Digoxin Dosing in Heart Failure: A Simplified Nomogram Versus Standard Care
Recruitment status was Active, not recruiting
Dosing methods for digoxin, a drug used to treat heart failure, have not been updated in decades despite evidence in recent years suggesting that blood levels of digoxin achieved with traditional dosing practices may increase the risk of adverse events. We developed a simple dosing tool that targets lower blood levels of digoxin that have been associated with improved outcomes compared to higher blood levels. The aim of this study is to determine if this simplified dosing tool is more effective than standard digoxin dosing practices at achieving lower blood levels and also to determine if digoxin dosing may be further optimized by incorporating patients' genetic information believed to influence the drug's properties.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Use of a Simplified Nomogram and Pharmacogenetics to Individualize Digoxin Dosing in Heart Failure Patients vs. Standard Care|
- Percent of patients achieving a desired steady-state serum digoxin concentration between 0.5 - 0.9ng/ml [ Time Frame: Steady-state (2 - 4 weeks after initiation) ] [ Designated as safety issue: Yes ]
- Difference in steady-state serum digoxin concentrations across C3435T genotypes [ Time Frame: Steady-state (2 - 4 weeks after initiation) ] [ Designated as safety issue: No ]
- Steady-state serum digoxin concentration between TTT haplotype carriers and non-carriers [ Time Frame: Steady-state (2 - 4 weeks after initiation) ] [ Designated as safety issue: No ]
|Study Start Date:||December 2006|
|Estimated Study Completion Date:||December 2009|
|Estimated Primary Completion Date:||December 2009 (Final data collection date for primary outcome measure)|
Experimental: Digoxin Dosing per Nomogram
Subjects will have their digoxin maintenance dose determined according to the nomogram we have developed.
Other: Dosing nomogram for digoxin
Simplified dosing nomogram for digoxin. The dose is determined by plotting a subject's creatinine clearance (x-axis) and ideal body weight (y-axis) on the nomogram. Alternatively, the dose may be determined by plotting creatinine clearance (x-axis) and gender/height (z-axis).
No Intervention: Standard Digoxin Dosing
This arm represents historical control subjects in whom the dose of digoxin was determined at the physician's discretion using traditional dosing methods.
Digoxin is recommended as adjunctive therapy in patients with left ventricular dysfunction and symptoms of heart failure despite treatment with standard therapy. Recently, the therapeutic range for digoxin in patients with heart failure has been redefined to a narrower therapeutic window (0.5 - 0.9 ng/ml) because lower serum levels in this range have been associated with improved survival whereas higher serum levels have been associated with increased mortality. However, dosing methods have not been updated to reflect the newly defined therapeutic range for digoxin. We developed a simplified dosing nomogram for digoxin in patients with heart failure designed to achieve serum digoxin concentrations (SDC) within the new therapeutic range using retrospective data. The long-term goal of this study is to prospectively validate the ability of our digoxin dosing nomogram to achieve desired SDC and provide clinicians a simplified tool to optimize digoxin dosing in patients with heart failure. Because digoxin is a substrate of the efflux pump p-glycoprotein (pGP) and genetic polymorphisms of the MDR1 gene (known to regulate pGP expression) have demonstrated conflicting results on the pharmacokinetic profile of digoxin, we will also characterize the influence MDR1 functional gene variants may have on digoxin dosing. This study will include a total of 170 subjects with symptomatic heart failure treated with digoxin, comparing steady-state SDC in a prospective group of patients dosed according to our nomogram to a historical control group in whom the dose of digoxin was derived from standard dosing practices. We will also conduct an analysis of genetic polymorphisms of the MDR1 gene known to affect digoxin pharmacokinetics. The primary objectives of the study are to compare the percentage of patients in each group achieving steady-state SDC within the desired range of 0.5 - 0.9 ng/ml, characterize the relationship between genetic variability in the MDR1 gene and digoxin dosing, and to update our digoxin dosing nomogram to account for the clinical and genetic variability shown to have the greatest influence on digoxin dosing. The rationale for this study is that lower doses of digoxin are recommended because lower SDC are associated with improved survival. Therefore, digoxin dosing methods must be updated to reflect these recommendations and account for genetic variability of the MDR1 gene in an effort to improve clinical outcomes and minimize the potential for adverse events. To address these issues, the specific aims of this research are:
Aim 1: Compare steady-state SDC observed using our dosing nomogram to those obtained using standard dosing practices.
Aim 2: Characterize the relationship of the genetic variability of the MDR1 gene and SDC observed using our digoxin dosing nomogram.
|United States, Illinois|
|University of Illinois at Chicago|
|Chicago, Illinois, United States, 60612|
|Principal Investigator:||Robert J DiDomenico, PharmD||University of Illinois at Chicago|