Digoxin Dosing in Heart Failure: A Simplified Nomogram Versus Standard Care

Use of a Simplified Nomogram and Pharmacogenetics to Individualize Digoxin Dosing in Heart Failure Patients vs. Standard Care

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01005602

Enrollment

131

Registered

2009-11-02

Start date

2006-12-31

Completion date

2009-12-31

Last updated

2014-05-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heart Failure

Keywords

Digoxin, Pharmacokinetics, Dosing, Heart Failure

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.

Interventions

OTHERDigoxin Dosing per Nomogram

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).

DRUGDigoxin

All patients included in the trial were treated with digoxin as clinically indicated. The intervention for this study required determining the digoxin dose via a proposed nomogram.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

22 Years to No maximum

Healthy volunteers

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)

Design outcomes

Primary

Measure	Time frame
Percent of Patients Achieving a Desired Steady-state Serum Digoxin Concentration Between 0.5 - 0.9ng/ml	Steady-state (2 - 4 weeks after initiation)

Secondary

Measure	Time frame	Description
Mean Serum Digoxin Concentration	Steady-state (2 - 4 weeks after initiation)	—
Serum Digoxin Concentration < 1.0 ng/ml	Steady-state (2 - 4 weeks after initiation)	—
Serum Digoxin Concentration by ABCB1 Single Nucleotide Polymorphism (SNP) C1236T	Steady-state (2 - 4 weeks after initiation)	55 patients in the Digoxin Dosing per Nomogram group consented to the Pharmacogenetic substudy and provided blood samples to perform pharmacogenetic analyses. We compared serum digoxin concentrations by ABCB1 genotype.
Serum Digoxin Concentration by ABCB1 SNP C3435T	Steady-state (2 - 4 weeks after initiation)	Serum digoxin concentration by genotypes for the ABCB1 SNP C3435T
Serum Digoxin Concentration by ABCB1 SNP G2677T/A	Steady-state (2 - 4 weeks after initiation)	Serum digoxin concentration by ABCB1 SNP genotypes

Countries

United States

Participant flow

Participants by arm

Arm	Count
Digoxin Dosing Per Nomogram Subjects will have their digoxin maintenance dose determined according to the nomogram we have developed. 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).	65
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.	66
Total	131

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Excluded due to unreliable clinical data	1	0

Baseline characteristics

Characteristic	Standard Digoxin Dosing	Total	Digoxin Dosing Per Nomogram
Age, Continuous	63 years STANDARD_DEVIATION 15	60 years STANDARD_DEVIATION 15	58 years STANDARD_DEVIATION 15
Body Mass Index	29.9 kg/m^2 STANDARD_DEVIATION 8.9	31.6 kg/m^2 STANDARD_DEVIATION 9.8	33.2 kg/m^2 STANDARD_DEVIATION 10.4
Creatinine clearance	51 ml/min STANDARD_DEVIATION 22	58 ml/min STANDARD_DEVIATION 25	66 ml/min STANDARD_DEVIATION 10
Estimated Glomerular Filtration Rate	59 ml/min/1.73m^2 STANDARD_DEVIATION 23	65 ml/min/1.73m^2 STANDARD_DEVIATION 23	71 ml/min/1.73m^2 STANDARD_DEVIATION 22
Ideal body weight	62 kg STANDARD_DEVIATION 11	65 kg STANDARD_DEVIATION 11	67 kg STANDARD_DEVIATION 10
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	40 Participants	86 Participants	46 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	11 Participants	23 Participants	12 Participants
Race (NIH/OMB) White	15 Participants	22 Participants	7 Participants
Sex: Female, Male Female	36 Participants	63 Participants	27 Participants
Sex: Female, Male Male	30 Participants	68 Participants	38 Participants
Total body weight	85 kg STANDARD_DEVIATION 27	92 kg STANDARD_DEVIATION 32	100 kg STANDARD_DEVIATION 34

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 65	0 / 66
serious Total, serious adverse events	0 / 65	0 / 66