perspec tives anticoagulants has an important role in improving the effectiveness and safety of coumarin therapy. The European trials confirm that, and we should not ignore the mass of observational data that has been produced over the past decade showing the importance of genetics in determining daily dosing of these drugs. Indeed, in the world of genomics, where investigators are criticized for the lack of replication of their genetic findings, it is important to remember that the effect of CYP2C9 and VKORC1 genetic polymorphisms in determining dose requirements for the coumarin anticoagulants is one of the most highly replicated phenotype– genotype associations. We should not throw out the baby with the bathwater!
CONFLICT OF INTEREST The authors declared no conflict of interest. © 2014 ASCPT
1. Verhoef, T.I., Redekop, W.K., Daly, A.K., van Schie, R.M., de Boer, A. & Maitland-van der Zee, A.H. Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon. Br. J. Clin. Pharmacol. 77, 626–641 (2014). 2. Leendertse, A.J., Egberts, A.C., Stoker, L.J., van den Bemt, P.M.; HARM Study Group. Frequency of and risk factors for preventable medication-related hospital admissions in the Netherlands. Arch. Intern. Med. 168, 1890–1896 (2008). 3. Pirmohamed, M. et al.; EU-PACT Group. A randomized trial of genotype-guided dosing of warfarin. N. Engl. J. Med. 369, 2294–2303 (2013). 4. Verhoef, T.I. et al.; EU-PACT Group. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N. Engl. J. Med. 369, 2304–2312 (2013).
5.
6.
7.
8.
9.
10.
Verhoef, T.I. et al.; EU-PACT Group. Long-term anticoagulant effects of the CYP2C9 and VKORC1 genotypes in acenocoumarol users. J. Thromb. Haemost. 10, 606–614 (2012). Verhoef, T.I., Redekop, W.K., Hegazy, H., de Boer, A. & Maitland-van der Zee, A.H.; EU-PACT group. Long-term anticoagulant effects of CYP2C9 and VKORC1 genotypes in phenprocoumon users. J. Thromb. Haemost. 10, 2610–2612 (2012). Kimmel, S.E. et al.; COAG Investigators. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N. Engl. J. Med. 369, 2283–2293 (2013). Hernandez, W. et al. Ethnicity-specific pharmacogenetics: the case of warfarin in African-Americans. Pharmacogenomics J.; e-pub ahead of print 10 September 2013. Howard, R. et al. Genotyping for CYP2C9 and VKORC1 alleles by a novel point of care assay with HyBeacon® probes. Clin. Chim. Acta 412, 2063–2069 (2011). Nutescu, E.A. et al. Feasibility of implementing a comprehensive warfarin pharmacogenetics service. Pharmacotherapy 33, 1156–1164 (2013).
New Oral Anticoagulants vs. Warfarin Treatment: No Need for Pharmacogenomics? WL Baker1,2 and KW Chamberlin1,2
For patients requiring long-term anticoagulation, oral vitamin K antagonists (VKAs) such as warfarin have overwhelming efficacy data and present significant challenges. In addition to the potential exposure to numerous drug– drug and drug–food interactions, patients receiving warfarin require frequent monitoring. It had been hoped that the integration of pharmacogenomic with clinical information would improve anticoagulation control with warfarin, but trials have not supported this aim. Novel oral anticoagulants (NOACs) offer both advantages and disadvantages and deserve consideration in appropriate patients. Warfarin for preventing stroke in atrial fibrillation
The benefits of oral VKAs such as warfarin in patients with atrial fibrillation are well established.1 In patients at high risk
of events, VKA therapy can be expected to prevent 15 deaths and 15 nonfatal strokes per 1,000 patients while resulting in 8 additional nonfatal major extracranial bleeds.1 These benefits become more dramatic in individuals at higher risk. Despite the benefits of VKAs, fewer than half of eligible patients are receiving such therapy, and many are not having it optimized. A meta-analysis of trials published in the United States showed that only 55% (95% confidence interval (CI) 51–58%) of patient treatment time is within the therapeutic international normalized ratio (INR) range (TTR).2 Those seen in dedicated anticoagulation clinics had a higher TTR (63%; 95% CI 58–68%) compared with patients receiving community-based care (51%; 95% CI 51–58%).2 Improving the control of warfarin levels is important given the strong relation-
ship between TTR and event rates.3 Apart from excessively elevated or depressed values, a single INR outside the therapeutic range poses little risk. However, when patients have lower TTR than desired, significant increases in major adverse events have been seen.3 Therefore, identifying strategies to optimize control of VKA therapy and potentially improve clinical outcomes is paramount. Role of pharmacogenomics in warfarin dosing
Warfarin is a racemic mixture of its R- and S-enantiomers, with S-warfarin having the higher potency (two- to fourfold).3 By inhibiting the vitamin K– epoxide reductase complex (VKORC), warfarin prevents the carboxylation of the vitamin K–dependent clotting factors (II, VII, IX, and X), resulting in their partial activation. The hepatic metabo-
1Department of Pharmacy Practice, School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA; 2School of Medicine, University of Connecticut, Farmington, Connecticut, USA. Correspondence: WL Baker ([email protected])
doi:10.1038/clpt.2014.48 Clinical pharmacology & Therapeutics | VOLUME 96 NUMBER 1 | JULY 2014
17
perspec tives lism of S-warfarin occurs primarily via cytochrome P450 (CYP) 2C9 and, to a lesser extent, CYP3A4 (ref. 3). Several mutations in the genes encoding both the CYP2C9 and VKORC1 enzymes have been identified. The two most common polymorphisms are the CYP2C9*2 and CYP2C9*3 variants. 4 Individuals with either or both of these variants have an impaired ability to metabolize S-warfarin and require lower doses than those homozygous for the wild type (CYP2C9*1). A function variant in the promoter region of the VKORC1 gene (-1639G>A) alters the transcription factor binding site, with -1639A carriers having lower warfarin dose requirements than those with the wild type (-1639G).4 When combined with various clinical characteristics, the polymorphisms to CYP2C9 and VKORC1 may explain approximately 50% of the variability in warfarin dose requirements. Clinical trials have constructed models to improve prediction of dose requirements and, potentially, efficacy and safety of warfarin.5,6 The International Warfarin Pharmacogenetics Consortium used data from more than 5,000 patients to derive and validate a warfarin dosing algorithm that included both clinical and pharmacogenomic variables.5 Their algorithm provided better prediction of dose in those requiring either ≤21 or ≥49 mg/ week, representing just less than half of the entire cohort. The CoumaGen study randomized 206 patients who were beginning warfarin therapy to either a pharma-
cogenetic-guided or a standard empirical dosing strategy.6 Although the pharmacogenetic-guided strategy better predicted stable doses (P < 0.001) and required fewer dose changes and INRs (P = 0.06), the primary end point of the per-patient percentage of out-of-range INRs did not differ between the groups (P = 0.47). Citing the apparent overall lack of evidence demonstrating either clinical benefit or cost-effectiveness, guidelines recommend against the routine use of pharmacogenetic testing for guiding dosing of VKAs.7 Moreover, third-party payers do not currently reimburse for the cost of warfarin-related genetic testing outside of a clinical trial setting. Thus, patients would incur any resultant costs. Two recently published clinical trials evaluated the benefit of pharmacogenomic testing for initiation of anticoagulation with warfarin.8,9 Pirmohamed and colleagues randomized 455 patients from the United Kingdom and Sweden who were initiating warfarin to either a genotypeguided or a standard dosing scheme.8 Warfarin genotyping was performed using a point-of-care system that provided results within two hours and was incorporated into a computerized loading-dose algorithm for the first three days of treatment. An INR was checked on day 4 of therapy, and the dose was individualized using the algorithm that incorporated both genetic and clinical factors. Anticoagulation control was maintained thereafter using a software program according to usual clinical care in the region. Over the first three days,
the control group received a standard warfarin loading dose of 10, 5, and 5 mg (or 5, 5, and 5 mg if over 75 years of age). The genotyping arm had a significantly higher TTR (67.4%) during the 12 weeks than the standard-dosing arm (60.3%; P < 0.001). Genotyped patients also had significantly fewer INR values ≥4.0 (27.0% vs. 36.6%; P = 0.03) and a shorter time to reach a therapeutic INR (median: 21 days vs. 29 days; P = 0.003). There were no major bleeding events while only a single thromboembolic event occurred in the control group. Kimmel and colleagues randomized 1,015 patients from the United States who were initiating warfarin (regardless of indication) to receive warfarin dosed according to either a genotype-guided or clinically based strategy (control).9 Genotyping, determined using standard platforms, was incorporated into a prespecified dosing algorithm that also used clinical data. This enabled individualized dosing on the first three days of therapy; on days 4 and 5, a dose-revision algorithm was used. Standardized doseadjustment techniques were used thereafter. Patients in the control group had their warfarin dosed with the genotyping information omitted from the algorithm. No significant difference in TTR was found between the genotype and control groups after 4 weeks of therapy (45.2% vs. 45.4%, respectively; P = 0.91). Interestingly, in black patients genotyping led to TTRs that were significantly lower than those for the control group (35.2% vs. 43.5%; P = 0.01), suggesting
Table 1 Oral anticoagulant metabolism, transport, and monitoring comparisons Warfarin
Dabigatran
Rivaroxaban
Apixaban
Drug class
Vitamin K antagonist
Direct thrombin inhibitor
Direct factor Xa inhibitor
Direct factor Xa inhibitor
CYP450 interactions
Substrate of 2C9 (major); 1A2, 2C8, 2C18, 2C19, 3A4 (minor)
None
Substrate of 2J2, 3A4 (major)
Substrate of 3A4 (major); 1A2, 2C8, 2C9, 2C19, 2J2 to inactive metabolites (minor)
Transport interactions None
P-glycoprotein substrate
P-glycoprotein substrate
P-glycoprotein substrate and BCRP
Elimination
Urine (80%), 12–17 hours; extends to 28 hours in severe renal impairment
Urine (66% via active tubular secretion, 36% as unchanged drug, 30% as inactive metabolites), 5–9 hours (11–13 hours in elderly) Feces (28%, 7% unchanged, 21% as inactive metabolites)
Urine (27% as parent drug), 2.5 mg, 8 hours; 5 mg, 15 hours Feces (25% of dose recovered as metabolites)
Routine monitoring not required
Routine monitoring not required
Routine monitoring not required
Urine (92%), primarily as metabolites, 40 hours (20–60 hours)
Monitoring parameters PT, INR
BCRP, breast cancer resistant protein; CYP, cytochrome P450; INR, international normalized ratio; PT, prothrombin time. 18
VOLUME 96 NUMBER 1 | JULY 2014 | www.nature.com/cpt
perspec tives that these patients may benefit very little from genetic warfarin testing. The mechanism behind these results is not clear. It is possible that previous studies did not enroll sufficient numbers of black patients and thus were not appropriately powered to identify this signal of differing effect. Significant differences in the mean percentage of time above or below the INR range or time to first INR in the therapeutic range were not seen. The occurence of principal secondary outcomes of any INR≥4—major bleeding or thromboembolism—were similar between the groups (P = 0.93). Taken together, these clinical trial results suggest that incorporating genotype information into dosing schemes during initiation of warfarin provides inconsistent benefit, depending on the algorithm used. It is likely that the differences in warfarin dosing algorithms between these two studies led to the disparate results. They reflect the style of practice in specific countries or regions studied. For the United States, the algorithm used by Pirmohamed and co-workers8 has little external validity; thus, the results of Kimmel and colleagues’ trial9 are more applicable to a North American population. Moreover, no data exist on changes in clinically relevant outcomes such as bleeding or thromboembolism. However, these trials were not powered to show differences in clinical events and generally had low event rates. Thus, more reliable approaches to improving anticoagulation and reducing adverse outcomes are desirable. Newer oral anticoagulant alternatives to warfarin
In the past few years, three novel oral anticoagulants (NOACs) have been approved for clinical use (Table 1). Dabigatran is a direct thrombin inhibitor and rivaroxaban and apixaban are direct factor Xa inhibitors. These intriguing agents offer advantages and disadvantages over warfarin. Each of these agents has been directly compared with warfarin in large clinical trials, reviewed in ref. 10. It should be acknowledged, however, that none of these studies dosed warfarin with the aid of pharmacogenomic information; therefore, they should not be directly consid-
ered in context with those that have. The NOACs are at least as good as warfarin— and in some cases superior—at reducing the risk of stroke and systemic emboli, all-cause mortality, hemorrhagic stroke, and major bleeding in patients with nonvalvular atrial fibrillation.10 In addition to the differences between agents, the populations of the individual trials differed slightly, reflecting various levels of risk. Increased risk of gastrointestinal bleeding has been seen with a few of the agents (dabigatran and rivaroxaban). Similarly, some signal for increased risk of myocardial infarctions exists with dabigatran, although a mechanism is not currently known. Because there have been no headto-head clinical trials directly comparing the NOACs, selection of an agent should be individualized on the basis of insurance coverage, concomitant drugs, and convenience of dosing. An advantage of the NOACs over warfarin is their stable and consistent pharmacokinetics, allowing for elimination of routine anticoagulation monitoring. This is valuable for patients who have difficulty reaching a laboratory to have their INR checked. The NOACs have fewer drug– drug interactions than warfarin, although there are a few of note. Each NOAC is a substrate for the P-glycoprotein drug transporter and should be used with caution in patients taking strong inhibitors, inducers, or other substrates. Apixaban and rivaroxaban should be used with caution in patients taking strong CYP3A4 inhibitors or inducers, whereas there have been few reports of drug–drug interactions with apixaban. Each NOAC also has a component of renal elimination, with dabigatran having the largest effect at 80%. Among the disadvantages of the NOACs is the absence of an antidote in the event of major bleeding, although one is under development. In addition, currently available strategies, including freshfrozen plasma and prothrombin complex concentrates, lack efficacy data. Despite being significantly more costly than warfarin (approximately $6–7 per day), the NOACs have shown to be cost-effective and are most appropriate for those with adequate prescription drug coverage to minimize the out-of-pocket expenses.
Conclusion
Although additional studies are in progress, the currently available data may not support routine use of genotyping for the initiation of warfarin in patients requiring anticoagulation. Studies have shown inconsistent effects on TTR and have not demonstrated reduction in adverse outcomes such as bleeding or thrombotic events. Thus, until more evidence is available, alternative treatment options such as the NOACs may be considered for patients who require long-term anticoagulation and desire an alternative to warfarin. CONFLICT OF INTEREST The authors declared no conflict of interest. © 2014 ASCPT
1. You, J.J. 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 141, e531S– e575S (2012). 2. Baker, W.L., Cios, D.A., Sander, S.D. & Coleman, C.I. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J. Manag. Care. Pharm. 15, 244–252 (2009). 3. Ageno, W., Gallus, A.S., Wittkowsky, A., Crowther, M., Hylek, E.M. & Palareti, G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141, e44S– e88S (2012). 4. Johnson, J.A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin. Pharmacol. Ther. 90, 625–629 (2011). 5. The International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N. Engl. J. Med. 360, 753–764 (2009). 6. Anderson, J.L. et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 116, 2563–2570 (2007). 7. Holbrook, A. et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidencebased clinical practice guidelines. Chest 141, e152S–e184S (2012). 8. Pirmohamed, M. et al. A randomized trial of genotype-guided dosing of warfarin. N. Engl. J. Med. 369, 2294–2303 (2013). 9. Kimmel, S.E. et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N. Engl. J. Med. 369, 2283–2293 (2013). 10. Baker, W.L. & Phung, O.J. Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ. Cardiovasc. Qual. Outcomes. 5, 711–719 (2012).
Clinical pharmacology & Therapeutics | VOLUME 96 NUMBER 1 | JULY 2014
19
CONFLICT OF INTEREST The authors declared no conflict of interest. © 2014 ASCPT
1. Verhoef, T.I., Redekop, W.K., Daly, A.K., van Schie, R.M., de Boer, A. & Maitland-van der Zee, A.H. Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon. Br. J. Clin. Pharmacol. 77, 626–641 (2014). 2. Leendertse, A.J., Egberts, A.C., Stoker, L.J., van den Bemt, P.M.; HARM Study Group. Frequency of and risk factors for preventable medication-related hospital admissions in the Netherlands. Arch. Intern. Med. 168, 1890–1896 (2008). 3. Pirmohamed, M. et al.; EU-PACT Group. A randomized trial of genotype-guided dosing of warfarin. N. Engl. J. Med. 369, 2294–2303 (2013). 4. Verhoef, T.I. et al.; EU-PACT Group. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N. Engl. J. Med. 369, 2304–2312 (2013).
5.
6.
7.
8.
9.
10.
Verhoef, T.I. et al.; EU-PACT Group. Long-term anticoagulant effects of the CYP2C9 and VKORC1 genotypes in acenocoumarol users. J. Thromb. Haemost. 10, 606–614 (2012). Verhoef, T.I., Redekop, W.K., Hegazy, H., de Boer, A. & Maitland-van der Zee, A.H.; EU-PACT group. Long-term anticoagulant effects of CYP2C9 and VKORC1 genotypes in phenprocoumon users. J. Thromb. Haemost. 10, 2610–2612 (2012). Kimmel, S.E. et al.; COAG Investigators. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N. Engl. J. Med. 369, 2283–2293 (2013). Hernandez, W. et al. Ethnicity-specific pharmacogenetics: the case of warfarin in African-Americans. Pharmacogenomics J.; e-pub ahead of print 10 September 2013. Howard, R. et al. Genotyping for CYP2C9 and VKORC1 alleles by a novel point of care assay with HyBeacon® probes. Clin. Chim. Acta 412, 2063–2069 (2011). Nutescu, E.A. et al. Feasibility of implementing a comprehensive warfarin pharmacogenetics service. Pharmacotherapy 33, 1156–1164 (2013).
New Oral Anticoagulants vs. Warfarin Treatment: No Need for Pharmacogenomics? WL Baker1,2 and KW Chamberlin1,2
For patients requiring long-term anticoagulation, oral vitamin K antagonists (VKAs) such as warfarin have overwhelming efficacy data and present significant challenges. In addition to the potential exposure to numerous drug– drug and drug–food interactions, patients receiving warfarin require frequent monitoring. It had been hoped that the integration of pharmacogenomic with clinical information would improve anticoagulation control with warfarin, but trials have not supported this aim. Novel oral anticoagulants (NOACs) offer both advantages and disadvantages and deserve consideration in appropriate patients. Warfarin for preventing stroke in atrial fibrillation
The benefits of oral VKAs such as warfarin in patients with atrial fibrillation are well established.1 In patients at high risk
of events, VKA therapy can be expected to prevent 15 deaths and 15 nonfatal strokes per 1,000 patients while resulting in 8 additional nonfatal major extracranial bleeds.1 These benefits become more dramatic in individuals at higher risk. Despite the benefits of VKAs, fewer than half of eligible patients are receiving such therapy, and many are not having it optimized. A meta-analysis of trials published in the United States showed that only 55% (95% confidence interval (CI) 51–58%) of patient treatment time is within the therapeutic international normalized ratio (INR) range (TTR).2 Those seen in dedicated anticoagulation clinics had a higher TTR (63%; 95% CI 58–68%) compared with patients receiving community-based care (51%; 95% CI 51–58%).2 Improving the control of warfarin levels is important given the strong relation-
ship between TTR and event rates.3 Apart from excessively elevated or depressed values, a single INR outside the therapeutic range poses little risk. However, when patients have lower TTR than desired, significant increases in major adverse events have been seen.3 Therefore, identifying strategies to optimize control of VKA therapy and potentially improve clinical outcomes is paramount. Role of pharmacogenomics in warfarin dosing
Warfarin is a racemic mixture of its R- and S-enantiomers, with S-warfarin having the higher potency (two- to fourfold).3 By inhibiting the vitamin K– epoxide reductase complex (VKORC), warfarin prevents the carboxylation of the vitamin K–dependent clotting factors (II, VII, IX, and X), resulting in their partial activation. The hepatic metabo-
1Department of Pharmacy Practice, School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA; 2School of Medicine, University of Connecticut, Farmington, Connecticut, USA. Correspondence: WL Baker ([email protected])
doi:10.1038/clpt.2014.48 Clinical pharmacology & Therapeutics | VOLUME 96 NUMBER 1 | JULY 2014
17
perspec tives lism of S-warfarin occurs primarily via cytochrome P450 (CYP) 2C9 and, to a lesser extent, CYP3A4 (ref. 3). Several mutations in the genes encoding both the CYP2C9 and VKORC1 enzymes have been identified. The two most common polymorphisms are the CYP2C9*2 and CYP2C9*3 variants. 4 Individuals with either or both of these variants have an impaired ability to metabolize S-warfarin and require lower doses than those homozygous for the wild type (CYP2C9*1). A function variant in the promoter region of the VKORC1 gene (-1639G>A) alters the transcription factor binding site, with -1639A carriers having lower warfarin dose requirements than those with the wild type (-1639G).4 When combined with various clinical characteristics, the polymorphisms to CYP2C9 and VKORC1 may explain approximately 50% of the variability in warfarin dose requirements. Clinical trials have constructed models to improve prediction of dose requirements and, potentially, efficacy and safety of warfarin.5,6 The International Warfarin Pharmacogenetics Consortium used data from more than 5,000 patients to derive and validate a warfarin dosing algorithm that included both clinical and pharmacogenomic variables.5 Their algorithm provided better prediction of dose in those requiring either ≤21 or ≥49 mg/ week, representing just less than half of the entire cohort. The CoumaGen study randomized 206 patients who were beginning warfarin therapy to either a pharma-
cogenetic-guided or a standard empirical dosing strategy.6 Although the pharmacogenetic-guided strategy better predicted stable doses (P < 0.001) and required fewer dose changes and INRs (P = 0.06), the primary end point of the per-patient percentage of out-of-range INRs did not differ between the groups (P = 0.47). Citing the apparent overall lack of evidence demonstrating either clinical benefit or cost-effectiveness, guidelines recommend against the routine use of pharmacogenetic testing for guiding dosing of VKAs.7 Moreover, third-party payers do not currently reimburse for the cost of warfarin-related genetic testing outside of a clinical trial setting. Thus, patients would incur any resultant costs. Two recently published clinical trials evaluated the benefit of pharmacogenomic testing for initiation of anticoagulation with warfarin.8,9 Pirmohamed and colleagues randomized 455 patients from the United Kingdom and Sweden who were initiating warfarin to either a genotypeguided or a standard dosing scheme.8 Warfarin genotyping was performed using a point-of-care system that provided results within two hours and was incorporated into a computerized loading-dose algorithm for the first three days of treatment. An INR was checked on day 4 of therapy, and the dose was individualized using the algorithm that incorporated both genetic and clinical factors. Anticoagulation control was maintained thereafter using a software program according to usual clinical care in the region. Over the first three days,
the control group received a standard warfarin loading dose of 10, 5, and 5 mg (or 5, 5, and 5 mg if over 75 years of age). The genotyping arm had a significantly higher TTR (67.4%) during the 12 weeks than the standard-dosing arm (60.3%; P < 0.001). Genotyped patients also had significantly fewer INR values ≥4.0 (27.0% vs. 36.6%; P = 0.03) and a shorter time to reach a therapeutic INR (median: 21 days vs. 29 days; P = 0.003). There were no major bleeding events while only a single thromboembolic event occurred in the control group. Kimmel and colleagues randomized 1,015 patients from the United States who were initiating warfarin (regardless of indication) to receive warfarin dosed according to either a genotype-guided or clinically based strategy (control).9 Genotyping, determined using standard platforms, was incorporated into a prespecified dosing algorithm that also used clinical data. This enabled individualized dosing on the first three days of therapy; on days 4 and 5, a dose-revision algorithm was used. Standardized doseadjustment techniques were used thereafter. Patients in the control group had their warfarin dosed with the genotyping information omitted from the algorithm. No significant difference in TTR was found between the genotype and control groups after 4 weeks of therapy (45.2% vs. 45.4%, respectively; P = 0.91). Interestingly, in black patients genotyping led to TTRs that were significantly lower than those for the control group (35.2% vs. 43.5%; P = 0.01), suggesting
Table 1 Oral anticoagulant metabolism, transport, and monitoring comparisons Warfarin
Dabigatran
Rivaroxaban
Apixaban
Drug class
Vitamin K antagonist
Direct thrombin inhibitor
Direct factor Xa inhibitor
Direct factor Xa inhibitor
CYP450 interactions
Substrate of 2C9 (major); 1A2, 2C8, 2C18, 2C19, 3A4 (minor)
None
Substrate of 2J2, 3A4 (major)
Substrate of 3A4 (major); 1A2, 2C8, 2C9, 2C19, 2J2 to inactive metabolites (minor)
Transport interactions None
P-glycoprotein substrate
P-glycoprotein substrate
P-glycoprotein substrate and BCRP
Elimination
Urine (80%), 12–17 hours; extends to 28 hours in severe renal impairment
Urine (66% via active tubular secretion, 36% as unchanged drug, 30% as inactive metabolites), 5–9 hours (11–13 hours in elderly) Feces (28%, 7% unchanged, 21% as inactive metabolites)
Urine (27% as parent drug), 2.5 mg, 8 hours; 5 mg, 15 hours Feces (25% of dose recovered as metabolites)
Routine monitoring not required
Routine monitoring not required
Routine monitoring not required
Urine (92%), primarily as metabolites, 40 hours (20–60 hours)
Monitoring parameters PT, INR
BCRP, breast cancer resistant protein; CYP, cytochrome P450; INR, international normalized ratio; PT, prothrombin time. 18
VOLUME 96 NUMBER 1 | JULY 2014 | www.nature.com/cpt
perspec tives that these patients may benefit very little from genetic warfarin testing. The mechanism behind these results is not clear. It is possible that previous studies did not enroll sufficient numbers of black patients and thus were not appropriately powered to identify this signal of differing effect. Significant differences in the mean percentage of time above or below the INR range or time to first INR in the therapeutic range were not seen. The occurence of principal secondary outcomes of any INR≥4—major bleeding or thromboembolism—were similar between the groups (P = 0.93). Taken together, these clinical trial results suggest that incorporating genotype information into dosing schemes during initiation of warfarin provides inconsistent benefit, depending on the algorithm used. It is likely that the differences in warfarin dosing algorithms between these two studies led to the disparate results. They reflect the style of practice in specific countries or regions studied. For the United States, the algorithm used by Pirmohamed and co-workers8 has little external validity; thus, the results of Kimmel and colleagues’ trial9 are more applicable to a North American population. Moreover, no data exist on changes in clinically relevant outcomes such as bleeding or thromboembolism. However, these trials were not powered to show differences in clinical events and generally had low event rates. Thus, more reliable approaches to improving anticoagulation and reducing adverse outcomes are desirable. Newer oral anticoagulant alternatives to warfarin
In the past few years, three novel oral anticoagulants (NOACs) have been approved for clinical use (Table 1). Dabigatran is a direct thrombin inhibitor and rivaroxaban and apixaban are direct factor Xa inhibitors. These intriguing agents offer advantages and disadvantages over warfarin. Each of these agents has been directly compared with warfarin in large clinical trials, reviewed in ref. 10. It should be acknowledged, however, that none of these studies dosed warfarin with the aid of pharmacogenomic information; therefore, they should not be directly consid-
ered in context with those that have. The NOACs are at least as good as warfarin— and in some cases superior—at reducing the risk of stroke and systemic emboli, all-cause mortality, hemorrhagic stroke, and major bleeding in patients with nonvalvular atrial fibrillation.10 In addition to the differences between agents, the populations of the individual trials differed slightly, reflecting various levels of risk. Increased risk of gastrointestinal bleeding has been seen with a few of the agents (dabigatran and rivaroxaban). Similarly, some signal for increased risk of myocardial infarctions exists with dabigatran, although a mechanism is not currently known. Because there have been no headto-head clinical trials directly comparing the NOACs, selection of an agent should be individualized on the basis of insurance coverage, concomitant drugs, and convenience of dosing. An advantage of the NOACs over warfarin is their stable and consistent pharmacokinetics, allowing for elimination of routine anticoagulation monitoring. This is valuable for patients who have difficulty reaching a laboratory to have their INR checked. The NOACs have fewer drug– drug interactions than warfarin, although there are a few of note. Each NOAC is a substrate for the P-glycoprotein drug transporter and should be used with caution in patients taking strong inhibitors, inducers, or other substrates. Apixaban and rivaroxaban should be used with caution in patients taking strong CYP3A4 inhibitors or inducers, whereas there have been few reports of drug–drug interactions with apixaban. Each NOAC also has a component of renal elimination, with dabigatran having the largest effect at 80%. Among the disadvantages of the NOACs is the absence of an antidote in the event of major bleeding, although one is under development. In addition, currently available strategies, including freshfrozen plasma and prothrombin complex concentrates, lack efficacy data. Despite being significantly more costly than warfarin (approximately $6–7 per day), the NOACs have shown to be cost-effective and are most appropriate for those with adequate prescription drug coverage to minimize the out-of-pocket expenses.
Conclusion
Although additional studies are in progress, the currently available data may not support routine use of genotyping for the initiation of warfarin in patients requiring anticoagulation. Studies have shown inconsistent effects on TTR and have not demonstrated reduction in adverse outcomes such as bleeding or thrombotic events. Thus, until more evidence is available, alternative treatment options such as the NOACs may be considered for patients who require long-term anticoagulation and desire an alternative to warfarin. CONFLICT OF INTEREST The authors declared no conflict of interest. © 2014 ASCPT
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Clinical pharmacology & Therapeutics | VOLUME 96 NUMBER 1 | JULY 2014
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