Although it has been used for more than 60 years, warfarin remains a difficult drug to manage due to its narrow therapeutic index and the wide interpatient variability in its dose requirements. The VKORC1 and CYP2C9 genotypes together account for approximately 25% to 30% of the interpatient warfarin dose variability. Guiding warfarin dosing using VKORC1 and CYP2C9 genetic information has the potential to improve dosing accuracy and shorten the time to dose stabilization, thus reducing the risk for adverse bleeding and thrombotic events during warfarin initiation. However, the translation of warfarin genetic data into clinical practice has been slow to catch on. The nuances of considering both genetic and clinical factors for warfarin dose estimation requires a level of expertise to support clinical decision making that can be best provided via a specialized clinical pharmacogenetics service. Thus, to potentially improve warfarin dosing and safety, we developed a coordinated, genotype-guided dosing and management approach for patients newly initiating warfarin at the University of Illinois Hospital & Health Sciences System (UI-Health).

Table 1. Responsibilities of Warfarin Pharmacogenetics Service
Select genotyping methodology.
Validate genetic tests.
Build the information technology infrastructure to support genetic testing.
Coordinate provider education.
Provide consultative services.
Serve as an information resource to support clinical decision making.
Explore methods to improve workflow.
Examine use of ancestry-specific dosing models.

We formed a multidisciplinary team, consisting of experts in pharmacogenetics, anticoagulation, clinical pathology, and clinical decision support, to develop genotype and clinical strategies for implementing warfarin genetics at UI-Health. Specific responsibilities of the pharmacogenetics team are listed in Table 1. Members of the team also serve as co-directors of the newly formed warfarin genetics consult service, which serves an integral role in translating genetic information in the context of clinical factors to provide an informed warfarin dose recommendation to the primary medical team. A supporting website provides resources and guidance on pharmacogenetics-based dosing and links to the UI Health Warfarin Clinical Care Guidelines.

As of August 2012, all patients newly starting warfarin while hospitalized at UI-Health are routinely genotyped for variants influencing warfarin dose requirements. Each genotyping order is accompanied by an automatic consult with the warfarin genetics consult service (Figure). An automatic order for warfarin genotyping and consultation with the pharmacogenetics service is initiated in response to a warfarin order for a patient with no warfarin order documented in the medical record within the previous 6 months. At the time of the new warfarin order, an alert appears to notify the ordering physician that genetic testing and consultation are now routine for new patients starting warfarin.

Figure. Pharmacogenetics Consult Service workflow.
CDS, clinical decision support; MP, molecular pathology; PGx, pharmacogenomic a CDS rules: new order for warfarin (any indication, inpatient or 23-hour, no warfarin order within 6 months, no prior warfarin PGx test).
Table 2. Genotypes Interrogated And Effect on Warfarin Dose
Gene Variant(s) Effect on Warfarin Dose
VKORC1 –1639G>A
AA genotype:
decreased dose requirement (approximately 3 mg/d)
AG genotype:
intermediate dose requirement (approximately 5 mg/d)
GG genotype:
increased dose requirement (approximately 6 mg/d)
CYP2C9 *2, *3, *5, *6, *11, *14, *15, *16 Decreased warfarin dose requirement (by approximately 20% to 30% per allele)

A residency-trained pharmacy fellow screens each genotype order for appropriateness, by checking whether the patient was receiving warfarin on admission. If the patient was, the fellow cancels the genotype and consult order and provides a note in the medical record to this effect. For genotyping orders deemed appropriate, the phlebotomy service draws blood, and the blood is sent to the CLIA-certified laboratory for genotyping. The aim is to have the genotype result available prior to the second warfarin dose. Table 2 shows the genotypes tested and related clinical consequences.

Once the patient’s genotype is available, the pharmacy fellow initiates a consult note, discusses the case with the medical team, and estimates a warfarin maintenance dose based on genotype and clinical factors. A medical fellow from either the cardiology or hematology service then assesses the patient, addends the pharmacy fellow’s note, and forwards the completed note to the attending physician for signature. The pharmacy fellow continues to provide a daily dose recommendation until the patient is discharged or reaches stable international normalized ratio. A pharmacy faculty member provides attending oversight to the pharmacy fellows and manages daily issues related to the service.

To our knowledge, the UI-Health initiative to implement warfarin pharmacogenetics is among the first in the nation and is consistent with our commitment to providing personalized medicine and translating genetic information into optimal medication management. Our population consists largely of patients of African ancestry or Hispanic ethnicity. Thus, implementation of warfarin pharmacogenetics at our institution provides a unique opportunity to examine the feasibility and optimize the delivery of genotype-guided medicine to underrepresented patient populations. Our ultimate goal is to provide personalized medication to reduce health care disparities and improve outcomes in our underserved population.

Drs. Cavallari and Nutescu reported no relevant financial conflicts of interest.