Bleeding Complications With Warfarin Use

Wysowski, Diane K.; Nourjah, Parivash; Swartz, Lynette

doi:10.1001/archinte.167.13.1414

Cited by 501 publications

(165 citation statements)

References 25 publications

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“…1 However, warfarin ranks among the top 10 drugs causing serious adverse events and emergency room visits. 2 The safe use of warfarin is hampered by a narrow therapeutic index and substantial interindividual variation in dose requirements. Until an individual's therapeutic dose of warfarin is known, patients on warfarin therapy are at high risk for serious adverse health events, especially during drug initiation and when the international normalization ratio (INR) is above the therapeutic target range.…”

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A randomized controlled trial of genotype-based Coumadin initiation

Burmester¹,

Berg

Yale

et al. 2011

Genetics in Medicine

108

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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 Ͼ4, 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 Ͻ 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 Ͼ4 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. Genet Med 2011:13(6):509 -518.Key Words: anticoagulation, bleeding, CYP2C9, CYP4F2, INR, VKORC1, warfarin dosing U ntil very recently, warfarin has been the only US Food and Drug Administration-approved oral anticoagulant and is still the drug of choice for long-term anticoagulation. 1 However, warfarin ranks among the top 10 drugs causing serious adverse events and emergency room visits. 2 The safe use of warfarin is hampered by a narrow therapeutic index and substantial interindividual variation in dose requirements. Until an individual's therapeutic dose of warfarin is known, patients on warfarin therapy are at high risk for serious adverse health events, especially during drug initiation and when the international normalization ratio (INR) is above the therapeutic target range. 3 Interindividual variation in warfarin dose is mediated by multiple factors. 4 -6 Approximately 20% of the variability is explained by age, presence of comorbidities (e.g., diabetes, cancer, renal or liver disease, and concomitant use of some medications), and other personal characteristics (e.g., gender, smoking, and body size). 7 An additional 35% of dose variability is attributed to polymorphisms in CYP2C9, VKORC1, and CYP4F2 genes. 8 -10 For each of these genes, there is a clear biological pathway linking genetic variations to warfarin dose response. The CYP2C9 enzyme metabol...

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confidence: 99%

A randomized controlled trial of genotype-based Coumadin initiation

Burmester¹,

Berg

Yale

et al. 2011

Genetics in Medicine

108

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“…1 Warfarin is highly efficacious but continues to pose significant management challenges. [2][3][4][5][6][7] In wellconducted randomized controlled trials, time in therapeutic range (TTR) is usually only 60% to 65%.…”

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The First Evaluation of a Novel Vitamin K Antagonist, Tecarfarin (ATI-5923), in Patients With Atrial Fibrillation

et al. 2009

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Background-Tecarfarin (ATI-5923) is a novel oral vitamin K antagonist. Unlike warfarin, it is metabolized by esterases, escaping metabolism by the cytochrome P450 system and thereby avoiding cytochrome P450 -mediated drug-drug or drug-food interactions as well as genetic variations found in the cytochrome P450 system. Both tecarfarin and warfarin can be monitored with the international normalized ratio. We hypothesized that the time in therapeutic range for tecarfarin will exceed values usually experienced with warfarin. Methods and Results-This was a 6-to 12-week open-label, multicenter, phase IIA study of 66 atrial fibrillation patients with a mild to moderate risk of stroke to determine the safety and tolerability of tecarfarin and to ascertain an optimal tecarfarin dosing regimen. Sixty-four subjects (97%) were taking warfarin at enrollment and were switched to tecarfarin. After the initial 3 weeks of tecarfarin treatment, the mean interpolated time in therapeutic range was 71.4%. Only 10.9% of patients had time in therapeutic range of Ͻ45%. Times in extreme international normalized ratio ranges of Ͻ1.5 and Ͼ4.0 were 1.2% and 1.2%, respectively. The median daily dose (for an individual patient) to maintain an international normalized ratio between 2 and 3 was 15.6 mg (range, 6 to 29 mg). Conclusions-This is the first study of tecarfarin in patients with atrial fibrillation. It appears that tecarfarin may possess advantages over the currently available standard of care, warfarin, by improving time in therapeutic range. Adequately powered prospective trials are warranted to definitively compare tecarfarin with warfarin in clinical settings for which warfarin is indicated.

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“…In addition to the scientific advancements, oral anticoagulant treatments have been widely used before and after the medical and surgical treatments, in order to prevent arterial venous thrombus. Wysowski, Nourjah and Swartz (2007) OAC types of drugs have side effects that are caused by individual factors, as well as ones caused by the drugs themselves, such as the chemical structure of the drug and its administration duration (Ansell, Hirsh, Dalen, Anderson andDeykin 2001, Khudair andHanssens 2012). The most common and life threatening side effect that has been seen in patients, who use oral anti-coagulants, is bleeding (Budnitz, Shehab, Kegle and Richards 2007;Rubboli, Becattini andVerheugt 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Beyth (2001) and Jeffree, Gordon, Sivasubramaniam and Chapman (2009) have shown that the prevalence of bleeding in the patients taking oral anticoagulants is nearly 50% and that they have described these incidents as potentially fatal intra-cranial bleedings that require 4 or more blood transfusions within 48 hours. In a study which scanned the reports of AERS (Adverse Evert Reporting System), it was found that among the 9,766 patients who were admitted to emergency units with bleeding, between 1993 and 2006 in the USA, 8,415 patients had been using anticoagulants and that 999 of them died (Wysowski, Nourjah and Swartz 2007).…”

Section: Introductionmentioning

confidence: 99%