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

• ClinicalTrials.gov Identifier: NCT01005602
• Recruitment Status: Completed
• First Posted: November 1, 2009
• Results First Posted: May 19, 2014
• Last Update Posted: May 22, 2014
• Sponsor: University of Illinois at Chicago
• Collaborator: American College of Clinical Pharmacy
• Information provided by (Responsible Party): Robert J. DiDomenico, University of Illinois at Chicago

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Heart Failure	Other: Digoxin Dosing per Nomogram; Drug: Digoxin	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 131 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Study Start Date: December 2006
• Actual Primary Completion Date: December 2009
• Actual Study Completion Date: December 2009

Arms and Interventions

Arm	Intervention/treatment
Experimental: Digoxin Dosing per Nomogram; Subjects will have their digoxin maintenance dose determined according to the nomogram we have developed.	Other: Digoxin 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).; Drug: Digoxin; 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.; Other Name: Lanoxin
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.	Drug: Digoxin; 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.; Other Name: Lanoxin

Outcome Measures

Primary Outcome Measures :

1. 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) ]

Secondary Outcome Measures :

1. Mean Serum Digoxin Concentration [ Time Frame: Steady-state (2 - 4 weeks after initiation) ]
2. Serum Digoxin Concentration < 1.0 ng/ml [ Time Frame: Steady-state (2 - 4 weeks after initiation) ]
3. Serum Digoxin Concentration by ABCB1 Single Nucleotide Polymorphism (SNP) C1236T [ Time Frame: 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.
4. Serum Digoxin Concentration by ABCB1 SNP C3435T [ Time Frame: Steady-state (2 - 4 weeks after initiation) ]
   Serum digoxin concentration by genotypes for the ABCB1 SNP C3435T
5. Serum Digoxin Concentration by ABCB1 SNP G2677T/A [ Time Frame: Steady-state (2 - 4 weeks after initiation) ]
   Serum digoxin concentration by ABCB1 SNP genotypes

Eligibility Criteria

• Ages Eligible for Study: 22 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

United States, Illinois

University of Illinois at Chicago

Chicago, Illinois, United States, 60612

Sponsors and Collaborators

University of Illinois at Chicago

American College of Clinical Pharmacy

Investigators

• Principal Investigator: Robert J DiDomenico, PharmD; University of Illinois at Chicago

More Information

Publications:

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. Erratum in: Arch Intern Med. 2007 Mar 12;167(5):496. Dosage error in article text.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Robert J. DiDomenico, Clinical Associate Professor, University of Illinois at Chicago
• ClinicalTrials.gov Identifier: NCT01005602
• Other Study ID Numbers: ACCP 2006-07; 2008-05762
• First Posted: November 1, 2009
• Results First Posted: May 19, 2014
• Last Update Posted: May 22, 2014
• Last Verified: May 2014

Keywords provided by Robert J. DiDomenico, University of Illinois at Chicago:

Digoxin; Pharmacokinetics; Dosing; Heart Failure

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases; Digoxin; Anti-Arrhythmia Agents; Cardiotonic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs