John R. Schmelzer

CYP4F2 genetic variant alters required warfarin dose.

Warfarin is an effective, commonly prescribed anticoagulant used to treat and prevent thrombotic events. Because of historically high rates of drug-associated adverse events, warfarin remains underprescribed. Further, interindividual variability in therapeutic dose mandates frequent monitoring until target anticoagulation is achieved. Genetic polymorphisms involved in warfarin metabolism and sensitivity have been implicated in variability of dose. Here, we describe a novel variant that influences warfarin requirements. To identify additional genetic variants that contribute to warfarin requirements, screening of DNA variants in additional genes that code for drug-metabolizing enzymes and drug transport proteins was undertaken using the Affymetrix drug-metabolizing enzymes and transporters panel. A DNA variant (rs2108622; V433M) in cytochrome P450 4F2 (CYP4F2) was associated with warfarin dose in 3 independent white cohorts of patients stabilized on warfarin representing diverse geographic regions in the United States and accounted for a difference in warfarin dose of approximately 1 mg/day between CC and TT subjects. Genetic variation of CYP4F2 was associated with a clinically relevant effect on warfarin requirement.

Evaluation of genetic factors for warfarin dose prediction.

Objectives: Warfarin is a commonly prescribed anticoagulant drug used to prevent thromboses that may arise as a consequence of orthopedic and vascular surgery or underlying cardiovascular disease. Warfarin is associated with a notoriously narrow therapeutic window where small variations in dosing may result in hemorrhagic or thrombotic complications. To ultimately improve dosing of warfarin, we evaluated models for stable maintenance dose that incorporated both clinical and genetic factors. Method: A model was constructed by evaluating the contribution to dosing variability of the following clinical factors: age, gender, body surface area, and presence or absence of prosthetic heart valves or diabetes. The model was then sequentially expanded by incorporating polymorphisms of cytochrome P450 (CYP) 2C9; vitamin K 2,3 epoxide reductase complex, subunit 1 (VKORC1); gamma carboxylase; factor VII; and apolipoprotein (Apo) E genes. Results: Of genetic factors evaluated in the model, CYP2C9 and VKORC1 each contributed substantially to dose variability, and together with clinical factors explained 56% of the individual variability in stable warfarin dose. In contrast, gamma carboxylase, factor VII and Apo E polymorphisms contributed little to dose variability. Conclusion: The importance of CYP2C9 and VKORC1 to patient-specific dose of warfarin has been confirmed, while polymorphisms of gamma carboxylase, factor VII and Apo E genes did not substantially contribute to predictive models for stable warfarin dose.

A randomized controlled trial of genotype-based Coumadin initiation

Purpose: A randomized controlled trial was conducted in patients initiating warfarin to determine whether algorithms that incorporate genotypes affecting warfarin metabolism and function, and Vitamin K metabolism improve prediction of therapeutic warfarin dose and anticoagulation management.Methods: A total of 230 patients were randomized to either a clinical arm where dosing algorithms considered only clinical information or an interventional arm where dosing algorithms used clinical and genotypic variables (CYP2C9, CYP4F2, and VKORC1). Subjects in the interventional arm were genotyped within 5 hours, and the initial dose was informed by genotype. Primary endpoints were absolute prediction error relative to therapeutic dose, and time in therapeutic target range during the first 14 days. Secondary endpoints included time to stable dose in therapeutic range, time to first international normalization ratio >4, and warfarin-related adverse events.Results: The model including genetics more accurately identified therapeutic dose twice as often as the clinical model (65.3% vs. 34.7%) (P < 0.0001). Patients in the interventional arm did not achieve greater time in therapeutic range. Study arms were similar regarding time to international normalization ratio >4 and adverse events.Conclusion: Genotype-informed dosing clearly improved prediction of therapeutic dose beyond that available with clinical parameters. Genetic information did not affect time in therapeutic target range during the first 14 days of therapy. Current management practices with the vagaries in dose adjustment after warfarin initiation exert a strong influence on traditional clinical outcomes.

Absence of Novel CYP4F2 and VKORC1 Coding Region DNA Variants in Patients Requiring High Warfarin Doses

Objective Warfarin is an FDA-approved oral anticoagulant for long-term prevention of thromboembolism. Substantial inter-individual variation in dosing requirements and the narrow therapeutic index of this widely-prescribed drug make safe initiation and dose stabilization challenging. Single nucleotide polymorphisms (SNPs) occurring in CYP2C9, VKORC1, and CYP4F2 genes are known to impact dose, and VKORC1 and CYP4F2 polymorphisms are associated with higher therapeutic dose requirements in our cohort. However, the most advanced regression models using personal, clinical, and genetic factors to predict individual stable dose account for only 50% to 60% of the observed variability in stable theapeutic dose in Caucasians. Design and Methods In this study, we used DNA sequence analysis to determine whether additional variants in CYP4F2 and VKORC1 gene coding regions contribute to variable dosing requirements among individuals for whom the actual dose was the highest relative to regression model- predicted dose. Results and Conclusions No novel DNA variants in the coding regions of these genes were identified among subjects requiring high warfarin doses, suggesting that other factors yet to be defined contribute to variability in warfarin dose requirements in this subset of our cohort.

Catheter Ablation in the Elderly in the United States: Use in the Medicare Population from 1991 to 1998

SMITH, P.N., et al.: Catheter Ablation in the Elderly in the United States: Use in the Medicare Population from 1991 to 1998. The safety and efficacy of catheter ablation for the treatment of drug refractory cardiac arrhythmias is well established in young patients. Little is known about its effectiveness or use in the elderly. We determined trends in the use of catheter ablation in the United States Medicare population. Data were obtained from the approximately 30 million patients covered each year by Medicares fee‐for‐service program of the Health Care Financing Administration of the Department of Health and Human Services. From 1991 to 1998, Medicares fee‐for‐service beneficiaries covered 80%–93% of all adults > 65 years old in the United States. All catheter‐based ablative procedures performed in this population were identified through the use of the Current Procedural Terminology codes 93650, 93651, and 93652. Use rate per 1 million beneficiaries grew from 33 in 1991 to 603 in 1998. While during this 7‐year period the Medicare fee‐for‐service population decreased by 8%, ablations increased 16‐fold (1,608%). The use of catheter ablation in the older American grew exponentially during the 1990s. Further research is needed to determine the optimal use of this potentially curative technique in the elderly.

Reinitiating Warfarin: Relationships Between Dose and Selected Patient, Clinical and Hospital Measures

Background Warfarin is an oral anticoagulant used in the long-term treatment/prevention of venothromboembolic disease. Patients undergoing elective surgical and non-surgical procedures may require temporary warfarin discontinuation followed by reinitiation after their procedure. Because little information is available regarding best methods for warfarin reinitiation, we investigated current practices to inform management decisions. Methods Subjects were required to have a known and stable warfarin dose prior to discontinuation, which was operationalized by requiring, within 7-days prior to discontinuation, that they have at least one INR in therapeutic range (2.0–3.5), no INR(s) out of range, and no more than a 15% change in warfarin dose. Stable dose prior to discontinuation was defined as the average daily dose received in the 7 days immediately prior to discontinuation. Reinitiation dose was defined as the average daily dose received in the first 3 days after warfarin was restarted. Subjects were divided into three groups based on whether they received approximately the same, a higher, or a lower dose at reinitiation and were also grouped by calendar time into three distinct periods that reflected differing levels of availability of electronic and patient care data that may impact reinitiation dose decisions. These groupings facilitated analyses and descriptions of trends in reinitiation dosing and supported other analyses, including tests for association between dose group and selected subject demographic, clinical, medication and hospitalization measures. All study data were abstracted from Marshfield Clinic electronic patient care and administrative databases and electronic patient care databases from Ministry St. Joseph’s Hospital (Marshfield, WI). Results We identified 205 subjects with warfarin temporarily discontinued between 1994 and 2012: 99 subjects in same dose group, 32 subjects in the low group, and 74 subjects in the high group. Because relatively wide differences were observed in the proportion of same dose subjects during more recent years (2007–2012) compared to earlier years (54% vs 35%), we focused our analyses on this recent period, which included 140 subjects. Review of physician notes and other documents yielded virtually no information about reasons for reinitiation dose decisions. In addition, tests for association between reinitiation dose group and subject demographic, clinical, medication and hospital measures were uniformly uninformative. Conclusions We observed varied dosing strategies for reinitiating patients on warfarin and, in more recent years, an apparent trend toward reinitiating patients on the same dose. However we could not associate dosing strategy with specific patient demographic, clinical, medication or hospital factors. Many factors influence whether a physician reinitiates a patient at a different dose than his/her prior stable warfarin dose. However, in the absence of clinical indications for modification, we believe patients with a previously established effective dose should be reinitiated at that same dose following temporary warfarin discontinuation.

Anxiety, Depression, and Adverse Clinical Outcomes in Patients With Atrial Fibrillation Starting Warfarin: Cardiovascular Research Network WAVE Study

Background Anxiety and depression are associated with worse outcomes in several cardiovascular conditions, but it is unclear whether they affect outcomes in atrial fibrillation (AF). In a large diverse population of adults with AF, we evaluated the association of diagnosed anxiety and/or depression with stroke and bleeding outcomes. Methods and Results The Cardiovascular Research Network WAVE (Community‐Based Control and Persistence of Warfarin Therapy and Associated Rates and Predictors of Adverse Clinical Events in Atrial Fibrillation and Venous Thromboembolism) Study included adults with AF newly starting warfarin between 2004 and 2007 within 5 health delivery systems in the United States. Diagnosed anxiety and depression and other patient characteristics were identified from electronic health records. We identified stroke and bleeding outcomes from hospitalization databases using validated International Classification of Diseases, Ninth Revision (ICD‐9), codes. We used multivariable Cox regression to assess the relation between anxiety and/or depression with outcomes after adjustment for stroke and bleeding risk factors. In 25 570 adults with AF initiating warfarin, 490 had an ischemic stroke or intracranial hemorrhage (1.52 events per 100 person‐years). In multivariable analyses, diagnosed anxiety was associated with a higher adjusted rate of combined ischemic stroke and intracranial hemorrhage (hazard ratio, 1.52; 95% confidence interval, 1.01–2.28). Results were not materially changed after additional adjustment for patient‐level percentage of time in therapeutic anticoagulation range on warfarin (hazard ratio, 1.56; 95% confidence interval, 1.03–2.36). In contrast, neither isolated depression nor combined depression and anxiety were significantly associated with outcomes. Conclusions Diagnosed anxiety was independently associated with increased risk of combined ischemic stroke and intracranial hemorrhage in adults with AF initiating warfarin that was not explained by differences in risk factors or achieved anticoagulation quality.

PS1-18: A Feasibility Pilot to Determine the Practicality of Using the HMO Research Network to Research the Genetics of Drug-Induced Serious Adverse Events

Background/Aims The International Serious Adverse Events Consortium (iSAEC) is a pharmaceutical industry and FDA-led consortium focused on identifying DNA variants useful for predicting risk of drug-induced rare serious adverse events (SAEs). We assessed the feasibility of using electronic medical databases at six HMORN sites to identify provisional cases of three SAEs: drug-induced liver injury (DILI), serious skin rashes (SSR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and angioedema, and extreme weight gain (EWG) among adults on atypical antipsychotics. Methods Project work was divided among three teams. HealthPartners and Marshfield Clinic led the DILI team, Kaiser Permanente Hawaii and Kaiser Permanente Georgia led the SSR team and Group Health and Geisinger guided the EWG study. Teams met routinely via biweekly conference calls to coordinate their study efforts; monthly conference calls were conducted to coordinate the overall project, mark progress and discuss challenges and solutions. For each study, standardized case identification criteria were developed with input from iSAEC, expert panels, and medical literature. Potential cases were identified through electronic data searches using diagnoses, medication histories, laboratory test results, and other clinical data elements indicative of DILI and SSR during 2000–2009, or EWG from 2004–2009. Potential cases of DILI and SSR were abstracted to assess provisional case status and determine implicated drugs. Weight trajectories of suspected EWG cases were visually inspected to confirm EWG during atypical antipsychotic treatment period. Results A total of 99 provisional cases of DILI, 41 cases of SJS/TEN and 56 provisional cases of angioedema were identified from the electronic records of the participating HMOs. For EWG, 249 cases were confirmed and an additional 341 were categorized as “possible” cases, with additional chart review and patient interview required for confirmation. Confirmation rates varied from 17% for DILI to 2–79% for SSR and 23–30% for EWG. Conclusions The SAEC and HMORN study sites identified well-phenotyped cases with the targeted drug-induced SAEs of interest. The relative success of these efforts has been critical in the planning of a larger second study that will include analyses of genetic factors associated with provisional case SAEs.

PS1-31: Assessing the Potential for Research on Genetics of Drug Induced Liver Injury in the HMORN

Background/Aims Drug Induced Liver Injury (DILI) is a major cause of liver failure in the US and the leading reason for failure of investigational drugs in clinical trials, lack of drug approval, and post-market withdrawal of approved drugs. Recent genome-wide association studies have identified variations within the major histocompatibility complex in Caucasians to be linked with flucloxacillin and lumiracoxib-related liver injury. The need for replication of these findings and extension of these investigations to other drug exposures and other ethnic groups will require substantial case numbers with supporting medical record documentation. With support from The Serious Adverse Event Consortium, an international consortium led by the pharmaceutical industry in conjunction with the FDA, we conducted a feasibility study to evaluate the potential for using electronic clinical and administrative data from two HMORN sites to identify provisional DILI cases. Methods Building upon previous research, we developed data specifications for electronic searches of ICD-9 codes with time proximate laboratory results indicative of liver-related disease. Electronic criteria were used to ‘rule out’ other liver diseases and other co-morbid conditions indicative of systematic liver-related effects. For feasibility testing, two methods of population identification were incorporated: the VDW and EMR reporting. All records from 1/1/00–8/1/09 that were identified as ‘potential DILI cases’ were reviewed manually, and selected data were abstracted, including suspected implicated drug(s). Results Records for 1,123,173 individuals were screened for potential case status; 29,893 records with one or more diagnoses of interest were identified. After application of the “rule out’ exclusion criteria, 584 potential DILI cases were reviewed and 99 ultimately met provisional case status. Drugs commonly associated with provisional DILI cases were sulfa-containing antibiotics, anticonvulsants, isoniazid, and statins. Roughly one-half of provisional DILI cases were associated with a single implicated drug. Conclusions Electronic infrastructures currently available within many highly integrated health care delivery systems can be efficiently leveraged to support identification of provisional DILI events. Systems that have comprehensive episodic, historic and post-event data, including lab, diagnostic, treatment, imaging, and medication records that can be accessed electronically should be considered primary systems for expanding DILI case accumulation efforts.