Clinical trial NCT01005602: Digoxin Dosing in Heart Failure: A Simplified Nomogram Versus Standard Care
Official title: Use of a Simplified Nomogram and Pharmacogenetics to Individualize Digoxin Dosing in Heart Failure Patients vs. Standard Care
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Heart Failure
Keywords: Digoxin
Pharmacokinetics
Dosing
Heart Failure
Lead sponsor: University of Illinois at Chicago
Sponsor class: OTHER
Collaborators: name: American College of Clinical Pharmacy
First posted: 2009-11-01
Enrollment: 131
Sex: ALL
Minimum age (years): 22
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Age \> 21 years
* Diagnosis of heart failure secondary to left ventricular dysfunction
* Receiving chronic digoxin therapy or digoxin therapy is being initiated

Exclusion Criteria:

* Pregnant
* Unstable renal function, defined as either a rise in serum creatinine by \> 0.5mg/dl from baseline or a decrease in creatinine clearance by 25% or more within two to four weeks of study entry.
* End-stage renal disease requiring hemodialysis
* Concomitant therapy with drugs known to interact with digoxin (e.g., amiodarone, quinidine, verapamil, macrolide antibiotics)

Primary outcomes:
measure: Percent of Patients Achieving a Desired Steady-state Serum Digoxin Concentration Between 0.5 - 0.9ng/ml
timeFrame: Steady-state (2 - 4 weeks after initiation)
Secondary outcomes:
measure: Mean Serum Digoxin Concentration
timeFrame: Steady-state (2 - 4 weeks after initiation)
measure: Serum Digoxin Concentration < 1.0 ng/ml
timeFrame: Steady-state (2 - 4 weeks after initiation)
measure: Serum Digoxin Concentration by ABCB1 Single Nucleotide Polymorphism (SNP) C1236T
timeFrame: Steady-state (2 - 4 weeks after initiation)
measure: Serum Digoxin Concentration by ABCB1 SNP C3435T
timeFrame: Steady-state (2 - 4 weeks after initiation)
measure: Serum Digoxin Concentration by ABCB1 SNP G2677T/A
timeFrame: Steady-state (2 - 4 weeks after initiation)
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
Study officials:
affiliation: University of Illinois at Chicago
name: Robert J DiDomenico, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bauman JL, DiDomenico RJ, Viana M, Fitch M. A method of determining the dose of digoxin for heart failure in the modern era. Arch Intern Med. 2006 Dec 11-25;166(22):2539-45. doi: 10.1001/archinte.166.22.2539.
citation: DiDomenico RJ, Bress AP, Na-Thalang K, Tsao YY, Groo VL, Deyo KL, Patel SR, Bishop JR, Bauman JL. Use of a simplified nomogram to individualize digoxin dosing versus standard dosing practices in patients with heart failure. Pharmacotherapy. 2014 Nov;34(11):1121-31. doi: 10.1002/phar.1480. Epub 2014 Aug 28.