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T
HE DIGITALIS INVESTIGATION Design, Setting, and Patients Post hoc analysis of the randomized, double-
Group (DIG) trial, a random- blinded, placebo-controlled DIG trial, conducted from August 1991 to December 1995,
ized, double-blinded, placebo- with the main analysis restricted to men with a left ventricular ejection fraction of 45%
controlled study evaluating or less (n=3782). Patients randomly assigned to receive digoxin were divided into 3
the efficacy of digoxin therapy for pa- groups based on SDC at 1 month (0.5-0.8 ng/mL, n=572; 0.9-1.1 ng/mL, n=322;
tients with heart failure, found that and ⱖ1.2 ng/mL, n=277) and compared with patients randomly assigned to receive
placebo (n=2611).
digoxin therapy had no effect on mor-
tality but modestly reduced hospitaliza- Main Outcome Measure All-cause mortality at a mean follow-up of 37 months.
tions due to worsening heart failure.1 Results Higher SDCs were associated with increased crude all-cause mortality rates
Patients were randomly assigned to di- (0.5-0.8 ng/mL, 29.9%; 0.9-1.1 ng/mL, 38.8%; and ⱖ1.2 ng/mL, 48.0%; P=.006
goxin with the objective of achieving a for trend). Patients with SDCs of 0.5 to 0.8 ng/mL had a 6.3% (95% confidence
therapeutic serum digoxin concentra- interval [CI], 2.1%-10.5%) lower mortality rate compared with patients receiving
tion (SDC) in the range of 0.5 to 2.0 placebo. Digoxin was not associated with a reduction in mortality among patients
with SDCs of 0.9 to 1.1 ng/mL (2.6% increase; 95% CI,−3.0% to 8.3%), whereas
ng/mL.1,2 However, this range was de- patients with SDCs of 1.2 ng/mL and higher had an 11.8% (95% CI, 5.7%-18.0%)
fined to avoid concentrations associ- higher absolute mortality rate than patients receiving placebo. The association
ated with digoxin toxicity and was not between SDC and mortality persisted after multivariable adjustment (SDC 0.5-0.8
specified as a result of evaluations of the ng/mL hazard ratio [HR] 0.80, 95% CI, 0.68-0.94; SDC 0.9-1.1 ng/mL HR 0.89,
relative efficacy of different SDCs.3 95% CI, 0.74-1.08; SDC ⱖ1.2 ng/mL HR 1.16, 95% CI, 0.96-1.39; and HR of 1.00
Since the publication of the DIG trial, [referent] for placebo).
concerns have been raised regarding the Conclusions Our findings demonstrate that higher SDCs were associated with in-
relative efficacy of SDCs greater than creased mortality and suggest that the effectiveness of digoxin therapy in men with
1.0 ng/mL. Higher SDCs in this range heart failure and a left ventricular ejection fraction of 45% or less may be optimized in
have been associated with improved left the SDC range of 0.5 to 0.8 ng/mL.
ventricular function4-6 but have not JAMA. 2003;289:871-878 www.jama.com
shown a beneficial effect on neurohor-
monal function, hemodynamic pro-
Author Affiliations: The Section of Cardiovascular Medi- Haven Hospital, New Haven, Conn (Dr Krumholz).
file, or exercise tolerance.4,5,7 Conse- cine (Messrs Rathore and Wang and Drs Curtis and Financial Disclosure: Dr Bristow is the founder, di-
quently, current clinical practice Krumholz), Department of Internal Medicine and the rector, officer of, and holds equity in Myogen, a bio-
Section of Health Policy and Administration (Dr Krum- pharmaceutical company.
guidelines of the American College of holz), Department of Epidemiology and Public Health, Corresponding Author: Harlan M. Krumholz, MD, SM,
Cardiology and the American Heart As- Yale University School of Medicine, New Haven, Conn; Department of Internal Medicine, Yale University
Division of Cardiology, University of Colorado Health School of Medicine, Room I-456 SHM, 333 Cedar St,
sociation state “large doses of digoxin Sciences Center, Denver (Dr Bristow); and the Center PO Box 208025, New Haven, CT 06520 (e-mail:
may not be more effective than small for Outcomes Research and Evaluation, Yale-New harlan.krumholz@yale.edu).
©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, February 19, 2003—Vol 289, No. 7 871
©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, February 19, 2003—Vol 289, No. 7 873
and Mortality
0.7
There was no difference in all-cause
mortality among patients randomly as-
0.6 signed to placebo and patients ran-
domly assigned to digoxin who had
Placebo SDCs assessed (36.2% placebo vs 36.6%
0.5 SDC 0.5-0.8 ng/mL
SDC 0.9-1.1 ng/mL
digoxin, P = .80). Kaplan-Meier sur-
SDC ≥1.2 ng/mL vival curves, however, differed based on
0 patients’ SDCs (P⬍.001) (FIGURE 2).
0 4 8 12 16 20 24 28 32 36 40 44 48
Months
Higher SDCs were associated with
No. at Risk
higher crude all-cause mortality
Placebo 2611 2514 2405 2302 2213 2117 2024 1948 1858 1625 1385 1111 852 (P =.006 for trend) and cardiovascular
SDC 0.5-0.8 ng/mL 572 566 549 533 512 490 477 459 441 427 419 361 290 mortality (P⬍.001 for trend), but not
SDC 0.9-1.1 ng/mL 322 319 306 295 282 267 250 240 232 225 211 180 138
SDC ≥1.2 ng/mL 277 262 246 234 221 206 187 177 166 159 150 133 116
mortality due to worsening heart fail-
ure (P =.68 for trend) (TABLE 2).
SDC indicates serum digoxin concentration. The figure presents the cumulative survival rates for patients as-
signed to placebo and patients assigned to digoxin in the 3 SDC groups over a mean follow-up of 37 months. The effectiveness of digoxin therapy
compared with placebo varied based on
patients’ SDCs. Patients with SDCs of
and symptoms, systolic blood pres- women who had valid SDCs evaluated 0.5 to 0.8 ng/mL had a 6.3% (95% con-
sure, heart rate, estimated glomerular fil- at 1 month and compared their out- fidence interval [CI], 2.1%-10.5%)
tration rate, duration of heart failure, pri- comes with the 756 women in the DIG lower rate of all-cause mortality, a 3.7%
mary cause of heart failure, history of trial randomly assigned to placebo. (95% CI, 0.4%-7.7%) lower rate of car-
myocardial infarction, angina, diabe- The study was approved by the Yale diovascular mortality, and a 4.7% (95%
tes, hypertension, prior use of digoxin, University School of Medicine Human CI, 2.1%-7.3%) lower rate of mortal-
and use of potassium-sparing diuret- Investigation Committee. All analyses ity due to worsening heart failure com-
ics, all other diuretics, angiotensin- were conducted using SAS 8.02 statis- pared with patients randomly as-
converting enzyme inhibitors, nitrates, tical software (SAS Institute Inc, Cary, signed to placebo. Patients with SDCs
hydralazine, and other vasodilators.14 NC). of 0.9 to 1.1 ng/mL had similar rates of
Multivariable analyses were repeated all-cause mortality, cardiovascular mor-
for the end points of death due to RESULTS tality, and mortality due to worsening
cardiovascular causes, death due to Study Sample heart failure as patients randomly as-
worsening heart failure, all-cause Of the 1171 men with SDCs assessed signed to placebo. In contrast, pa-
hospitalization, and hospitalization due at 1 month following randomization, tients with SDCs of 1.2 ng/mL and
to worsening heart failure. 572 (49%) patients had an SDC of 0.5 higher had an 11.8% (95% CI, 5.7%-
Analyses were repeated modeling to 0.8 ng/mL, 322 (27%) patients had 18.0%) higher all-cause mortality rate
SDCs as a continuous variable with risk- an SDC of 0.9 to 1.1 ng/mL, and 277 and an 11.5% (95% CI, 5.4%-17.5%)
adjusted all-cause mortality rates esti- (24%) patients had an SDC of 1.2 higher cardiovascular mortality rate
mated using fractional polynomial mod- ng/mL or greater. Patients with higher than patients randomly assigned to pla-
eling.15 Secondary analyses also were SDCs were older, had greater num- cebo, but no increased risk of mortal-
conducted by excluding patients with an bers of heart failure signs or symp- ity due to worsening heart failure (1.9%,
SDC greater than 2.0 ng/mL, which was toms, and had lower median BMIs and 95% CI -2.6% to 6.3%) (Table 2).
outside of the DIG trial’s prespecified estimated glomerular filtration rates. A Patients with an SDC of 0.5 to 0.8
therapeutic range. Although the sample greater proportion of patients with ng/mL remained at lower risk of all-
size did not confer adequate power, we higher SDCs were in New York Heart cause mortality (hazard ratio [HR], 0.80;
also evaluated the association of SDC Association class III/IV and had used 95% CI, 0.68-0.94) and mortality due to
and all-cause mortality among the 330 non–potassium-sparing diuretics and worsening heart failure (HR, 0.66; 95%
874 JAMA, February 19, 2003—Vol 289, No. 7 (Reprinted) ©2003 American Medical Association. All rights reserved.
Worsening Worsening
All-Cause Cardiovascular Heart Failure All-Cause Heart Failure Toxicity
Placebo (n = 2611) 36.2 (945) 30.4 (794) 13.3 (347) 67.8 (1769) 34.8 (910) 0.8 (22)
Digoxin overall (n = 1171) 36.6 (429) 32.4 (380) 11.9 (139) 66.8 (782) 25.7 (301) 1.6 (19)
Absolute difference, 0.4 (−2.9 to 3.8) 2.0 (−1.2 to 5.2) −1.4 (−3.7 to 0.8) −1.0 (−4.2 to 2.3) −9.2 (−12.2 to −6.0) 0.8 (0.0 to 1.6)
% (95% CI)†
P value‡ .80 .21 .23 .56 ⬍.001 .04
Serum digoxin concentration
0.5-0.8 ng/mL (n = 572) 29.9 (171) 26.8 (153) 8.6 (149) 61.9 (354) 20.8 (119) 1.2 (7)
Absolute difference, −6.3 (−10.5 to −2.1) −3.7 (−7.7 to 0.4) −4.7 (−7.3 to −2.1) −5.9 (−10.2 to −1.5) −14.0 (−17.8 to −10.2) 0.4 (−0.6 to 1.4)
% (95% CI)†
P value‡ .005 .09 .002 .007 ⬍.001 .39
0.9-1.1 ng/mL (n = 322) 38.8 (125) 34.5 (111) 14.9 (48) 72.4 (233) 31.1 (100) 0.9 (3)
Absolute difference, 2.6 (−3.0 to 8.3) 4.1 (−1.4 to 9.6) 1.6 (−2.5 to 5.7) 4.6 (−0.6 to 9.8) −3.8 (−9.2 to 1.6) 0.1 (−1.0 to 1.2)
% (95% CI)†
P value‡ .36 .14 .43 .10 .18 .87
ⱖ1.2 ng/mL (n = 277) 48.0 (133) 41.9 (116) 15.2 (42) 70.4 (195) 29.6 (82) 3.2 (9)
Absolute difference, 11.8 (5.7 to 18.0) 11.5 (5.4 to 17.5) 1.9 (−2.6 to 6.3) 2.6 (−3.0 to 8.3) −5.2 (−10.9 to 0.4) 2.4 (0.3 to 4.5)
% (95% CI)†
P value‡ ⬍.001 ⬍.001 .39 .37 .09 ⬍.001
Global P value§ ⬍.001 ⬍.001 .007 .006 ⬍.001 .004
P value for trend㛳 .006 ⬍.001 .68 .37 ⬍.001 .003
Abbreviation: CI, confidence interval.
*Values are presented as the percentage (No.) of patients experiencing mortality or hospitalization. Values have been rounded.
†Absolute differences are reported as the difference in the percentage of mortality or hospitalization among patients assigned to digoxin (overall, 3 serum digoxin concentration
groups [SDCs]) compared with patients assigned to placebo. A negative number indicates a lower rate among patients assigned to digoxin compared with patients assigned to
placebo while a positive number indicates a higher rate among patients assigned to digoxin compared with patients assigned to placebo.
‡P for the comparison of the rate among patients assigned to digoxin compared with the rate among patients assigned to placebo.
§P for the comparison of mortality and hospitalization rates among patients assigned to placebo and the 3 SDC groups.
㛳P for the comparison of the trend in mortality and hospitalization rates across the 3 SDC groups.
60
Mortality Rate was first published.19 The discordance
50
between our findings and previous
evaluations of SDCs and patient out-
40
comes4-7 may be attributable to several
30
factors. Previous attempts to examine
20
the efficacy of SDCs and patient out-
10
comes focused on intermediate out-
0
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 ≥2.0 comes rather than major clinical end
Serum Digoxin Concentration, ng/mL points, and thus only examined SDCs
in terms of relative efficacy (ie, changes
The figure presents the crude all-cause mortality rate with 95% confidence intervals and the risk-adjusted rate
for patients assigned to digoxin according to their serum digoxin concentration. The mortality rate in patients
in left ventricular contractility), not pos-
assigned to placebo is presented for comparison. The risk-adjusted mortality rate was estimated using frac- sible harm (ie, mortality).4-7 Further-
tional polynomial modeling. more, these studies were likely unable
to detect variations in outcomes based
on SDCs because they included small
pected digoxin toxicity (Table 2). Pa- 0.8 ng/mL, 96 (29.1%) had an SDC of numbers of patients observed during
tients with an SDC of 0.5 to 0.8 ng/mL 0.9 to 1.1 ng/mL, and 103 (31.1%) had brief follow-up periods.4-7 Prior stud-
had a 5.9% (95% CI, 1.5%-10.2%) lower an SDC of 1.2 ng/mL and higher. ies also did not account for the sex and
crude rate of all-cause hospitalization Women also exhibited a pattern of in- digoxin therapy interaction we identi-
than patients randomly assigned to creased all-cause mortality rates at higher fied in a prior evaluation of the DIG
placebo. This relationship primarily re- SDCs (0.5-0.8 ng/mL, 25.2%; 0.9-1.1 ng/ trial,13 indicating earlier findings con-
flected a 14.0% (95% CI, 10.2%- mL, 33.3%; ⱖ1.2 ng/mL, 41.8%; P=.009 cerning SDCs may represent an artifi-
17.8%) lower absolute rate of hospital- for trend). Compared with the 756 cial combination of sex-specific varia-
ization for worsening heart failure. women randomly assigned to placebo, tions in digoxin’s effect.
Patients with an SDC of 0.9 to 1.1 ng/mL higher SDCs continued to be associ- The association of SDC and patient
and 1.2 ng/mL and higher had all- ated with all-cause mortality after mul- outcomes may reflect the dissociated
cause hospitalization rates comparable tivariable adjustment (0.5-0.8 ng/mL: neurohormonal and inotropic effects of
with patients randomly assigned to pla- HR, 0.89; 95% CI, 0.61-1.29; 0.9-1.1 ng/ digoxin observed at different concen-
cebo. Hospitalization for suspected di- mL: HR, 1.18; 95% CI, 0.81-1.72; and trations.11,20-22 Neurohormonal modu-
goxin toxicity was higher among pa- ⱖ1.2 ng/mL: HR, 1.26; 95% CI, 0.90- lation is believed to contribute to digox-
tients with an SDC of 1.2 ng/mL and 1.76), although the findings were not in’s symptomatic benefits among
higher (2.4%; 95% CI, 0.3%-4.5%) com- statistically significant. patients with stable heart failure in si-
pared with patients randomly assigned nus rhythm.5,20,22-24 These benefits are
to placebo. Rates of hospitalization for COMMENT achieved at an SDC of 0.7 to 0.8 ng/mL
suspected digoxin toxicity were com- Our results indicate that the effective- and do not appear to increase at higher
parable with placebo in the other SDC ness of digoxin in the DIG trial varied SDCs.3 In contrast, digoxin-associated
groups (Table 2). Findings were simi- according to patients’ SDCs, such that harms are believed to reflect inotropic-
lar after multivariable adjustment, al- higher SDCs were associated with associated increases in myocardial oxy-
though the higher risk of hospitaliza- higher rates of mortality and hospital- gen consumption and arrhythmogen-
tion due to worsening heart failure was ization. Furthermore, our analyses sug- esis at higher serum concentrations.5,25,26
reduced among patients with SDCs of gest that previously accepted SDCs of Thus, our findings are consistent with
0.9 to 1.1 ng/mL and 1.2 ng/mL and 1.2 ng/mL and higher 3,16,17 may be the hypothesis that digoxin provides a
higher (Table 3). harmful and that currently recom- neurohormonal benefit with minimal
mended therapeutic SDCs of approxi- inotropic-associated risk at lower
Serum Digoxin Concentration and mately 1.0 ng/mL9,18 may not provide SDCs.3,20,21,25,26 As the SDC increases, the
All-Cause Mortality in Women any clinical benefit compared with pla- inotropic action of digoxin becomes
Of the 330 women who had SDCs mea- cebo. Our findings suggest that an SDC stronger and begins to offset the thera-
sured at 1 month following randomiza- of 0.5 to 0.8 ng/mL likely constitutes peutic benefits provided by neurohor-
tion, 131 (39.6%) had an SDC of 0.5 to the optimal therapeutic range for di- monal modulation and may account for
876 JAMA, February 19, 2003—Vol 289, No. 7 (Reprinted) ©2003 American Medical Association. All rights reserved.
the increased risk of mortality at con- with an SDC of 0.5 to 0.8 ng/mL had a centrations, in patients with left ven-
centrations of 1.2 ng/mL and higher ob- mortality risk point estimate below that tricular systolic dysfunction. In the ab-
served in our study and previous evalu- of women randomly assigned to pla- sence of such a trial, these data provide
ations.27,28 Thus, an SDC of 0.5 to 0.8 cebo, our analysis was insufficiently the best available evidence concern-
ng/mL may represent the most clini- powered to determine whether di- ing the relative value of digoxin therapy
cally efficacious balance of digoxin’s goxin use was associated with benefit, in the heart failure armamentarium.
competing neurohormonal and inotro- harm, or had a neutral effect for women Our study is the first, to our knowl-
pic effects. in this or any SDC range. These data edge, to examine the association of dif-
Our findings challenge the belief that are consistent with our prior findings ferent SDCs and major clinical end
digoxin is not associated with mortal- of a digoxin-associated harm in wom- points. Although based on a post hoc
ity among patients with heart failure in en13 in that they suggest there is no se- analysis of the DIG trial, our results sug-
sinus rhythm and suggest that the neu- rum concentration range in which di- gest that an SDC of 0.5 to 0.8 ng/mL
tral association of digoxin and all-cause goxin may provide a benefit to women was associated with lower rates of mor-
mortality reported in the main DIG trial nor a range in which a digoxin- tality and hospitalization. Given that no
publication likely obscured an associa- associated increased mortality risk in study has demonstrated any substan-
tion between SDC and mortality. women can be definitively excluded. tive clinical benefit for higher SDCs,
Digoxin-associated mortality risks have Our study has certain issues to con- prudent practice would support an SDC
previously been shown to be dose- sider. First, because our study is a post of 0.5 to 0.8 ng/mL as a revised thera-
dependent in patients recovering from hoc analysis of nonrandomized treat- peutic range. The feasibility of achiev-
acute myocardial infarction29 and are ment subgroups in the DIG trial, we can- ing SDCs within this range in daily
similar to serum concentration– not exclude the influence of unmea- clinical practice is unclear. Only a ran-
dependent mortality risks reported for sured factors. However, our analysis domized controlled trial can confirm
other positive inotropic agents. 3 0 accounted for BMI and estimated glo- this recommendation; however, we be-
Digoxin, however, was associated with merular filtration rate, 2 of the primary lieve our data provide sufficient grounds
mortality reduction at an SDC of 0.5 to determinants of digoxin absorption and for consideration of lower target SDCs
0.8 ng/mL, suggesting that digoxin may excretion. We used SDCs measured at 1 for men with stable heart failure and left
offer a survival advantage in a narrow month after randomization, thus exclud- ventricular dysfunction.
therapeutic window. Because we can- ing a small group of patients who died
Author Contributions: Study concept and design: Ra-
not definitively exclude the possibility in the month following randomization. thore, Krumholz.
of residual confounding, our findings However, 1 month provided a reason- Acquisition of the data: Krumholz.
Analysis and interpretation of the data: Rathore, Cur-
should be considered hypothesis gen- able time frame in which to ensure se- tis, Wang, Bristow, Krumholz.
erating. A digoxin-associated mortality rum levels provided an accurate mea- Drafting of the manuscript: Rathore.
Critical revision of the manuscript: Rathore, Curtis,
reduction may be plausible if the neu- sure of patients’ steady state SDCs. Wang, Bristow, Krumholz.
rohormonal actions of digoxin observed Furthermore, SDC levels were gener- Statistical expertise: Rathore, Wang, Krumholz.
at low serum concentrations were suf- ally stable during the course of the DIG Study supervision: Krumholz.
Disclaimer: The Digitalis Investigation Group study
ficient to reduce the rate of heart failure trial.1 Serum digoxin concentrations may was conducted and supported by the National Heart,
progression by attenuating neuroendo- not accurately estimate digoxin tissue Lung, and Blood Institute (NHLBI) in collaboration with
the Digitalis Investigation Group Investigators. The
crine abnormalities associated with concentrations given variations in se- manuscript was not prepared in collaboration with in-
increased mortality.22,31 Trials of other rum level measurement.34 However, vestigators of the Digitalis Investigation Group and does
not necessarily reflect the opinions or the views of the
inotropic agents also have shown trends SDCs drawn at least 6 hours after the Digitalis Investigation Group or the NHLBI.
toward a reduction in mortality at low most recent dose in a cohort with a fixed Funding/Support: This project was conducted as an
unfunded analysis of the DIG trial database.
doses, but increased mortality at higher digoxin dose for 30 days are unlikely to
doses.32,33 Clearly, additional research is reflect inaccurate serum concentration
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