Association of Serum Digoxin Concentration and Outcomes …

1 Current as of August 3, 2009. Online article and related content . 2003;289(7):871-878 ( ) JAMA Saif S. Rathore; Jeptha P. Curtis; Yongfei Wang; et al. Outcomes in Patients With Heart FailureAssociation of Serum Digoxin Concentration and Correction Contact me if this article is corrected. Citations Contact me when this article is cited. This article has been cited 123 times. Topic collections Contact me when new articles are published in these topic Trial; Congestive Heart Failure/ Cardiomyopathy Men's Health; Men's Health, Other; Cardiovascular System; Randomized Related Letters.

2 2003;289(20) de Denus et al.. 2003;289(20) Carbonin et al. Optimal Digoxin concentrations for Patients With Heart Failure Alerts at Columbia University on August 3, 2009 from ORIGINAL CONTRIBUTIONA ssociation of Serum Digoxin Concentrationand Outcomes in PatientsWith Heart FailureSaif S. Rathore, MPHJ eptha P. Curtis, MDYongfei Wang, MSMichael R. Bristow, MD, PhDHarlan M. Krumholz, MD, SMTHEDIGITALISINVESTIGATIONG roup (DIG) trial, a random-ized, double-blinded, placebo-controlled study evaluatingthe efficacy of Digoxin therapy for pa-tients with heart failure, found thatdigoxin therapy had no effect on mor-tality but modestly reduced hospitaliza-tions due to worsening heart were randomly assigned to di-goxin with the objective of achieving atherapeutic Serum Digoxin concentra-tion (SDC)

3 In the range of to ,2 However, this range was de-fined to avoid concentrations associ-ated with Digoxin toxicity and was notspecified as a result of evaluations of therelative efficacy of different the publication of the DIG trial,concerns have been raised regarding therelative efficacy of SDCs greater ng/mL. Higher SDCs in this rangehave been associated with improved leftventricular function4-6but have notshown a beneficial effect on neurohor-monal function, hemodynamic pro-file, or exercise ,5,7 Conse-quently, current clinical practiceguidelines of the American College ofCardiology and the American Heart As-sociation state large doses of digoxinmay not be more effective than smallAuthor Affiliations.

4 The Section of Cardiovascular Medi-cine (Messrs Rathore and Wang and Drs Curtis andKrumholz), Department of Internal Medicine and theSection of Health Policy and Administration (Dr Krum-holz), Department of Epidemiology and Public Health,Yale University School of Medicine, New Haven, Conn;Division of Cardiology, University of Colorado HealthSciences Center, Denver (Dr Bristow); and the Centerfor Outcomes Research and Evaluation, Yale-NewHaven Hospital, New Haven, Conn (Dr Krumholz).Financial Disclosure:Dr Bristow is the founder, di-rector, officer of, and holds equity in Myogen, a bio-pharmaceutical Author:Harlan M.

5 Krumholz, MD, SM,Department of Internal Medicine, Yale UniversitySchool of Medicine, Room I-456 SHM, 333 Cedar St,PO Box 208025, New Haven, CT 06520 Digitalis Investigation Group (DIG) trial reported that Digoxin providedno overall mortality benefit and only a modest reduction in hospitalizations amongpatients with heart failure and depressed left ventricular systolic function. The clinicaloutcomes associated with Digoxin therapy at different Serum concentrations in the DIGtrial have not been assess variations in Serum Digoxin Concentration (SDC)

6 And their as-sociation with mortality and hospitalization in patients with heart , Setting, and PatientsPost hoc analysis of the randomized, double-blinded, placebo-controlled DIG trial, conducted from August 1991 to December 1995,with the main analysis restricted to men with a left ventricular ejection fraction of 45%or less (n = 3782). Patients randomly assigned to receive Digoxin were divided into 3groups based on SDC at 1 month ( ng/mL, n = 572; ng/mL, n = 322;and ng/mL, n = 277) and compared with patients randomly assigned to receiveplacebo (n = 2611).

7 Main outcome MeasureAll-cause mortality at a mean follow-up of 37 SDCs were associated with increased crude all-cause mortality rates( ng/mL, ; ng/mL, ; and ng/mL, ;P= .006for trend). Patients with SDCs of to ng/mL had a (95% confidenceinterval [CI], ) lower mortality rate compared with patients receivingplacebo. Digoxin was not associated with a reduction in mortality among patientswith SDCs of to ng/mL ( increase; 95% CI, to ), whereaspatients with SDCs of ng/mL and higher had an (95% CI, )higher absolute mortality rate than patients receiving placebo.

8 The associationbetween SDC and mortality persisted after multivariable adjustment (SDC hazard ratio [HR] , 95% CI, ; SDC ng/mL HR ,95% CI, ; SDC ng/mL HR , 95% CI, ; and HR of [referent] for placebo).ConclusionsOur findings demonstrate that higher SDCs were associated with in-creased mortality and suggest that the effectiveness of Digoxin therapy in men withheart failure and a left ventricular ejection fraction of 45% or less may be optimized inthe SDC range of to 2003;289 2003 American Medical Association .

9 All rights reserved.(Reprinted) JAMA,February 19, 2003 Vol 289, No. 7871 at Columbia University on August 3, 2009 from doses in the treatment of heart fail-ure, 8and some textbooks suggest thatclinicians pursue target SDCs lowerthan the upper therapeutic range ac-cepted in the DIG ,10 Published evaluations of the efficacyof various SDCs have relied on interme-diate end points, such as neurohor-monal function or risk of worseningheart failure,4,5,7rather than risks of hos-pitalization or ,5,7 Prior stud-ies have not accounted for clinical char-acteristics.

10 Such as age or renal function,that may confound the relationship be-tween SDC and patient published studies of SDC and the ef-ficacy of Digoxin therapy have beenbased on fewer than 210 total patients,drawn from single centers, and evalu-ated Outcomes after Digoxin with-drawal, thereby limiting their general-izability to other patient populations andtheir power to detect differences in ef-ficacy across a range of , we undertook a post hoc evalua-tion of the DIG trial to evaluate theassociation of SDC, risk of mortality, andrisk of hospitalization among patientswith heart failure and left Trial DatabaseWe obtained a public-use copy of thedatabase of the DIG trial by submit-ting a written request to the NationalHeart, Lung, and Blood Institute.