047368 creator A5066605195 @default.
• W2894047368 date "2018-10-01" @default.
• W2894047368 modified "2023-10-05" @default.
• W2894047368 title "Pharmacogenetics of Stroke" @default.
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