The Long and Winding Road to Warfarin Pharmacogenetic Testing

• warfarin
• genotyping
• pharmacogenomics
• comparative effectiveness

“The right dose of the right drug to the right person” is an often-stated goal of pharmacogenomics and personalized medicine. Pharmacogenetics primarily uses genetic variants to identify subgroups of patients that may respond differently to a certain class of medications. Warfarin has become an interesting and important case study for pharmacogenetics. The drug has a narrow therapeutic index with high interindividual variability in dose response; the use of genetic information improves the ability to predict warfarin dose requirements (1). The ultimate goals of genotype-guided warfarin therapy are to: 1) reduce the risk of major bleeding events by avoiding supratherapeutic international normalized ratio (INR) values; and 2) provide better protection from thrombosis by reducing subtherapeutic INR values during warfarin initiation. For over a decade, now investigators have reported that genetic variants in CYP2C9and, more recently, VKORC1alter warfarin dose requirements (2) and have extended these data to laboratory (3) and clinical adverse events (4) during standard dose warfarin initiation. Translating these observations into tools that physicians can use to improve health outcomes for individual patients is challenging and requires establishing evidence of improved outcomes: reduction in adverse events, reduction in cost, or improvements in quality of life. The appropriate level of evidence required for a pharmacogenetic test to be adopted into clinical practice, however, has not yet been established. An evidence-based review in 2008 found that CYP2C9and VKORC1variant testing to guide warfarin dosing had good analytic and clinical validity but also concluded that there was insufficient evidence to show a reduction in serious bleeding events (5). Although the bulk of evidence for genotype-guided warfarin therapy has been derived from retrospective data, small (n <200 patients) prospective studies have provided mixed results, with 1 study failing to find any benefit (6) when compared with standard warfarin therapy and another finding reductions in bleeding events (7). Although a prospective randomized controlled trial is considered the evidentiary “gold standard,” it has been criticized for genotype-guided warfarin therapy because the trial setting itself may result in closer monitoring than would be seen in the real world, an effect that may obscure any potential benefits. Cost-effectiveness analyses of a genotype-guided strategy for warfarin have also been inconclusive and suggest that cost savings are sensitive to the cost of genetic testing, overall effectiveness, and the individual patient's risk of hemorrhage (8). Thus, although 50% of the variance in warfarin dose requirements is accounted for by CYP2C9and VKORC1variants along with clinical and demographic variables, prediction algorithms based on these factors (1,2) to tailor the initial warfarin dose are seldom used because of the contradictory data and the lack evidence to support coverage of the cost of genotyping by insurers.

In other cases of pharmacogenetic testing, there appear to be different thresholds for adoption and coverage, thus highlighting the lack of uniform standards for evaluation. This is not altogether surprising, because a test that limits the useof an expensive (e.g., cetuximab) or potentially toxic (e.g., abacavir) medication to those most likely to benefit or least likely to experience toxicity should be held to a different standard than a test that guides the methods of initiating therapy(e.g., warfarin). Genotyping colonic adenocarcinomas for gain of function genetic variants in KRASto guide the use of cetuximab to those who benefit the most is considered standard of care by most oncologists and is covered by the Center for Medicare and Medicaid Services (CMS): a decision that was based on retrospective analyses of samples collected in randomized clinical trials (9). However, testing for HLA-B*5701prior to administering abacavir to avoid hypersensitivity reactions was only adopted after demonstration of efficacy in a prospective randomized clinical trial (10).

Pharmacogenetics-based warfarin therapy currently presents a conundrum to physicians, regulators, and payers. On this backdrop, in this issue of the JournalEpstein et al. (11) performed a “single arm” prospective intervention study of 896 patients initiating warfarin therapy. Potential study participants were identified at the time when a warfarin prescription was filled and then subsequently contacted for informed consent, genomic sample collection, genotyping, and reporting of CYP2C9and VKORC1genotypes to the patient's physician along with a basic interpretation of test results. The investigators chose as their control population a historical cohort of 2,688 age- and sex-matched patients drawn from the same geographical areas and insurance plans. The median time from warfarin initiation to providing genotype information was 32 days. The intervention group, compared with the historical controls, had 31% fewer hospitalizations overall (adjusted hazard ratio: 0.69, 95% confidence interval: 0.58 to 0.82, p < 0.001) and 28% fewer hospitalizations for bleeding or thromboembolism (hazard ratio: 0.72, 95% confidence interval: 0.53 to 0.97, p = 0.03) during the 6-month period following warfarin initiation. To account for potential biases in temporal trends, the investigators compared 2 external cohorts (contemporary vs. historical) and found no difference in hospitalizations during the 2 time periods.

Epstein et al. (11) should be commended for reporting outcomes on the largest cohort of patients receiving genotype-guided warfarin initiation in a real-world setting. However, the main limitation of this study is its use of a historical control group. This leaves open the possibility that the benefits of genotype-guided warfarin therapy may be exaggerated due to cofounding, either in the vigilance by the treating physicians or the kinds of patients who agreed to participate. Although the investigators went to great lengths (multivariable adjustment, propensity scoring, matching) to account for differences between groups, it is conceivable that there is bias in the types of physicians that agreed to participate in the intervention and/or that factors differed between the intervention and the historical groups that were not measured or captured, such as patient education and socioeconomic status. Furthermore, it was unexpected that a similar reduction for all-cause versus thromboembolic/hemorrhagic hospitalization outcomes was observed, when one would have anticipated a preferential reduction for the latter. This may reflect that the patients (or their treating physicians) were systematically different in the intervention versus historical cohorts in a way that confounds the primary outcomes. This limitation could have easily been overcome by randomly selecting a contemporary control population. Another limitation was that the genotype information was delivered at a median of 32 days after initiating warfarin therapy. The investigators state that this intervention influenced provider actions, as indicated by appropriate dose adjustments in the 3 weeks following genotyping that was consistent with individual patients' genotypes. Although the data are consistent with this assertion, one cannot arrive at this conclusion based on these data alone. The observed dose changes may have occurred even withoutthe genotype information because INR measurements were being made during the first 32 days of warfarin therapy (before the genotype information was delivered). In fact, INR values obtained during the first weekof warfarin initiation have been shown to be highly correlated with the final dose requirements (12). Therefore, although this study has its flaws, the results suggest that there may be benefits of genotype-guided warfarin therapy when implemented in the “real world” that include clinically meaningful reductions in patient outcomes: namely hospitalizations due to bleeding and thromboembolism.

So what is the path forward for warfarin pharmacogenetics? Two important, ongoing, National Heart, Lung, and Blood Institute–sponsored prospective clinical trials—the COAG (Clarification of Optimal Anticoagulation Through Genetics) and the GIFT (Genetics Informatics Trial of Warfarin to Prevent Deep Venous Thrombosis) studies—will enroll ∼1,200 and ∼1,600 patients, respectively, and will prospectively test the hypothesis that genetically guided therapy improves laboratory (COAG study) and thrombotic/hemorrhagic (GIFT study) outcomes. Both will be important studies; however, results are not anticipated until 2011 at the earliest. Until then, we believe that additional research should be performed that takes advantage of the coverage with evidence development (CED) status provided for warfarin pharmacogenetic testing by CMS that will reimburse the cost of genetic testing if a Medicare beneficiary is enrolled in a prospective, randomized, outcomes study. We implore other payers to follow suit with CED for this and other genetic tests where a pathway to evidence generation needs to be blazed. In addition, a standard dosing algorithm (13) should be used during warfarin initiation in prospective randomized trials and observational studies, and we encourage more comparative effectiveness research that uses these tools versus the standard of care.

Beyond the research agenda for pharmacogenetics, there are policy issues that need to be concurrently addressed for the path to adoption to be a clear one. Health systems and payers need to be prepared and aligned to implement pharmacogenetics-based testing. This will require: 1) physician education of genetic testing; 2) reimbursement of genetic tests by payers; and 3) infrastructure to perform and to report in a timely manner genetic testing by health care delivery systems. With better alignment of the stakeholders, when novel genetic tests become available, they can be introduced into the health care markets. Comparative effectiveness research can provide the initial signals of efficacy that would lay the groundwork for coverage decisions or randomized controlled trials, if necessary. Evaluation of pharmacogenetic testing could be treated in a similar fashion as have novel imaging modalities such as positron emission tomography (PET) scanning for initial diagnosis and staging of malignancies. Beginning in 2006, PET was covered by CMS under the CED program for certain malignancies with the stipulation that patients be placed in the National Oncologic PET Registry, and on the basis of this registry data, CMS expanded PET coverage in 2009 (14).

Defining the evidentiary paths for pharmacogenetic testing is important as we look to the future of pharmacogenetics in clinical practice. Through the National Heart, Lung, and Blood Institute's commitment, the COAG and GIFT studies will soon provide high-level evidence on warfarin pharmacogenetics. However, will this be the path for other pharmacogenetic tests? It is difficult to imagine requiring randomized controlled trials for every new drug-marker combination, particularly for approved drugs such as warfarin where there will be few incentives and resources for conducting these studies. Recently, for example, clopidogrel received a “black box” warning stating that carriers of CYP2C19loss of function alleles do not receive its full benefits. Alternative thienopyridines, such as prasugrel, might be prescribed for carriers to mitigate the increased risk of laboratory (15) and clinical (16) outcomes conferred by these alleles, although prospective genotyping has not been tested in a clinical trial. Applying CED status to CYP2C19variant testing within a registry, as was done for PET scanning, might encourage the use of genetic testing and generate evidence that might be sufficient to justify genotype-guided thienopyridine therapy. Having the appropriate resources and infrastructure to implement genotype-guided therapies will further enable the type of clinical research reported by Epstein et al. (11) to generate efficacy signals for statins (17–20) and other important classes of cardiovascular drugs, such as oral thrombin inhibitors, that have promising pharmacogenetic applications. For example, dabigatran, if approved, could be considered a superior, though more expensive, oral anticoagulant that might be reserved for difficult-to-manage carriers of CYP2C9or VKORC1variants while noncarriers are given warfarin. This framework could easily be explored in substudies of randomized controlled trials, if genomic samples were stored, and through observational data if genetic testing and interpretation were widely available. Such a strategy may ultimately require a randomized trial; however, until we lay the groundwork for developing the appropriate evidentiary path for pharmacogenetic testing, personalized medicine will remain an often-cited goal that remains on the research horizon without any tangible benefits for patients.

• American College of Cardiology Foundation