A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing

Abstract

BACKGROUND The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], −0.2; 95% confidence interval, −3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.)

Role of pharmacogenetics in public health and clinical health care: a SWOT analysis

“…Several recent clinical trials have challenged the overall benefits of genetics-based warfarin dosing by illustrating near-similar results of dosage optimisation using other clinical factors and INR monitoring. 54,55 A reconciliatory note here is that the availability of non-genetic alternatives, particularly that of aggressive monitoring, is predicated on having an efficient and rigorous health-care system that is able to diagnose and circumvent adverse effects or re-adjust dosages in a timely manner. A less rigorous (or more negligent) health-care system may see greater occurrences of missed diagnosis or delays in acknowledging adverse events or drug failures, which genetic tests act as early preventive measures to minimise.…”

Iterative Development and Evaluation of a Pharmacogenomic-Guided Clinical Decision Support System for Warfarin Dosing

“…The mock EHR system was purposely designed with limited ordering functionality, and users could only make modifications to a current warfarin order or initiate a new warfarin order. The usability of an initial and revised version of the CDSS prototype was evaluated in two iterations approximately one year apart to allow for the interface redesign and the data collection was completed prior to publication of conflicting reports related to the effectiveness of pharmacogenomic-guided warfarin dosing in 2013 [21,22]. Usability findings from the development iteration were used to inform an enhanced CDSS prototype for evaluation in the validation iteration (▶ Figure 1).…”

“…An important setback is the fact that there are conflicting reports regarding the effectiveness of incorporating genetic testing into warfarin dosing [21,22]. The aforementioned barrier in the complexity of the genetic output also presents clinical challenges given the large amount of data [17,19,23].…”

Returning pharmacogenetic secondary findings from genome sequencing: let’s not put the cart before the horse

“…This is illustrated robustly by recent work demonstrating that PGx guidance for warfarin dosing, long a poster child for the PGx field, simply does not matter when using this agent. 28,29 Thus, while many associations are suggested by ongoing studies, not all remain statistically significant after replication studies, and few reach a level at which clinical implementation is warranted. Thus, the notion, suggested by Nishimura et al, 24 that substantial resources are required to keep their alerts up to date is questionable.…”