Pharmacogenetic testing to increase the efficacy and safety of coumarins in the treatment of thromboembolic disorders is discussed
Rianne MF van Schie MSc
Talitha I Verhoef MSc
Anthonius de Boer MD PhD
Anke-Hilse Maitland-van der Zee PharmD PhD
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands
Felix JM van der Meer MD PhD
Department of Thrombosis and Hemostasis, Leiden University Medical Center,
Leiden, The Netherlands
Coumarin derivatives, such as warfarin, phenprocoumon and acenocoumarol, are very effective in the prevention and treatment of thromboembolic diseases. The most important indications are atrial fibrillation and venous thromboembolism. Patients with atrial fibrillation have an annual stroke risk of 4.5%, which decreases to 1.4% during treatment with warfarin.(1) However, it is challenging to find the appropriate dose for each patient, as dosages can differ up to tenfold.(2) The coumarin dose that is optimal for one patient may cause haemorrhages or thromboembolic events in another patient; this is caused by the large intra- and inter-patient variability in dose response and the narrow therapeutic window of coumarins.
Therefore, the anticoagulant effect of coumarins should be monitored in order to keep the international normalised ratio (INR) within limits: the target ranges. Despite frequent INR monitoring, anticoagulants are still an important cause of drug-related hospitalisations.(3) Presently, most patients receive a standard loading dosing leading to substantial variation in anticoagulant effect. It is important that patients receive the right coumarin dose immediately, because this will increase the effectiveness and safety of therapy.
In the early nineties, there was a boost in publications concerning coumarins, despite the fact that warfarin was approved for human use in 1954; this increase was related to pharmacogenetic studies of coumarins. Pharmacogenetics is the study of variations in DNA sequence as related to drug response. In 1992, Rettie et al identified cytochrome P450 2C9 (CYP2C9) as the main metabolising enzyme of warfarin(4) and,in 1995, Furuya et al showed that single nucleotide polymorphisms (SNPs) in CYP2C9 influenced coumarin dose requirements.(5) Vitamin K epoxide reductase complex subunit 1 (VKORC1) was identified as the target enzyme for the coumarins in 20046,(7) and in 2005, the influence on coumarin dose requirements was published. Based on this pharmacogenetic knowledge, it is hypothesised that anticoagulation therapy can be improved by individualised dosing.
The SNPs in CYP2C9 and VKORC1 are very common among the Caucasian population. Over 30% of the population has at least one variant allele in CYP2C9 and over 60% in VKORC1.(8,9) These SNPs together explain approximately 40% of the inter-patient coumarin dose variability.(9) In 2007, the US Food and Drug Administration updated the warfarin label and advised pharmacogenetic testing before commencing coumarin therapy.(10) However, at that time, no dosing strategies based on pharmacogenetic data were available. Furthermore, there was no evidence that genotype-guided dosing resulted in increased safety and efficacy. Therefore, several large randomised controlled trials were initiated to investigate the added value of pretreatment genotyping in order to individualise the coumarin dose before the start of coumarin therapy.
In 2008, we started the European pharmacogenetics of oral anticoagulants (EU-PACT) trial (unique ClinicalTrials.gov identifiers: NCT01119274, NCT01119261, and NCT01119300).(11) In this multicentre clinical trial in six European countries, the added value of pretreatment genotyping for the three most often used coumarins is investigated; warfarin (Sweden and UK), phenprocoumon (The Netherlands, Germany and Austria) and acenocoumarol (The Netherlands and Greece). Patients in the control arm of the acenocoumarol and phenprocoumon trials receive a personalised dose based on age, height, weight, gender, and amiodarone use, whereas patients randomised to the intervention arm receive an individualised loading dose based on aforementioned parameters plus their CYP2C9 and VKORC1 genotype.(9)
For warfarin, the control group will be dosed according to standard clinical care, and the intervention group receives a genotype-guided dose regimen based on the same parameters as patients using acenocoumarol and phenprocoumon. We developed clinically applicable easy to use dose algorithms to determine the individualised coumarin dose. Because the start of coumarins for most indications cannot be postponed, genotyping results should be quickly available. The current clinical practice is to collect blood samples of several patients and to genotype them at the same time.
This might take up to several weeks, which is undesirable, given that the therapy cannot always be postponed. Therefore, in the EU-PACT trial we use the Optisense Genie I in combination with a point-of-care assay containing HyBeacon probes.(12) This point-of-care test provides us with the CYP2C9 and VKORC1 genotypes in 100 minutes and is estimated to cost less than US$50 per patient for CYP2C9 and VKORC1 genotypes together. Results of the EU-PACT trial are expected in mid-2013.
Other randomised, controlled trial (RCTs) currently recruiting patients are the Clarification of Optimal Anticoagulation Through Genetics (COAG) study (NCT00839657) and Genetics Informatics Trial (GIFT; NCT01006733). A randomised and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualising warfarin dosing (CoumaGen-II; NCT00927862) completed in June 2011 and the results have been published.
The study compared pharmacogenetic dosing (n=479, consisting of two groups with different genotype-guided dosing strategies) with a parallel control group (n=1866). The results showed that pharmacogenetic dosing was superior (percentage of out-of-range INR 30% versus 42% at three months; percentage of time in therapeutic range 71% versus 59% at three months, respectively; p<0.001), mainly caused by a lower percentage time spent ≤INR 1.5, which indicates under-anticoagulation (11% versus 23%, respectively).
When the results of the ongoing clinical trials investigating the effect of genotyping before starting the use of coumarins become available, a decision on whether or not to implement genotype-guided dosing should be made. This decision will not only depend on the effectiveness and safety of genotype-guided dosing but also on the cost effectiveness, because an important factor for implementation will be the reimbursement of the genetic test by health insurance companies.
A cost-effectiveness analysis compares the total costs and effectiveness of two or more treatment strategies. All costs must be considered, including not just the cost of genotyping, but also the cost of, for example, INR monitoring and the cost of adverse events. In the US, the willingness to pay for one additional Quality Adjusted Life Year (QALY) is US$50,000–100,000. Several economic evaluations have been performed for coumarin derivatives (although mostly in the US), resulting in a wide variability in cost-effectiveness ratios among the studies that have been carried out, ranging from US$60,750 to US$347,000 per QALY gained. Changes in the costs of genotyping cause large differences in cost-effectiveness ratios.
At present, the costs of genotyping vary widely; however, it is assumed that these costs will decrease substantially, especially if genotyping before starting therapy becomes routine practice. In addition, costs can vary widely among different countries. To perform reliable cost effectiveness analysis of genotype-guided dosing, the results of several large RCTs on the effectiveness and safety of genotype-guided dosing, preferably performed in a number of countries, are awaited.
Leveraging pharmacogenetic testing might optimise anticoagulant prescribing. Large randomised controlled trials are still ongoing and results are expected soon. If these trials provide evidence for safer and more effective anticoagulation therapies when genotyping the patient before commencement of therapy, cost effectiveness analysis should evaluate the economic value of pretreatment genotyping.
- Coumarin derivatives, such as warfarin, phenprocoumon and acenocoumarol, are effectivein the prevention and treatment of thromboembolic diseases. However, patients are constantly balancing between under-dosing, which introduces a risk of thromboembolic events, and overdosing, which increases the risk of a haemorrhage.
- Pharmacogenetics has been proven to explain approximately 40% of the inter-patient dose variability.
- Several genotype-guided dose algorithms have been developed and are currently being tested in large randomised controlled trials, investigating the added value of pre-treatment genotyping.
- For most indications, the anticoagulation therapy with coumarins cannot be postponed. Therefore, genotype results should be made available quickly after diagnosis. Point-of-care tests might be useful instruments to obtain genotype information rapidly.
- Large randomised controlled trials are still on-going. These trials will provide data on (cost-) effectiveness of pre-coumarin-treatment genotyping. Results from the EU-PACT trials are expected to become available mid-2013.
- Albers GW et al. Stroke prevention in nonvalvular atrial fibrillation: a review of prospective randomized trials. Ann Neurol 1991;30(4):511-8.
- Rosendaal FR. The Scylla and Charybdis of oral anticoagulant treatment. N Engl J Med 1996;22;335(8):587–9.
- van der Hooft CS et al. Adverse drug reaction-related hospitalisations: a nationwide study in The Netherlands. Drug Saf 2006;29(2):161–8.
- Rettie AE et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 1992;5(1):54–9.
- Furuya H et al. Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics 1995;5(6):389–92.
- Li T et al. Identification of the gene for vitamin K epoxide reductase. Nature 2004;427(6974):541-4.
- Rost S et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004;427(6974):537–41.
- Schalekamp T, de Boer A. Pharmacogenetics of oral anticoagulant therapy. Curr Pharm Des 2010;16(2):187–203.
- van Schie RM et al. Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data. Eur Heart J 2011;32(15):1909–17.
- US Food and Drug Adminstration. Transcript of the FDA press conference on Warfarin;16 August 2007. www.fda.gov/downloads/NewsEvents/Newsroom/MediaTranscripts/ucm123583.pdf (accessed 13 December 2012).
- van Schie RM et al. Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design. Pharmacogenomics 2009;10(10):1687–95.
- Howard R et al. Genotyping for CYP2C9 and VKORC1 alleles by a novel point of care assay with HyBeacon(R) probes. Clin Chim Acta 2011;412(23-24):2063–9.