Clinical trials for pharmacogenomics testing for warfarin dosing: Relevance to general community practices

Abstract

O ral anticoagulation with warfarin requires a relatively individualized therapeutic approach to establish appropriate dosing. It is of the utmost importance to administer correct initial dosing given warfarin's narrow therapeutic index and devastating complications. Warfarin pharmacogenomic testing is one element of many that may be used to appropriately tailor therapy. Numerous studies have evaluated the clinical benefit of genotyping, and many times the results are equivocal. The majority of these studies have been performed in the specialized anticoagulation clinic setting.In this issue of the journal, Caldwell and coworkers 1 reported on "A randomized, controlled trial of genetic-based Coumadin initiation." The study setting is an anticoagulation clinic and they found, despite improved initial therapeutic dose estimation when genotype was known, outcomes were ultimately impacted by clinical management regardless of genotype knowledge. It is important when interpreting these conclusions, however, to acknowledge that there are two main oral anticoagulation management settings in the United States: specialized anticoagulation clinics and community clinics (usual care, health maintenance organization setting); the services and outcomes of which are not equivalent for numerous reasons. These differences prohibit meaningful generalization of results that universally invalidate the clinical impact of pharmacogenomics testing.Warfarin is the primary drug prescribed for long-term oral anticoagulation therapy in the United States with close to 4 million patients taking this medication. 2 It is used for the prevention of thromboembolic complications of various disorders including atrial fibrillation, venous thromboembolism, and valvular heart disease. 3 Despite the fact that this is a highly efficacious therapy when titrated to the appropriate therapeutic range, the titration and dosing of warfarin are the most challenging and labor-intensive aspects of this therapy. There are many factors that influence its pharmacokinetics and pharmacodynamics including patient age, concurrent medications, diet, comorbidities, and genetics. 4 Patient comprehension/health literacy, education, receptivity to details regarding medical illness, and various patient demographic and psychosocial factors that are associated with adherence to therapy and the associated monitoring also play a significant role in achieving a desirable therapeutic range. [5][6][7] All these factors combined, many of which are in a state of constant flux, result in significant inter-and intraindividual variability. This makes it difficult to accurately determine individual therapeutic dose to maintain a stable and appropriate international normalized ratio (INR). Accuracy in this regard, however, is crucial given warfarin's very narrow therapeutic index and the strong association between the time spent in the therapeutic range with risk of morbidity and mortality due to bleeding and thromboembolism. 8 -12 Ultimately, correct initial dosing and appropriate moni...

Association between Patients’ Knowledge and Adherence to Anticoagulants, and Its Effect on Coagulation Control

“…Of the patients, only 40% were aware of the effect of green vegetables on warfarin and others ignored this effect. This is crucial information for effective patient management, potentially affecting patient outcomes and INR control, as eating a balanced diet, maintaining an appropriate vitamin K level, and being able to interpret INR level and its effect are required for better outcomes [54, 55]. Our findings were consistent with other studies conducted in Germany and Saudi Arabia [56, 57].…”

Warfarin Pharmacogenetic Trials: Is there a Future for Pharmacogenetic-Guided Dosing?

“…Additionally, this setting likely does not reflect anticoagulation practice in other community clinics with fewer INR measurements [19]. …”

Variability of warfarin dose response associated with CYP2C9 and VKORC1 gene polymorphisms in Chinese patients

“…Warfarin is the most widely prescribed anticoagulant drug for the prophylaxis and treatment of patients with venous and arterial thromboembolic disorders. 1 Management of warfarin therapy is problematic, however, for a number of reasons: first, since it has a narrow therapeutic index, frequent assessment of blood prothrombin time using the standardized international normalized ratio (INR) is essential to decrease the risk of bleeding, which is the most common and dangerous warfarin-related complication; 2,3 secondly, patients exhibit large interindividual and interethnic variability in dose response to the anticoagulant effects; 4 thirdly, there are no fixed doses in relation to warfarin treatment, as dose requirements are affected by the patients’ weight, diet, age, disease state, concomitant use of other medications and genetic factors. 5…”