Available online at www.sciencedirect.com
ScienceDirect Pharmacogenetics and oral antithrombotic drugs William L Baker1 and Samuel G Johnson2 Warfarin and other oral vitamin K antagonists (VKAs) have been the primary pharmacologic options with well-established efficacy data in high-risk patient populations. Warfarin dose requirements to achieve therapeutic anticoagulation are highly variable. This variability in response results in increased risk for adverse events, including thromboembolism and bleeding. Genetic variants in CYP2C9 and VKORC1 have been identified and shown to explain some of the variability in warfarin response. Prospective trials suggest that incorporation of genotype results in faster time to therapeutic range than without; however, whether these improvements result in improved clinical outcomes is unclear. The target-specific anticoagulants are alternatives to warfarin and do not require laboratory monitoring. Some pharmacogenetic variation in their clinical response may exist as well. Ongoing trials will provide a clearer picture of whether genotype-based warfarin dosing improves outcomes and may, therefore, subsequently be compared with the target-specific agents. Addresses 1 Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT, USA 2 Applied Pharmacogenomics, Kaiser Permanente Colorado, Denver, CO, USA Corresponding author: Baker, William L ([email protected])
Current Opinion in Pharmacology 2016, 27:38–42 This review comes from a themed issue on Cardiovascular and renal Edited by Gary O Rankin and Nalini Santanam
http://dx.doi.org/10.1016/j.coph.2016.01.008 1471-4892/# 2016 Elsevier Ltd. All rights reserved.
Introduction An appreciable amount of research in recent years has been focused on the prevention and treatment of thromboembolic disorders. Until relatively recently, oral vitamin K antagonists (VKAs) such as warfarin were the primary pharmacologic options with well-established efficacy data in high-risk patient populations [1]. Despite the evidence supporting its benefit, only about half of patients receiving warfarin maintain therapeutic control of their anticoagulation via international normalized ratio (INR) testing [2]. Warfarin dose requirements to achieve therapeutic anticoagulation are highly variable; in fact, by as much as 20-fold between patients. This variability in Current Opinion in Pharmacology 2016, 27:38–42
control results in increased risk for adverse events, including thromboembolism and bleeding [3,4]. Data shows that up to one-third of hospitalizations for adverse drug events in older adults is related to warfarin [5]. Factors that may lead to this poor control include dietary vitamin K irregularities, drug–drug interactions, and inter-patient variability [6,7]. Attempts to minimize the variability of response seen with warfarin have included evaluating various anticoagulation management models, adding concomitant therapies such as low-dose vitamin K, identifying patient-related factors that explain the variability (e.g. pharmacogenetics), and alternative anticoagulants [6]. Pharmacogenetics is a term referring to a limited set of genes that affect drug response [4]. Given the high-risk nature of oral anticoagulants, it is important for clinicians to have a working understanding of the impact of pharmacogenetics on variability of response and its clinical implications for patient care. This review will focus on the pharmacogenetic determinants of drug response for oral antithrombotics and provide an overview of the data that has been published in recent years.
Warfarin pharmacogenetics The anticoagulant activity for warfarin derives from inhibition of vitamin K epoxide reductase which encodes VKORC1 and subsequently reduces the amount of vitamin K available for synthesis of intrinsic coagulation factors [8]. Genetic variants in warfarin’s target, VKORC1, and the enzyme that is principally responsible for S-warfarin metabolism, cytochrome P450 2C9 (CYP2C9), are associated with increased sensitivity to warfarin [9]. Lower warfarin doses are required to achieve therapeutic anticoagulation in patients carrying certain variants [VKORC1 rs9923231, CYP2C9 rs1799853 (*2), rs1057910 (*3)] [10]. Additionally, a higher incidence of aboverange INRs and bleeding risk have been associated with these variants and are related to excessive anticoagulation [11]. Beyond VKORC1 and CYP2C9, several other genes, including cytochrome P450 4F2 (CYP4F2) and gamma glutamyl carboxylase (GGCX), are involved in the vitamin K pathway have also been associated with altered warfarin dose requirements [12]. However, their specific impact on warfarin dose variability is relatively minor once variants in VKORC1 and CYP2C9 have been taken into account. While much of the clinical focus on warfarin pharmacogenetics remains on treatment in adult patients, significant associations between warfarin dose and VKORC1/ CYP2C9 genotypes have been seen in pediatric patients; this suggests that evaluation of warfarin genetic variants is of significance when caring for children [13]. Figure 1 www.sciencedirect.com
Pharmacogenetics and antithrombotics Baker and Johnson 39
Figure 1
CYP4F2 3%
Clinical Factors 20%
Age Sex Drugs Diet BMI
CYP2C9 12%
Unknown 40%
GGCX 1%
VKORC1 24% Current Opinion in Pharmacology
Factors affecting warfarin dose requirements. BMI, body mass index; CYP, cytochrome P-450; GGCx, gamma glytamyl carboxylase; VKOR, vitamin K epoxide reductase
shows the relative impact of various factors on warfarin dose requirements [14]. Clinical warfarin-dosing algorithms may prove more accurate for predicting the warfarin dose requirements for individual patients [15,16]. Many of these algorithms adjust for patient-specific factors, including age, gender, VKORC1/CYP2C9 genotype and concomitant medications in their dosing scheme. Engaged clinicians can incorporate pharmacogenetic information into patient management with online (for example, www.warfarindosing.org), or downloaded smartphone applications (for example, iWarfarin). In addition, the Food and Drug Administration (FDA) has provided a warfarin dosing table in the warfarin (Coumadin) product label according to VKORC1, CYP2C9*2 and *3 genotypes. Nevertheless, the clinical benefit of pharmacogenetic testing to guide warfarin dosing remains the subject of intense debate. The Clinical Pharmacogenetics Implementation Consortium (CPIC) published clinical practice recommendations in 2011 for warfarin dosing based on a known VKORC1/CYP2C9 genotype [17], while organizations such as the American College of Chest Physicians do not recommend genotyping due to insufficient evidence of benefit [18]. Importantly, the CPIC guidelines specifically avoid commenting on whether ordering a pharmacogenetic test is www.sciencedirect.com
appropriate and if that data should be used in medical decision making. On the basis of available data for genetic determination of warfarin dose requirements, the most recent CPIC guideline in 2011 strongly recommended warfarin dosing based on genotype when available. The guidelines also recommend use of either the Gage and colleagues [19] or International Warfarin Pharmacogenetics Consortium (IWPC) algorithms [20] to assist with dosing. Interestingly, the CPIC and ACCP guidelines provide a framework for warfarin pharmacogenetics highlighted by two different philosophies for use of warfarin pharmacogenetic data: (1) do available data support genotype-guided warfarin dosing; and (2) when warfarin pharmacogenetic data are readily available should they should be used? Two clinical trials, published after the release of the CPIC guidelines, evaluated the impact of algorithms incorporating warfarin pharmacogenetics versus either algorithms or clinical dosing alone in patients newly initiating warfarin [21,22]. Pirmohamed and colleagues [21] randomized 455 United Kingdom and Swedish patients who were initiating warfarin to either a genotype-guided or standard dosing scheme. Warfarin genotyping, determined a point-of-care system, was included in a computerized loading-dose algorithm in the initial 3 days. The dose was individualized thereafter using a computerized software program. Use of genotyping significantly increased the time within the therapeutic INR range (TTR; 67.4%) during the 12 weeks versus standard dosing (60.3%; p < 0.001). Patients in the pharmacogenetic arm had fewer INR values over 4.0 (27.0% versus 36.6%; p = 0.03) and required a shorter time to reach their therapeutic INR (median: 21 days versus 29 days; p = 0.003). No major bleeding events were seen and a single thromboembolic event occurred in the control group. Kimmel and colleagues [22] randomized 1015 patients from the United States received warfarin (used for any indication) dosed according to a genotype-guided strategy or a clinically based strategy (control). Genotyping was incorporated into a pre-specified dosing algorithm that also utilized clinical data. The control group received warfarin without incorporation of the genotyping information into the algorithm. By contrast to the findings of Pirmohamed and colleagues [21], following 4 weeks of therapy, no significant difference in TTR between the genotype and control groups was seen (45.2% versus 45.4%, respectively; p = 0.91). Interestingly, genotyping in black patients resulted in significantly lower TTR than the control group (35.2% versus 43.5%; p = 0.01), suggesting that these patients may yield especially low value from genetic warfarin testing. Neither the mean percentage of time above or below the INR range or the time to first INR in the therapeutic range were different between groups. The principle secondary outcome of any Current Opinion in Pharmacology 2016, 27:38–42
40 Cardiovascular and renal
Meta-analyses of warfarin pharmacogenetic studies have suggested that genotype-guided dosing of warfarin significantly increased the TTR compared with clinical-only algorithms [23]. However, no differences in either major bleeding or risk of thrombosis have been seen [24]. It should be noted that studies to date have not been powered to show differences in clinical outcomes. Future directions
Focused translational research in warfarin pharmacogenetics continues, with intent to determine the precise impact of genotype-guided therapy for warfarin versus clinical practice on pertinent patient outcomes across different patient population subgroups. This includes the Genetics Informatics Trial (GIFT; NCT01006733) and the Warfarin Adverse Event Reduction for Adults Receiving Genetic Testing at Therapy Initiation (WARFARIN; NCT01305148). Both of these studies are powered on clinical outcomes, rather than surrogate markers of anticoagulation (TTR) with results anticipated in the next few years.
Target-specific anticoagulant pharmacogenetics A number of target-specific oral anticoagulants (TSOACs) have been approved for clinical use over the past 5 years, changing the landscape of thromboembolic prevention and treatment. Currently available TSOACs include apixaban, dabigatran, edoxaban, and rivaroxaban with others in various stages of development. Approved for a variety of indications, including prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and prevention and treatment of thromboembolism, these agents promise a number of benefits over warfarin [25]. These include a lack of required INR monitoring, fewer food and drug interactions, and (in some cases) improved efficacy and safety [26]. Compared with warfarin, much less is known about the pharmacogenetic profile of these agents; however, data on dabigatran and edoxaban have been recently published [27,28]. The oral direct thrombin inhibitor dabigatran etexilate is rapidly converted by esterases, including CES1, to dabigatran. Dabigatran is also a substrate of the P-glycoprotein intestinal efflux transporter ABCB1 [29]. It was originally approved for the prevention of stroke and systemic embolism in 2010 based on the results of the Randomized Evaluation of Long-term Anticoagulation Therapy (RELY) trial [30]. RE-LY, which enrolled over 18,000 patients with non-valvular atrial fibrillation, showed that dabigatran etexilate 150 mg twice daily significantly reduced the risk of stroke (ischemic and hemorrhagic) versus warfarin, while the 110 mg twice daily dose had similar efficacy. Despite dabigatran exhibiting a more Current Opinion in Pharmacology 2016, 27:38–42
predictable pharmacokinetic profile versus warfarin, interindividual variability in blood concentrations of its active metabolite have been suggested [31,32]. In order to determine if genetic factors were responsible for this variability, a genome-wide analysis of 2944 participants from the RE-LY trial were analyzed [27]. They showed that alleles of the CES1 SNP rs2244613, present in nearly 33% of participants, was associated with 15% lower trough dabigatran concentrations and reduced risk for any bleeding (OR 0.67, 95% CI 0.55–0.82; p = 7 10 5). When compared to those receiving warfarin, carriers had less bleeding with dabigatran (HR 0.59, 95% CI 0.46–0.76; p = 5.2 10 5) while no difference was seen in noncarriers (HR 0.96, 95% CI 0.81–1.14; p = 0.65). Minor alleles of the ABCB1 SNP rs4148738 and the CESI SNP rs8192935 were each associated with 12% reductions in peak dabigatran concentrations; neither resulted in appreciable clinical bleeding or ischemic events. Fig. 2 shows impact of various clinical and pharmacogenetic factors on plasma dabigatran levels in a typical patient with atrial fibrillation receiving the 150 mg twice-daily dose [33]. The only pharmacogenetic study evaluating edoxaban compared it with genotype-based dosing of warfarin using data from the ENGAGE AF-TIMI 48 trial [28,34]. A subgroup of patients in the warfarin arm were genotyped for their CYP2C9 and VKORC1 status. Information was used to classify patients as either normal, sensitive, or highly sensitive responders to warfarin. The sensitive and highly sensitive warfarin responders, not surprisingly, spent a greater proportion of their time above the therapeutic INR range compared with the normal responders and had a higher risk of bleeding. As a result, risk of Figure 2
500
Plasma [Dabigatran] ng/mL)
INR 4, major bleeding, or thromboembolism was similar between groups ( p = 0.93).
Typical AF Patient CrCl 30 mL/min Age (93 vs. 68) CrCl 50 mL/min CES1 SNP (rs2244613) P-gp Inhibition P-gp Induction
450 400 350 300 250 200 150 100 50 0 0
6
12
18
24
Time since last dose (hr) Current Opinion in Pharmacology
Plasma concentrations of dabigatran 150 mg in atrial fibrillation patients. AF, atrial fibrillation; AUC, area under the concentration curve; CES1, carboxylesterase 1; SNP, single-nucleotide polymorphism; P-gp, P-glycoprotein. Reprinted with permission from Ref. [32]. www.sciencedirect.com
Pharmacogenetics and antithrombotics Baker and Johnson 41
bleeding was lower in patients receiving both low-dose (Pinteraction = 0.0036) and high-dose (Pinteraction = 0.0066) edoxaban than either the sensitive or highly sensitive warfarin responders versus the normal responders. After 90-days, no difference in bleeding risk was seen between edoxaban and any of the warfarin response groups. Future directions
Given the pharmacologic and pharmacokinetic profiles of the TSOACs, additional investigations into the impact of pharmacogenetic variation on their efficacy and safety profiles is warranted. Perhaps more importantly, a clinical trial investigating whether a TSOAC improves outcomes when compared to genotype-based dosing of warfarin would be of interest. The likelihood of such a trial appears remote, but may provide clinicians with a more complete picture of thrombosis management.
Conclusions Warfarin remains the most commonly used anticoagulant for preventing and treating thromboembolic disorders, although TSOACs use is increasing. It is probably that warfarin will continue to be used as the anticoagulant of choice by many practitioners. It is, therefore, imperative to identify the most effective means for initiating and chronically dosing warfarin therapy. Till date, the clinical utility of incorporative warfarin genotype information into the dosing strategy is unclear. Moreover, studies have questioned the cost-effectiveness of such a strategy [35–37]. Successful implementation of a warfarin pharmacogenomics service in a large academic institution has, however, been seen [38]. Until clinical trials show improvements in hard outcomes, it seems unlikely that third-party payers will reimburse for the cost of the pharmacogenetic testing and interpretation with such a service. Additional data in both pediatric and minority populations is also warranted. The TSOACs may be considered alternatives in these populations until this information becomes available.
Disclosures Dr. Baker serves on the speaker’s bureau for Boehringer Ingelheim.
Funding Dr. Baker was supported, in part, by the Connecticut Institute for Clinical and Translational Science (CICATS) at the University of Connecticut. The content is solely the responsibility of the authors and does not necessarily represent the official views of CICATS.
Conflict of interest statement Dr. Baker — speaker for Boehringer Ingelheim; Dr. Johnson — none.
Acknowledgement None. www.sciencedirect.com
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, Hylek EM, Schulman S, Go AS, Hughes M et al.: Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012, 141(2 Suppl):e531S-e575S. Stroke risk varies considerably across different groups of patients with atrial fibrillation (AF). Antithrombotic prophylaxis for stroke is associated with an increased risk of bleeding. Here are graded recommendations for antithrombotic treatment based on net clinical benefit for patients with AF at varying levels of stroke risk and in a number of common clinical scenarios.
2.
Baker WL, Cios DA, Sander SD, Coleman CI: Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm 2009, 15:244-252. This analysis included 8 studies and a total of 14 unique warfarin-treated groups; 3 of the 8 studies and 4 of the warfarin groups were not included in the previous meta-analysis (van Walraven et al., 2006). Overall, patients spent a mean 55% (95% CI = 51%–58%) of their time in the therapeutic INR range. Meta-regression suggested that AF patients treated in a community usual care setting compared with an anticoagulation clinic spent 11% (95% CI = 2%–20%, n = 6 studies with 9 study groups) less time in range. 3.
Hylek EM, Singer DE: Risk factors for intracranial hemorrhage in outpatients raking warfarin. Ann Intern Med 1994, 120:897-902.
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Johnson JA, Cavallari LH: Pharmacogenetics and cardiovascular disease – implications for personalized medicine. Pharmacol Rev 2013, 65:987-1009. The past decade has seen tremendous advances in our understanding of the genetic factors influencing response to a variety of drugs, including those targeted at treatment of cardiovascular diseases. In the case of clopidogrel, warfarin, and statins, the literature has become sufficiently strong that guidelines are now available describing the use of genetic information to guide treatment with these therapies, and some health centers are using this information in the care of their patients.
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Budnitz DS, Lovegrove MC, Shehab N, Richards CL: Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011, 365:2002-2012.
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Baker WL: The changing face of anticoagulation management: an improving countenance. Pharmacotherapy 2013, 33:1133-1135.
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Lutetsky A, Dekel-Stern E, Chetrit A, Lubin F, Halkin H: Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thromb Haemost 1999, 81:396-399.
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Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW: Identification of the gene for vitamin K epoxide reductase. Nature 2004, 427:541-544.
9. Weeke P, Roden DM: Applied pharmacogenomics in cardiovascular medicine. Annu Rev Med 2014, 65:81-94. Interindividual heterogeneity in drug response is a central feature of all drug therapies. Studies in individual patients, families, and populations over the past several decades have identified variants in genes encoding drug elimination or drug target pathways that in some cases contribute substantially to variable efficacy and toxicity. Important associations of pharmacogenomics in cardiovascular medicine include clopidogrel and risk for in-stent thrombosis, steady-state warfarin dose, myotoxicity with simvastatin, and certain drug-induced arrhythmias. 10. Anderson JL, Horne BD, Stevens SM, Grove AS, Barton S, Nicholas ZP, Kahn SF, May HT, Samuelson KM, Muhlestein JB, for the Couma-Gen Investigators et al.: Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007, 116:2563-2570. An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wildtype and multiple variant genotypes. 11. Biss TT, Avery PJ, Williams MD, Brandao LR, Grainger JD, Kamali F: The VKORC1 and CYP2C9 genotypes are associated Current Opinion in Pharmacology 2016, 27:38–42
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with over-anticoagulation during initiation of warfarin therapy in children. J Thromb Haemost 2013, 11:373-375. 12. Perez-Andreu V, Roldan V, Anton AL, GarciaBarbera N, Corral J, Vicente V, Gonzalez-Conejero R: Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy. Blood 2009, 113:497-4979. 13. Shaw K, Amstutz U, Hildebrand C, Rassekh SR, Hosking M, Neville K, Leeder JS, Hayden MR, Ross CJ, Carleton BC: VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children. Pediatr Blood Cancer 2014, 61:1055-1062. 14. McClain MR, Palomaki GE, Piper M, Haddow JE: A rapid-ACCE review of CYP2C9 and VKORC1 alleles testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding. Genet Med 2008, 10:89-98. 15. Klein TE, Altman RB, Eriksson N, Gage BJ, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ et al.: Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009, 360:753-764. The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation. 16. Lenzini PA, Grice GR, Milligan PE, Dowd MB, Subherwal S, Deych E, Eby CS, King CR, Porche-Sorbet RM, Murphy CV et al.: Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients. J Thromb Haemost 2008, 6:1655-1662. 17. Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M et al.: Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011, 90:625-629. Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for 50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician. 18. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palereti G: Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012, 141(2 Suppl):e44S-e88S. 19. Gage BF, Eby C, Johnson JA, Deyche E, Rieder MJ, Ridker PM, Milligan PE, Grice G, Lenzini P, Rettie AE et al.: Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 2008, 84:326-331. 20. Sagreiya H, Berube C, Wen A, Ramakrishnan R, Mir A, Hamilton A, Altman RB: Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9. Pharmacogenet Genomics 2010, 20:407-413. 21. Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, Kesteven P, Christersson C, Wahlstrom B, Stafberg C, for the EU-PACT Group et al.: A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013, 369:2294-2303. Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. 22. Kimmel SE, French B, Kasner SE, Johnson SA, Anderson JL, Gage BF, Rosenberg YD, Eby CS, Madigan RA, McBane RB, for the COAG Investigators et al.: A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013, 369:2283-2293. At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference [genotype-guided group minus clinically
Current Opinion in Pharmacology 2016, 27:38–42
guided group], 0.2; 95% confidence interval, 3.4 to 3.1; P = 0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. 23. Goulding R, Dawes D, Price M, Wilkie S, Dawes M: Genotypeguided drug prescribing: a systematic review and metaanalysis of randomized controlled trials. Br J Clin Pharmacol 2015, 80:868-877. 24. Stergiopoulos K, Brown DL: Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials. JAMA Intern Med 2014, 174:1330-1338. In this meta-analysis of randomized clinical trials, a genotype-guided dosing strategy did not result in a greater percentage of time that the INR was within the therapeutic range, fewer patients with an INR greater than 4, or a reduction in major bleeding or thromboembolic events compared with clinical dosing algorithms. 25. Baker WL, Phung OJ: Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ Cardiovasc Qual Outcomes 2012, 5:711-719. 26. Verheugt FW, Granger CB: Oral anticoagulants for stroke prevention in atrial fibrillation: current status, special situations, and unmet needs. Lancet 2015, 386:303-310. 27. Pare G, Eriksson N, Lehr T, Connolly S, Eikelboom J, Ezekowitz MD, Axelsson T, Haertter S, Oldgren J, Reilly P et al.: Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation 2013, 127:1404-1412. 28. Mega JL, Walker JR, Ruff CT, Vandell AG, Nordio F, Deenadayalu N, Murphy SA, Lee J, Mercuri MF, Giugliano RP et al.: Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015, 385:2280-2287. 29. Sangier J, Clemens A: Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 2009, 15:09S-16S. 30. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J et al.: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009, 361:1139-1151. 31. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W: The pharmacokinetics, pharmacodynamics, and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007, 64:292-303. 32. Bendel SD, Bona R, Baker WL: Dabigatran: an oral direct thrombin inhibitor for use in atrial fibrillation. Adv Ther 2011, 28:460-472. 33. Gong IY, Kim RB: Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol 2013, 29:S24-S33. 34. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J et al.: Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013, 369:2093-2104. 35. Eckman MH, Rosand J, Greenberg SM, Gage BF: Costeffectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med 2009, 150:73-83. 36. Patrick AR, Avorn J, Choudhry NK: Cost-effectiveness of genotype-guided warfarin dosing for patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2009, 2:429-436. 37. Pink J, Pirmohamed M, Lane S, Hughes DA: Cost-effectiveness of pharmacogenetics-guided warfarin therapy vs. alternative anticoagulation in atrial fibrillation. Clin Pharmacol Ther 2014, 95:199-207. 38. Nutescu EA, Drozda K, Bress AP, Galanter WL, Stevenson J, Stamos TD, Desai AA, Duarte JD, Gordeuk V, Peace D et al.: Feasibility of implementing a comprehensive warfarin pharmacogenomics service. Pharmacotherapy 2013, 33:1156-1164.
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ScienceDirect Pharmacogenetics and oral antithrombotic drugs William L Baker1 and Samuel G Johnson2 Warfarin and other oral vitamin K antagonists (VKAs) have been the primary pharmacologic options with well-established efficacy data in high-risk patient populations. Warfarin dose requirements to achieve therapeutic anticoagulation are highly variable. This variability in response results in increased risk for adverse events, including thromboembolism and bleeding. Genetic variants in CYP2C9 and VKORC1 have been identified and shown to explain some of the variability in warfarin response. Prospective trials suggest that incorporation of genotype results in faster time to therapeutic range than without; however, whether these improvements result in improved clinical outcomes is unclear. The target-specific anticoagulants are alternatives to warfarin and do not require laboratory monitoring. Some pharmacogenetic variation in their clinical response may exist as well. Ongoing trials will provide a clearer picture of whether genotype-based warfarin dosing improves outcomes and may, therefore, subsequently be compared with the target-specific agents. Addresses 1 Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT, USA 2 Applied Pharmacogenomics, Kaiser Permanente Colorado, Denver, CO, USA Corresponding author: Baker, William L ([email protected])
Current Opinion in Pharmacology 2016, 27:38–42 This review comes from a themed issue on Cardiovascular and renal Edited by Gary O Rankin and Nalini Santanam
http://dx.doi.org/10.1016/j.coph.2016.01.008 1471-4892/# 2016 Elsevier Ltd. All rights reserved.
Introduction An appreciable amount of research in recent years has been focused on the prevention and treatment of thromboembolic disorders. Until relatively recently, oral vitamin K antagonists (VKAs) such as warfarin were the primary pharmacologic options with well-established efficacy data in high-risk patient populations [1]. Despite the evidence supporting its benefit, only about half of patients receiving warfarin maintain therapeutic control of their anticoagulation via international normalized ratio (INR) testing [2]. Warfarin dose requirements to achieve therapeutic anticoagulation are highly variable; in fact, by as much as 20-fold between patients. This variability in Current Opinion in Pharmacology 2016, 27:38–42
control results in increased risk for adverse events, including thromboembolism and bleeding [3,4]. Data shows that up to one-third of hospitalizations for adverse drug events in older adults is related to warfarin [5]. Factors that may lead to this poor control include dietary vitamin K irregularities, drug–drug interactions, and inter-patient variability [6,7]. Attempts to minimize the variability of response seen with warfarin have included evaluating various anticoagulation management models, adding concomitant therapies such as low-dose vitamin K, identifying patient-related factors that explain the variability (e.g. pharmacogenetics), and alternative anticoagulants [6]. Pharmacogenetics is a term referring to a limited set of genes that affect drug response [4]. Given the high-risk nature of oral anticoagulants, it is important for clinicians to have a working understanding of the impact of pharmacogenetics on variability of response and its clinical implications for patient care. This review will focus on the pharmacogenetic determinants of drug response for oral antithrombotics and provide an overview of the data that has been published in recent years.
Warfarin pharmacogenetics The anticoagulant activity for warfarin derives from inhibition of vitamin K epoxide reductase which encodes VKORC1 and subsequently reduces the amount of vitamin K available for synthesis of intrinsic coagulation factors [8]. Genetic variants in warfarin’s target, VKORC1, and the enzyme that is principally responsible for S-warfarin metabolism, cytochrome P450 2C9 (CYP2C9), are associated with increased sensitivity to warfarin [9]. Lower warfarin doses are required to achieve therapeutic anticoagulation in patients carrying certain variants [VKORC1 rs9923231, CYP2C9 rs1799853 (*2), rs1057910 (*3)] [10]. Additionally, a higher incidence of aboverange INRs and bleeding risk have been associated with these variants and are related to excessive anticoagulation [11]. Beyond VKORC1 and CYP2C9, several other genes, including cytochrome P450 4F2 (CYP4F2) and gamma glutamyl carboxylase (GGCX), are involved in the vitamin K pathway have also been associated with altered warfarin dose requirements [12]. However, their specific impact on warfarin dose variability is relatively minor once variants in VKORC1 and CYP2C9 have been taken into account. While much of the clinical focus on warfarin pharmacogenetics remains on treatment in adult patients, significant associations between warfarin dose and VKORC1/ CYP2C9 genotypes have been seen in pediatric patients; this suggests that evaluation of warfarin genetic variants is of significance when caring for children [13]. Figure 1 www.sciencedirect.com
Pharmacogenetics and antithrombotics Baker and Johnson 39
Figure 1
CYP4F2 3%
Clinical Factors 20%
Age Sex Drugs Diet BMI
CYP2C9 12%
Unknown 40%
GGCX 1%
VKORC1 24% Current Opinion in Pharmacology
Factors affecting warfarin dose requirements. BMI, body mass index; CYP, cytochrome P-450; GGCx, gamma glytamyl carboxylase; VKOR, vitamin K epoxide reductase
shows the relative impact of various factors on warfarin dose requirements [14]. Clinical warfarin-dosing algorithms may prove more accurate for predicting the warfarin dose requirements for individual patients [15,16]. Many of these algorithms adjust for patient-specific factors, including age, gender, VKORC1/CYP2C9 genotype and concomitant medications in their dosing scheme. Engaged clinicians can incorporate pharmacogenetic information into patient management with online (for example, www.warfarindosing.org), or downloaded smartphone applications (for example, iWarfarin). In addition, the Food and Drug Administration (FDA) has provided a warfarin dosing table in the warfarin (Coumadin) product label according to VKORC1, CYP2C9*2 and *3 genotypes. Nevertheless, the clinical benefit of pharmacogenetic testing to guide warfarin dosing remains the subject of intense debate. The Clinical Pharmacogenetics Implementation Consortium (CPIC) published clinical practice recommendations in 2011 for warfarin dosing based on a known VKORC1/CYP2C9 genotype [17], while organizations such as the American College of Chest Physicians do not recommend genotyping due to insufficient evidence of benefit [18]. Importantly, the CPIC guidelines specifically avoid commenting on whether ordering a pharmacogenetic test is www.sciencedirect.com
appropriate and if that data should be used in medical decision making. On the basis of available data for genetic determination of warfarin dose requirements, the most recent CPIC guideline in 2011 strongly recommended warfarin dosing based on genotype when available. The guidelines also recommend use of either the Gage and colleagues [19] or International Warfarin Pharmacogenetics Consortium (IWPC) algorithms [20] to assist with dosing. Interestingly, the CPIC and ACCP guidelines provide a framework for warfarin pharmacogenetics highlighted by two different philosophies for use of warfarin pharmacogenetic data: (1) do available data support genotype-guided warfarin dosing; and (2) when warfarin pharmacogenetic data are readily available should they should be used? Two clinical trials, published after the release of the CPIC guidelines, evaluated the impact of algorithms incorporating warfarin pharmacogenetics versus either algorithms or clinical dosing alone in patients newly initiating warfarin [21,22]. Pirmohamed and colleagues [21] randomized 455 United Kingdom and Swedish patients who were initiating warfarin to either a genotype-guided or standard dosing scheme. Warfarin genotyping, determined a point-of-care system, was included in a computerized loading-dose algorithm in the initial 3 days. The dose was individualized thereafter using a computerized software program. Use of genotyping significantly increased the time within the therapeutic INR range (TTR; 67.4%) during the 12 weeks versus standard dosing (60.3%; p < 0.001). Patients in the pharmacogenetic arm had fewer INR values over 4.0 (27.0% versus 36.6%; p = 0.03) and required a shorter time to reach their therapeutic INR (median: 21 days versus 29 days; p = 0.003). No major bleeding events were seen and a single thromboembolic event occurred in the control group. Kimmel and colleagues [22] randomized 1015 patients from the United States received warfarin (used for any indication) dosed according to a genotype-guided strategy or a clinically based strategy (control). Genotyping was incorporated into a pre-specified dosing algorithm that also utilized clinical data. The control group received warfarin without incorporation of the genotyping information into the algorithm. By contrast to the findings of Pirmohamed and colleagues [21], following 4 weeks of therapy, no significant difference in TTR between the genotype and control groups was seen (45.2% versus 45.4%, respectively; p = 0.91). Interestingly, genotyping in black patients resulted in significantly lower TTR than the control group (35.2% versus 43.5%; p = 0.01), suggesting that these patients may yield especially low value from genetic warfarin testing. Neither the mean percentage of time above or below the INR range or the time to first INR in the therapeutic range were different between groups. The principle secondary outcome of any Current Opinion in Pharmacology 2016, 27:38–42
40 Cardiovascular and renal
Meta-analyses of warfarin pharmacogenetic studies have suggested that genotype-guided dosing of warfarin significantly increased the TTR compared with clinical-only algorithms [23]. However, no differences in either major bleeding or risk of thrombosis have been seen [24]. It should be noted that studies to date have not been powered to show differences in clinical outcomes. Future directions
Focused translational research in warfarin pharmacogenetics continues, with intent to determine the precise impact of genotype-guided therapy for warfarin versus clinical practice on pertinent patient outcomes across different patient population subgroups. This includes the Genetics Informatics Trial (GIFT; NCT01006733) and the Warfarin Adverse Event Reduction for Adults Receiving Genetic Testing at Therapy Initiation (WARFARIN; NCT01305148). Both of these studies are powered on clinical outcomes, rather than surrogate markers of anticoagulation (TTR) with results anticipated in the next few years.
Target-specific anticoagulant pharmacogenetics A number of target-specific oral anticoagulants (TSOACs) have been approved for clinical use over the past 5 years, changing the landscape of thromboembolic prevention and treatment. Currently available TSOACs include apixaban, dabigatran, edoxaban, and rivaroxaban with others in various stages of development. Approved for a variety of indications, including prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and prevention and treatment of thromboembolism, these agents promise a number of benefits over warfarin [25]. These include a lack of required INR monitoring, fewer food and drug interactions, and (in some cases) improved efficacy and safety [26]. Compared with warfarin, much less is known about the pharmacogenetic profile of these agents; however, data on dabigatran and edoxaban have been recently published [27,28]. The oral direct thrombin inhibitor dabigatran etexilate is rapidly converted by esterases, including CES1, to dabigatran. Dabigatran is also a substrate of the P-glycoprotein intestinal efflux transporter ABCB1 [29]. It was originally approved for the prevention of stroke and systemic embolism in 2010 based on the results of the Randomized Evaluation of Long-term Anticoagulation Therapy (RELY) trial [30]. RE-LY, which enrolled over 18,000 patients with non-valvular atrial fibrillation, showed that dabigatran etexilate 150 mg twice daily significantly reduced the risk of stroke (ischemic and hemorrhagic) versus warfarin, while the 110 mg twice daily dose had similar efficacy. Despite dabigatran exhibiting a more Current Opinion in Pharmacology 2016, 27:38–42
predictable pharmacokinetic profile versus warfarin, interindividual variability in blood concentrations of its active metabolite have been suggested [31,32]. In order to determine if genetic factors were responsible for this variability, a genome-wide analysis of 2944 participants from the RE-LY trial were analyzed [27]. They showed that alleles of the CES1 SNP rs2244613, present in nearly 33% of participants, was associated with 15% lower trough dabigatran concentrations and reduced risk for any bleeding (OR 0.67, 95% CI 0.55–0.82; p = 7 10 5). When compared to those receiving warfarin, carriers had less bleeding with dabigatran (HR 0.59, 95% CI 0.46–0.76; p = 5.2 10 5) while no difference was seen in noncarriers (HR 0.96, 95% CI 0.81–1.14; p = 0.65). Minor alleles of the ABCB1 SNP rs4148738 and the CESI SNP rs8192935 were each associated with 12% reductions in peak dabigatran concentrations; neither resulted in appreciable clinical bleeding or ischemic events. Fig. 2 shows impact of various clinical and pharmacogenetic factors on plasma dabigatran levels in a typical patient with atrial fibrillation receiving the 150 mg twice-daily dose [33]. The only pharmacogenetic study evaluating edoxaban compared it with genotype-based dosing of warfarin using data from the ENGAGE AF-TIMI 48 trial [28,34]. A subgroup of patients in the warfarin arm were genotyped for their CYP2C9 and VKORC1 status. Information was used to classify patients as either normal, sensitive, or highly sensitive responders to warfarin. The sensitive and highly sensitive warfarin responders, not surprisingly, spent a greater proportion of their time above the therapeutic INR range compared with the normal responders and had a higher risk of bleeding. As a result, risk of Figure 2
500
Plasma [Dabigatran] ng/mL)
INR 4, major bleeding, or thromboembolism was similar between groups ( p = 0.93).
Typical AF Patient CrCl 30 mL/min Age (93 vs. 68) CrCl 50 mL/min CES1 SNP (rs2244613) P-gp Inhibition P-gp Induction
450 400 350 300 250 200 150 100 50 0 0
6
12
18
24
Time since last dose (hr) Current Opinion in Pharmacology
Plasma concentrations of dabigatran 150 mg in atrial fibrillation patients. AF, atrial fibrillation; AUC, area under the concentration curve; CES1, carboxylesterase 1; SNP, single-nucleotide polymorphism; P-gp, P-glycoprotein. Reprinted with permission from Ref. [32]. www.sciencedirect.com
Pharmacogenetics and antithrombotics Baker and Johnson 41
bleeding was lower in patients receiving both low-dose (Pinteraction = 0.0036) and high-dose (Pinteraction = 0.0066) edoxaban than either the sensitive or highly sensitive warfarin responders versus the normal responders. After 90-days, no difference in bleeding risk was seen between edoxaban and any of the warfarin response groups. Future directions
Given the pharmacologic and pharmacokinetic profiles of the TSOACs, additional investigations into the impact of pharmacogenetic variation on their efficacy and safety profiles is warranted. Perhaps more importantly, a clinical trial investigating whether a TSOAC improves outcomes when compared to genotype-based dosing of warfarin would be of interest. The likelihood of such a trial appears remote, but may provide clinicians with a more complete picture of thrombosis management.
Conclusions Warfarin remains the most commonly used anticoagulant for preventing and treating thromboembolic disorders, although TSOACs use is increasing. It is probably that warfarin will continue to be used as the anticoagulant of choice by many practitioners. It is, therefore, imperative to identify the most effective means for initiating and chronically dosing warfarin therapy. Till date, the clinical utility of incorporative warfarin genotype information into the dosing strategy is unclear. Moreover, studies have questioned the cost-effectiveness of such a strategy [35–37]. Successful implementation of a warfarin pharmacogenomics service in a large academic institution has, however, been seen [38]. Until clinical trials show improvements in hard outcomes, it seems unlikely that third-party payers will reimburse for the cost of the pharmacogenetic testing and interpretation with such a service. Additional data in both pediatric and minority populations is also warranted. The TSOACs may be considered alternatives in these populations until this information becomes available.
Disclosures Dr. Baker serves on the speaker’s bureau for Boehringer Ingelheim.
Funding Dr. Baker was supported, in part, by the Connecticut Institute for Clinical and Translational Science (CICATS) at the University of Connecticut. The content is solely the responsibility of the authors and does not necessarily represent the official views of CICATS.
Conflict of interest statement Dr. Baker — speaker for Boehringer Ingelheim; Dr. Johnson — none.
Acknowledgement None. www.sciencedirect.com
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
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Current Opinion in Pharmacology 2016, 27:38–42
guided group], 0.2; 95% confidence interval, 3.4 to 3.1; P = 0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. 23. Goulding R, Dawes D, Price M, Wilkie S, Dawes M: Genotypeguided drug prescribing: a systematic review and metaanalysis of randomized controlled trials. Br J Clin Pharmacol 2015, 80:868-877. 24. Stergiopoulos K, Brown DL: Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials. JAMA Intern Med 2014, 174:1330-1338. In this meta-analysis of randomized clinical trials, a genotype-guided dosing strategy did not result in a greater percentage of time that the INR was within the therapeutic range, fewer patients with an INR greater than 4, or a reduction in major bleeding or thromboembolic events compared with clinical dosing algorithms. 25. Baker WL, Phung OJ: Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ Cardiovasc Qual Outcomes 2012, 5:711-719. 26. Verheugt FW, Granger CB: Oral anticoagulants for stroke prevention in atrial fibrillation: current status, special situations, and unmet needs. Lancet 2015, 386:303-310. 27. Pare G, Eriksson N, Lehr T, Connolly S, Eikelboom J, Ezekowitz MD, Axelsson T, Haertter S, Oldgren J, Reilly P et al.: Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation 2013, 127:1404-1412. 28. Mega JL, Walker JR, Ruff CT, Vandell AG, Nordio F, Deenadayalu N, Murphy SA, Lee J, Mercuri MF, Giugliano RP et al.: Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015, 385:2280-2287. 29. Sangier J, Clemens A: Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 2009, 15:09S-16S. 30. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J et al.: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009, 361:1139-1151. 31. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W: The pharmacokinetics, pharmacodynamics, and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007, 64:292-303. 32. Bendel SD, Bona R, Baker WL: Dabigatran: an oral direct thrombin inhibitor for use in atrial fibrillation. Adv Ther 2011, 28:460-472. 33. Gong IY, Kim RB: Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol 2013, 29:S24-S33. 34. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J et al.: Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013, 369:2093-2104. 35. Eckman MH, Rosand J, Greenberg SM, Gage BF: Costeffectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med 2009, 150:73-83. 36. Patrick AR, Avorn J, Choudhry NK: Cost-effectiveness of genotype-guided warfarin dosing for patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2009, 2:429-436. 37. Pink J, Pirmohamed M, Lane S, Hughes DA: Cost-effectiveness of pharmacogenetics-guided warfarin therapy vs. alternative anticoagulation in atrial fibrillation. Clin Pharmacol Ther 2014, 95:199-207. 38. Nutescu EA, Drozda K, Bress AP, Galanter WL, Stevenson J, Stamos TD, Desai AA, Duarte JD, Gordeuk V, Peace D et al.: Feasibility of implementing a comprehensive warfarin pharmacogenomics service. Pharmacotherapy 2013, 33:1156-1164.
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