JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 7, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.04.070
EDITORIAL COMMENT
Outcomes With Digoxin in Atrial Fibrillation More Data, No Answers* Matthew R. Reynolds, MD, MSCyz
D
espite—or perhaps because of—a very long
from Sweden have reached differing conclusions
history of clinical use, high-quality evi-
regarding a possible link between digoxin and
dence regarding the long-term clinical
mortality in AF patients after adjustment for con-
outcomes with digoxin and related cardiac glycosides
founding factors, one reporting an association (2), the
is limited. It took until the late 1990s to complete a
other finding none (3). Likewise, 2 simultaneously
large randomized trial that clarified digoxin’s role in
published post-hoc analyses of the AFFIRM (Atrial
the treatment of heart failure (HF) (decreased hospi-
Fibrillation
talization, no effect on mortality) (1). With respect
Management) trial, using different analytic methods,
to atrial fibrillation (AF), digoxin’s other main thera-
reported opposite conclusions as to whether or not
peutic target, no such randomized outcomes trial
digoxin increases mortality (4,5).
Follow-Up
Investigation
of
Rhythm
has ever been completed. As a result, the best avail-
Into this fray enters a new analysis of outcomes in
able evidence on clinical outcomes with digoxin in
AF patients treated with digoxin, based on a large
AF patients comes from post-hoc analyses of clinical
national sample of patients treated in the Veteran’s
trials designed to answer other questions, or from
Administration (VA) health system (6). In a program
observational studies.
called TREAT-AF (The Retrospective Evaluation and
Patients treated with digoxin tend to be older and
Assessment of Therapies in AF), Turakhia et al. (6), in
sicker than those not treated with digoxin (2). In
this issue of the Journal, using novel linkages
several studies, digoxin treatment in AF patients has
between clinical, pharmacy, claims, and mortality
been associated with increased crude mortality rates,
databases, have assembled a cohort of more than
raising the question: Is it the patients, or the drug?
120,000 veterans with incident AF between 2004 and
The key to answering this question lies in fully
2008. This unique database was used to explore the
accounting for the differences between the patients
potential association between digoxin use and mor-
who do and do not receive the drug. There are
tality over a roughly 3-year period.
different ways to adjust for such differences in observational research. However, even when similar
SEE PAGE 660
analysis methods are used, data elements can vary
A remarkable 23% of the study cohort was pre-
depending on data sources. Even “exposure” to a
scribed digoxin within 90 days of the first AF
drug can be defined in more than 1 way. It should not
encounter, with
VOL. 64, NO. 7, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.04.070
EDITORIAL COMMENT
Outcomes With Digoxin in Atrial Fibrillation More Data, No Answers* Matthew R. Reynolds, MD, MSCyz
D
espite—or perhaps because of—a very long
from Sweden have reached differing conclusions
history of clinical use, high-quality evi-
regarding a possible link between digoxin and
dence regarding the long-term clinical
mortality in AF patients after adjustment for con-
outcomes with digoxin and related cardiac glycosides
founding factors, one reporting an association (2), the
is limited. It took until the late 1990s to complete a
other finding none (3). Likewise, 2 simultaneously
large randomized trial that clarified digoxin’s role in
published post-hoc analyses of the AFFIRM (Atrial
the treatment of heart failure (HF) (decreased hospi-
Fibrillation
talization, no effect on mortality) (1). With respect
Management) trial, using different analytic methods,
to atrial fibrillation (AF), digoxin’s other main thera-
reported opposite conclusions as to whether or not
peutic target, no such randomized outcomes trial
digoxin increases mortality (4,5).
Follow-Up
Investigation
of
Rhythm
has ever been completed. As a result, the best avail-
Into this fray enters a new analysis of outcomes in
able evidence on clinical outcomes with digoxin in
AF patients treated with digoxin, based on a large
AF patients comes from post-hoc analyses of clinical
national sample of patients treated in the Veteran’s
trials designed to answer other questions, or from
Administration (VA) health system (6). In a program
observational studies.
called TREAT-AF (The Retrospective Evaluation and
Patients treated with digoxin tend to be older and
Assessment of Therapies in AF), Turakhia et al. (6), in
sicker than those not treated with digoxin (2). In
this issue of the Journal, using novel linkages
several studies, digoxin treatment in AF patients has
between clinical, pharmacy, claims, and mortality
been associated with increased crude mortality rates,
databases, have assembled a cohort of more than
raising the question: Is it the patients, or the drug?
120,000 veterans with incident AF between 2004 and
The key to answering this question lies in fully
2008. This unique database was used to explore the
accounting for the differences between the patients
potential association between digoxin use and mor-
who do and do not receive the drug. There are
tality over a roughly 3-year period.
different ways to adjust for such differences in observational research. However, even when similar
SEE PAGE 660
analysis methods are used, data elements can vary
A remarkable 23% of the study cohort was pre-
depending on data sources. Even “exposure” to a
scribed digoxin within 90 days of the first AF
drug can be defined in more than 1 way. It should not
encounter, with
