Received: 7 February 2022 Revised: 27 March 2022 Accepted: 11 April 2022

DOI: 10.1111/bcpt.13733

ORIGINAL ARTICLE

Digoxin use and outcomes after myocardial infarction in

patients with atrial fibrillation

Ville Kytö1,2,3,4,5 | Antti Saraste1 | Päivi Rautava6,7 | Aleksi Tornio8,9

1
Heart Center, Turku University Hospital
and University of Turku, Turku, Finland Abstract
2
Research Center of Applied and Digoxin is used for rate control in atrial fibrillation (AF), but evidence for its
Preventive Cardiovascular Medicine, efficacy and safety after myocardial infarction (MI) is scarce and mixed. We
University of Turku, Turku, Finland
3
studied post-MI digoxin use effects on AF patient outcomes in a nationwide
Center for Population Health Research,
Turku University Hospital and University registry follow-up study in Finland. Digoxin was used by 18.6% of AF patients
of Turku, Turku, Finland after MI, with a decreasing usage trend during 2004–2014. Baseline differences
in digoxin users (n = 881) and controls (n = 3898) were balanced with inverse
4
Administrative Center, Hospital District
of Southwest Finland, Turku, Finland
5
probability of treatment weight adjustment. The median follow-up was
Department of Public Health, University
of Helsinki, Helsinki, Finland
7.4 years. Patients using digoxin after MI had a higher cumulative all-cause
6
Department of Public Health, University mortality (77.4% vs. 72.3%; hazard ratio [HR]: 1.19; confidence interval [CI]:
of Turku, Turku, Finland 1.07–1.32; p = 0.001) during a 10-year follow-up. Mortality differences were
7
Turku Clinical Research Centre, Turku detected in a subgroup analysis of patients without baseline heart failure
University Hospital, Turku, Finland
8
(HF) (HR: 1.23; p = 0.019) but not in patients with baseline HF (HR: 1.05;
Integrative Physiology and
Pharmacology, Institute of Biomedicine,
p = 0.413). Cumulative incidences of HF hospitalizations, stroke and new MI
University of Turku, Turku, Finland were similar between digoxin group and controls. In conclusion, digoxin use
9
Unit of Clinical Pharmacology, Turku after MI is associated with increased mortality but not with HF hospitaliza-
University Hospital, Turku, Finland
tions, new MI or stroke in AF patients. Increased mortality was detected in
Correspondence patients without baseline HF. Results suggest caution with digoxin after MI in
Ville Kytö, Heart Center, Turku AF patients, especially in the absence of HF.
University Hospital, PO Box 52, 20521,
Turku, Finland. KEYWORDS
Email: [email protected]
atrial fibrillation, cardiovascular pharmacology, digitalis glycosides, ischemic heart disease,
pharmacoepidemiology
Funding information
State Research Funding (VTR); Finnish
Cultural Foundation; Paulo Foundation;
Finnish Foundation for Cardiovascular
Research

1 | INTRODUCTION AND has declined, and it is currently mainly used as a

BACKGROUND second-line therapy to achieve rate control in patients
with atrial fibrillation (AF). Digoxin is eliminated, largely
Digoxin is a cardiac glycoside that has been in clinical unchanged, in the urine. Despite its lack of metabolism
use for decades. In the past, it was widely used in the by the cytochrome P450 enzymes, digoxin is subject to
treatment of heart failure (HF), but more recently its use P-glycoprotein-mediated drug interactions, and drugs

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former
Nordic Pharmacological Society).

Basic Clin Pharmacol Toxicol. 2022;130:655–665. wileyonlinelibrary.com/journal/bcpt 655

656 KYTÖ ET AL.

that inhibit P-glycoprotein—such as clarithromycin, died within 90 days after discharge, patients not dis-
itraconazole and verapamil—can increase digoxin con- charged to their homes or to home-like facilities (includ-
centrations to toxic levels.1 Due to digoxin’s narrow ther- ing nursing homes), and patients with prolonged
apeutic range and its pharmacokinetics that are affected (>90 days) admissions were excluded (Figure 1). In addi-
by many patient-specific factors, therapeutic drug moni- tion, patients lost to follow-up (n = 17) and those treated
toring is frequently utilized in digoxin therapy.2 with non-coronary cardiac surgery were excluded
There is an ongoing controversy surrounding the (Figure 1). Subgroup analyses were performed for
impact of digoxin on clinical outcomes. The randomized patients with and without HF at baseline. Index MI was
DIG trial in the 1990s found no association between defined as the use of an ICD-10 code I21 as the primary
digoxin use and mortality, although it did find a link discharge diagnosis. AF was defined as the use of an
between digoxin use and reduced HF hospitalizations, in ICD-10 code I48 during the index admission. Cardiovas-
HF patients with normal sinus rhythms.3 However, cular medications are only available from pharmacies by
digoxin was later associated with increased mortality in prescription in Finland. Digoxin usage after MI was
HF.4,5 The data concerning the effects of digoxin in AF defined as drug purchase within 90 days after discharge.
are scarce, with no randomized studies available and No digoxin therapy was defined as not having purchased
meta-analyses of studies suggesting either increased digoxin 90 days before MI or 90 days after discharge. Ini-
mortality5 or not enough data for conclusions.4 Older tial digoxin dosage was defined as the tablet strength of
studies from the 1990s found a correlation between the first digoxin prescription purchase after
digoxin use and increased mortality after myocardial MI. Definitions of outcomes, comorbidities, baseline fea-
infarction (MI).6–8 However, current knowledge about tures and prescription medications are presented in the
the potential impact of digoxin on clinical outcomes Supporting Information.
after MI is very limited. Two recent studies of acute cor-
onary syndrome9 and STEMI10 patients found no associ-
ation between digoxin and short-term mortality, but 2.2 | Data sources and permissions
there are no recent long-term data on the influence of
digoxin on outcomes after MI. Thus, we investigated the The CRHF Registry and Finnish Cancer Registry were
impact of digoxin therapy on long-term post-MI out- obtained from the National Institute for Health and
comes in AF patients. Welfare of Finland (permission no: THL/2245/5.05.00/
2019). Mortality and cause of death data were obtained
from a nationwide cause of death registry held by Statis-
2 | MATERIALS AND METHODS tics Finland (permission no: TK-53-484-20). Prescription
medication purchase data (including ATC codes and pur-
2.1 | Study design chase dates) and drug reimbursement permission data
were obtained from the Social Insurance Institution of
We studied the impact of digoxin on the outcomes of AF Finland (permission no: 91/522/2015). The collection and
patients after MI. The inverse probability of treatment reporting of data within the included registries are man-
weight (IPTW) method was used to create comparable dated by law; therefore, the data from these registries
study groups.11 The primary outcome of interest was all- provide a full picture of the Finnish population. Follow-
cause mortality. Secondary outcomes were cardiovascular up started at 90 days and ended 10 years after
mortality, HF hospitalization, stroke and new MI. Follow-up data were available up to 31 December
MI. Consecutive MI patients with AF admitted to hospi- 2018. Because this was a retrospective registry study, no
tals between 1 April 2004 and 31 December 2014 were informed consent was required, nor were the participants
studied using a combination of nationwide mandatory contacted. The legal basis for the processing of personal
registries. Study patients were identified from the Care data is public interest and scientific research (EU General
Register for Healthcare in Finland (CRHF), which Data Protection Regulation 2016/679 (GDPR), Article 6
includes data on all hospital admissions and interven- (1)(e) and Article 9(2)(j); Data Protection Act, Sections
tional procedures in Finland.12 All hospitals in Finland 4 and 6). The data that support the findings of this study
equipped with a coronary catherization laboratory and are available with permission from Findata (www.
treating MI patients (n = 20) were included in the study. findata.fi). Restrictions apply to the availability of these
Hospital-surviving patients with out-of-hospital MI data, which were used under licence for this study. The
admitted to medical, surgical or intensive care wards study was conducted in accordance with the Basic &
were included. To capture only patients with the ability Clinical Pharmacology & Toxicology policy for experi-
and need to purchase post-MI medications, patients who mental and clinical studies.13
KYTÖ ET AL. 657

F I G U R E 1 Study flowchart. IPTW, inverse

probability of treatment weight

2.3 | Statistical analysis were studied using the stabilized IPTW-adjusted Kaplan–
Meier method and robust Cox regression modelling with
Effect sizes in the baseline characteristics between the sandwich-type estimators. The association of initial
study groups were evaluated using standardized mean digoxin dosage with outcomes was studied with multivar-
differences (SMD). Logistic regression was used to create iable Cox modelling. The median follow-up period for
propensity scores based on age, sex, alcohol abuse, anae- the survivors was 7.4 (interquartile range [IQR]: 5.3–10)
mia, cerebrovascular disease, chronic pulmonary disease, years. Cause-specific hazard models were applied in the
coagulopathy, dementia, depression, insulin-dependent outcome analyses. Schoenfeld residuals were used to con-
diabetes, non-insulin-dependent diabetes, HF, hyperten- firm proportional hazard assumptions. The number
sion, hypothyroidism, liver disease, malignancy, meta- needed to harm (NNH) was calculated as previously
static cancer, paralysis, peripheral vascular disease, described.16 The results are given in terms of mean,
psychotic disorder, rheumatic disease, renal failure, val- median, percentage and hazard ratio (HR) with a 95%
vular disease, revascularization by PCI or CABG, ST- confidence interval (CI) or
SD. Statistical significance
elevation MI, cardiovascular pharmacotherapy after MI was defined as a p value <0.05. SAS version 9.4 (SAS
(ADP-inhibitor, anticoagulant, ACEi/ARB, aldosterone Institute Inc., Cary, NC, USA) was used to carry out the
antagonist, antiarrhythmic, beta blocker, calcium chan- analyses.
nel blocker, statin), treating hospital, and study year.
IPTWs were calculated using propensity scores.11 To
improve the balancing, patients with non-overlapping 3 | RESULTS
propensity scores (1 in the digoxin group and 32 in the
control group) were excluded, and IPTWs were stabi- The mean age of the study patients was 76.7 (SD: 9.4,
lized.14 Separate propensity scoring and IPTW calcula- range: 40–100) years, with no difference between digoxin
tions were performed for subgroups of patients with and users and controls (p = 0.259, Table 1). Digoxin therapy
without diagnosed HF up until the time of index MI was applied more frequently to women and to patients
admission. Unmeasured confounding was estimated by with HF (Table S1). Patients treated with digoxin were
calculating the E value.15 less frequently revascularized by percutaneous coronary
Differences between study groups were analysed intervention and had a lower frequency of ADP-inhibitor
using Jonckheere–Terpstra, t and chi-square tests. Trends usage but a higher frequency of anticoagulation and beta
were tested using the Cochrane–Armitage test. Outcomes blocker usage after MI (Table S1). The proportion of AF
658 KYTÖ ET AL.

T A B L E 1 Baseline features of inverse probability of treatment weight (IPTW)-adjusted myocardial infarction patients with atrial
fibrillation with and without post-infarction digoxin therapy

Digoxin Control
Variable n = 881 n = 3898 p value jSMDj
Age, years (SD) 77.2 (9.3) 76.9 (9.4) 0.314 0.041
Women 53.1% 54.9% 0.317 0.036
Comorbidities
Alcohol abuse 2.1% 2.5% 0.503 0.025
Anaemia 4.7% 4.7% 0.916 0.004
Cerebrovascular disease 16.7% 17.2% 0.738 0.012
Chronic pulmonary disease 14.1% 15.1% 0.454 0.027
Coagulopathy 0.5% 0.6% 0.787 0.010
Dementia 7.1% 6.2% 0.339 0.034
Depression 10.9% 11.0% 0.920 0.004
Diabetes 31.5% 30.5% 0.556 0.021
Insulin dependent 11.5% 10.4% 0.329 0.035
Non-insulin dependent 20.0% 20.1% 0.941 0.003
Heart failure 50.5% 49.6% 0.311 0.004
Hypertension 64.8% 64.7% 0.956 0.002
Hypothyroidism 5.4% 5.4% 0.999 0.0001
Liver disease 1.1% 1.0% 0.885 0.005
Malignancy 14.2% 14.1% 0.934 0.003
Metastatic tumour 0.2% 0.1% 0.711 0.013
Paralysis 0.5% 0.6% 0.864 0.006
Peripheral vascular disease 11.7% 10.8% 0.448 0.027
Prior CABG 5.6% 5.5% 0.952 0.008
Prior myocardial infarction 25.2% 23.9% 0.389 0.031
Psychotic disorder 2.6% 2.6% 0.954 0.002
Rheumatic disease 7.9% 7.6% 0.791 0.010
Renal failure 4.7% 4.6% 0.857 0.007
Valvular disease 10.6% 10.5% 0.977 0.001
ST-elevation MI 26.6% 26.1% 0.754 0.011
Revascularization 36.4% 37.8% 0.437 0.028
PCI 29.4% 29.8% 0.806 0.009
CABG 7.6% 8.4% 0.424 0.029
Pharmacotherapy after MI
ADP-inhibitor 38.5% 39.8% 0.447 0.028
Anticoagulant 66.0% 66.0% 0.999 0.0001
ACEi or ARB 66.3% 67.0% 0.689 0.015
Aldosterone antagonist 7.8% 7.4% 0.729 0.013
Antiarrhythmic 4.5% 4.1% 0.565 0.021
Beta blocker 81.9% 83.7% 0.179 0.048
Ca blocker 20.8% 21.6% 0.605 0.019
Statin 67.5% 68.7% 0.467 0.026
(Continues)
KYTÖ ET AL. 659

TABLE 1 (Continued)

Digoxin Control
Variable n = 881 n = 3898 p value jSMDj
Treating hospital (n = 20) 0.684 0.026
Year 0.436 0.041

Abbreviations: ADP, adenosine diphosphate; ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; SMD, standardized mean
difference.

F I G U R E 2 Persistence with digoxin therapy and digoxin F I G U R E 3 Survival of atrial fibrillation patients by digoxin
usage in the control group during follow-up in atrial fibrillation use after myocardial infarction. Adjusted with inverse probability of
patients after myocardial infarction (MI) treatment weight

patients treated with digoxin after MI decreased from versus 13.4% in the control group (p = 0.038), and the
23.4% in 2004 to 9.6% in 2014 (p < 0.0001 for trend), with 5-year mortality rate was 54.4% in the digoxin group ver-
an 18.6% usage rate during the whole study period. The sus 48.0% in the control group (p = 0.002). The all-cause
continuity rate of pharmacy purchased digoxin therapy mortality rate within the 10-year follow-up period was
was 81.9% within the first follow-up year and gradually 77.4% in the digoxin group versus 72.3% in the control
declined to 41.8% within the 10th follow-up year group (HR: 1.19; CI: 1.07–1.32; p = 0.001). The digoxin-
(Figure 2) (p < 0.0001 for trend). Less than 14% of control associated NNH for 10-year mortality after MI was 16.7
patients used digoxin later during the follow-up period (CI: 10.7–42.0) in the total study cohort. The E value was
(Figure 2). Digoxin was used prior to MI by 36.6% of the 1.66 (CI: 1.34–1.97). The 10-year cardiovascular mortality
patients who used post-MI digoxin therapy. Differences was 65.1% in the digoxin group versus 59.0% in the con-
in baseline features and medication usage were balanced trol group (HR: 1.23; CI: 1.09–1.39; p = 0.001). Initial
by IPTW adjustment, resulting in 881 digoxin users and digoxin dosage after MI was not associated with mortality
3898 controls (Table 1). (Table 2).
In the subgroup analyses, significant differences in
mortality were detected only in patients without baseline
3.1 | Mortality HF. In the subgroup with baseline HF, the 10-year all-
cause mortality rate was 85.7% in the digoxin group ver-
During the 10-year follow-up period, 3079 patients sus 84.9% in the control group (HR: 1.05; CI: 0.93–1.18;
(628 in the digoxin group) died. Patients who used p = 0.413). In patients without baseline HF, all-cause
digoxin therapy after MI had a higher rate of mortality mortality was 70.9% in the digoxin group versus 64.4% in
during the follow-up period (Figure 3). The 1-year all- the control group (HR: 1.23; CI: 1.03–1.46; p = 0.019)
cause mortality rate was 16.5% in the digoxin group during the 10-year follow-up.
660 KYTÖ ET AL.

3.2 | HF hospitalization

p value

Note: The results were adjusted for age, sex, alcohol abuse, anaemia, cerebrovascular disease, chronic pulmonary disease, coagulopathy, dementia, depression, diabetes, heart failure, hypertension, hypothyreoidism,
New myocardial infarction

0.764

0.501
0.511
During the follow-up period, 399 patients in the digoxin

malignancy, paralysis, peripheral vascular disease, prior coronary bypass, prior myocardial infarction, psychotic disorder, rheumatic disease, renal failure, ST-elevation myocardial infarction, revascularization,
group and 1795 in the control group were hospitalized
with HF. The cumulative incidence of HF hospitalization
was 46.0% in the digoxin group versus 45.9% in the con-

0.87 (0.58–1.31)
0.82 (0.46–1.47)
HR (95% CI)
trol group at 5 years and 60.5% versus 62.3% for the

Reference
digoxin group and the control group, respectively, at
10 years (HR: 1.03; CI: 0.91–1.18; p = 0.608) (Figure 4).
The 10-year incidence of HF hospitalization in patients
with baseline HF was 78.3% in the digoxin group versus
77.3% in the control group (HR: 1.02; CI: 0.88–1.17;
p value

p = 0.835). New HF requiring hospitalization occurred in

0.388

0.218
0.219

54.7% of patients without baseline HF in the digoxin

group and in 51.0% of patients in the control group (HR:
1.22; CI: 0.98–1.52; p = 0.068) during the follow-up
0.76 (0.49–1.18)
0.66 (0.33–1.29)

period. Initial digoxin dosage was not associated with HF

HR (95% CI)

pharmacotherapy (ADP-inhibitor, anticoagulant, ACEi/ARB, aldosterone antagonist, antiarrhtyhmic beta blocker, Ca blocker, statin) and study year.
Association of initial digoxin dosage with 10-year outcomes after myocardial infarction in atrial fibrillation patients

hospitalization (Table 2).

Reference
Stroke

3.3 | Stroke

Stroke occurred in 799 patients (153 in the digoxin group)

p value

within the follow-up period (Figure 5). The cumulative

Heart failure hospitalization

0.905

0.987
0.730

10-year incidence of stroke was 30.5% in the digoxin

group versus 29.2% in the control group (HR: 1.09; CI:
0.90–1.33; p = 0.383). The incidence of stroke was 25.5%
in the digoxin group versus 30.5% in the control group
1.00 (0.77–1.31)
1.07 (0.74–1.53)

(HR: 0.89; CI: 0.68–1.17; p = 0.413) in the HF subgroup

HR (95% CI)

and 33.3% versus 28.8% in the digoxin group and the con-
Reference

trol group, respectively, in the non-HF subgroup (HR:

p value
0.697

0.781
0.426
All-cause mortality

0.97 (0.76–1.22)
0.88 (0.63–1.21)

Abbreviations: CI, confidence interval; HR, hazard ratio.

HR (95% CI)
Outcome

Reference
152
623
119
n
Digoxin dosage
0.0625 mg
0.125 mg
0.25 mg
TABLE 2

F I G U R E 4 Cumulative freedom from heart failure

hospitalization in atrial fibrillation patients with and without
digoxin therapy after myocardial infarction. Adjusted with inverse
probability of treatment weight
KYTÖ ET AL. 661

0.86; CI: 0.64–1.16; p = 0.329). Initial digoxin dosage was

not associated with the incidence of new MI (Table 2).

4 | DISCUSSION

This population-based study investigated the impact of

digoxin on long-term outcomes after MI in AF patients.
Digoxin usage was independently associated with long-
term mortality but not with the occurrence of HF hospi-
talizations, stroke or new MI. Digoxin exerts positive ino-
tropic effects by inhibiting cardiac Na+/K+-ATPase,
which causes an increase in intracellular Na+, resulting
in inhibition of the efflux of Ca+ and an increase in
intracellular Ca+ concentration. Furthermore, digoxin
has parasympathomimetic activity. These effects translate
to increased cardiac contractibility and slower AV-nodal
conduction. Importantly, digoxin has a low therapeutic
index, and high digoxin concentrations are associated
with adverse effects, commonly manifesting as arrhyth-
mias, nausea, cognitive impairment and disturbed vision.
There is an ongoing controversy about the potential
increase in mortality with digoxin treatment. The largest
and most recent randomized digitalis trial, the 1990s DIG
trial, found digoxin to have a neutral effect on mortality
in HF patients,3 and a meta-analysis of previous random-
ized trials showed similar results.4 However, observa-
tional studies have found increased mortality with
digoxin in HF,5 but the association weakens with more
detailed baseline adjustments.4 Studies on the impact of
digoxin in AF are fewer, with no randomized controlled
F I G U R E 5 Cumulative freedom from stroke (A) and new
trials (RCTs) available. Meta-analyses have suggested
myocardial infarction (B) in atrial fibrillation patients with and both that digoxin increases the risk of mortality5 and that
without digoxin therapy after myocardial infarction. Adjusted with there is not enough data to draw conclusions4 about the
inverse probability of treatment weight effects of digoxin in AF patients. The ongoing random-
ized DIGIT-HF trial will provide contemporary evidence
for the efficacy and safety of digoxin in HF with and
1.24; CI: 0.93–1.67; p = 0.145) during the 10-year follow- without AF.17
up period. There was no association between initial Uncertainty about the impact of digoxin is reflected
digoxin dosage and stroke incidence (Table 2). in guideline recommendations. Most recent European
Society of Cardiology (ESC) HF guidelines recommend
digoxin only for treatment of HF patients with rapid
3.4 | New MI heart rate and reduced ejection fraction.18 The HF guide-
lines of the AHA/ACC give a level IIaB recommendation
Out of all patients, 1159 (206 in the digoxin group) had for the reduction of HF hospitalizations.19 The AF guide-
new MI with a cumulative incidence of 33.7% in the lines of the ESC recommend digoxin or beta blockers as a
digoxin group versus 34.7% in the control group within first-line therapy to control heart rate in patients with
the follow-up period (HR: 0.99; CI: 0.82–1.19; p = 0.893) reduced ejection fraction and digoxin as a second-line
(Figure 5). In HF patients, the 10-year incidence of new therapy in patients with normal or near normal myocar-
MI was 42.1% in the digoxin group versus 40.9% in the dial contractility.20 AHA/ACC/HRS guidelines recom-
control group (HR: 1.05; CI: 0.85–1.29; p = 0.678). In mend digoxin only as a second-line therapy for rate
non-HF patients, the incidence of new MI was 27.5% in control in AF patients with HF.21 Digoxin is rec-
the digoxin group versus 29.9% in the control group (HR: ommended by the ESC for rate control in the acute phase
662 KYTÖ ET AL.

of STEMI with extensive myocardial damage or severe and scarring after MI, in addition to potential residual
left ventricular dysfunction,22 but guidelines give no rec- ischaemia, expose patients to ventricular tachyarrhyth-
ommendations regarding digoxin use after MI.22,23 mias and sudden cardiac death.1 Parasympathomimetic
The potential impact of digoxin on clinical outcomes activity of digoxin may contribute to proarrhythmic auto-
after MI has been less studied, and there is currently a nomic dysfunction.28 Although digoxin concentrations
definite gap in evidence concerning how to use digoxin are typically monitored, digoxin’s therapeutic index is
after the acute phase of MI. To the best of our knowledge, extremely narrow, and adverse effects can occur at thera-
there are no RCTs or ongoing studies on digoxin after peutic concentrations as well.2 Thus, it is mechanistically
acute MI in AF patients. The DIGIT-HF trial will provide plausible that post-MI patients are more susceptible to
important information about digoxin but will exclude the potentially hazardous adverse effects of digoxin.
patients with recent MI.17 Previous studies enrolling in Elevated serum digoxin concentration (SDC) is linked
the early 1990s found increased mortality after MI in to increased mortality.29–31 Contrary to our expectations,
digoxin users.6–8 Post hoc analysis of the DIG trial also we found no association between initial digoxin dosage
indicated an association between long-term digoxin use after MI and long-term clinical outcomes. Because labo-
and mortality in patients with previous MI.24 In contrast, ratory data were not available, we were unable to study
an analysis of the AFFIRM study enrolling AF patients in SDCs. After reports of higher SDCs associated with mor-
the 1990s found no independent association between tality, measurement of SDC after digoxin initiation,
digoxin use and mortality in the subgroup of MI followed by dose adjustment as needed, became a clinical
patients.25 Similarly, a pooled analysis of CARPICON, routine in Finland’s centralized healthcare system. Fur-
EPHESUS, OPTIMAAL and VALIANT post-MI trials thermore, clinical laboratories in Finland have updated
enrolling in the late 1990s and early 2000s found no asso- their normal range for SDC to reflect the accumulating
ciation between digoxin and all-cause mortality in a clinical evidence. Concurrently, recent data from the
3-year follow-up of AF patients.26 However, the recent United States show a decreasing trend in digoxin toxicity
data are limited to short-term follow-up periods. Garvia- and adverse outcomes.32 Thus, the observed neutral asso-
Rubira et al. found that previous digoxin treatment did ciation between initial digoxin dosage and clinical out-
not influence the in-hospital mortality of acute coronary comes likely reflects an awareness of patient-specific
syndrome patients,9 and Metawee et al. observed no asso- factors, such as kidney function and age, that affect SDC
ciation between digoxin and 30-day mortality in STEMI and improved monitoring rather than biological effects.
patients.10 We found that post-MI digoxin usage was sig- The DIG trial found that digoxin was associated with
nificantly associated with increased long-term mortality reduced HF hospitalizations in HF patients with normal
after MI in AF patients, with an NNH of 16.7 for death sinus rhythms,3 and a meta-analysis shows a similar
after adjustment for many potential confounders. To our effect.4 However, data on AF patients is much more lim-
knowledge, the current study, with a median follow-up ited.4 In our data on AF patients, there was no associa-
period of 7.4 years, is the first contemporary long-term tion between post-MI digoxin use and HF
analysis of digoxin use and clinical outcomes after acute hospitalizations. This is in line with the previous findings
MI, and it is among the first to focus on AF patients. in post-MI AF patients26 and AF patients without base-
In the sensitivity analysis, we found post-MI digoxin line HF.33 We also found digoxin to have no association
use to be associated with increased mortality in patients with the occurrence of stroke or new MI, indicating that
without a baseline diagnosis of HF but not in those with digoxin does not significantly influence thrombogenesis
an HF diagnosis. This finding agrees with previous RCTs in clinical use. These associations were previously rarely
of digoxin’s neutral effect on mortality in HF.4 In addi- studied.4 An analysis of AF patients in the AFFIRM study
tion, a previous observational Swedish study found that found digoxin to be associated with stroke risk, but the
digoxin use was associated with an increase in 1-year patients were not anticoagulated.34 In the more recent
mortality in AF patients without baseline HF but not in ENGAGE AF-TIMI 48 trial using anticoagulation, there
those with baseline HF.27 The detrimental post-MI was no association between digoxin use and risk of stroke
impact of digoxin is also linked to patients without sys- or MI in AF patients.33
tolic HF.26 However, because an HF diagnosis may be Our study has strengths and limitations. We used a
omitted in acute MI when the patient has reduced con- combination of previously validated nationwide
tractility but not symptomatic HF, these subgroup results mandated-by-law registries35,36 with complete follow-up
should be interpreted with caution, especially regarding on the primary clinical outcome. Propensity scoring and
the lack of HF. IPTW were used to balance differences in major risk fac-
In healthy persons, ventricular arrhythmias induced tors and concurrent medications between the study
by digoxin are rare. Myocardial damage, remodelling, groups. It is nevertheless possible that unrecognized
KYTÖ ET AL. 663

residual confounders may have impacted the results, In conclusion, our study shows that digoxin usage
although propensity scoring with IPTW is one of the after MI is associated with increased long-term risk of
strongest methods to control confounding factors. Based mortality in patients with AF. Notably, in a subgroup
on the E value, the observed higher all-cause mortality in analysis, an increased risk of death with digoxin usage
digoxin users could be explained by an unmeasured con- was detected in patients without baseline HF but not
founding associated with both digoxin use and all-cause in those with HF. Digoxin usage was not associated
mortality by a risk ratio of 1.7-fold each, above and with HF hospitalizations, new MIs or stroke after
beyond the measured confounders, but weaker con- MI. Our results suggest that digoxin should be used
founding could not do so.15 Medication usage was studied with caution after MI in AF patients, especially if HF is
with a standard method using drug purchase data from a not present.
database covering all prescription drug purchases in
Finland,37 but we did not have data on the actual usage ACKNOWLEDGEMENT
of purchased medications, nor was it possible to study None.
the temporal changes in the drug therapies. Furthermore,
the available data limited the analysis of digoxin dosage F U N D I N G IN F O R M A T I O N
to the initial tablet strength and did not account for tablet This study was supported by grant funding from the
splitting, alternate day dosing, or the use of multiple tab- Finnish Foundation for Cardiovascular Research, the
lets per day. We did not have access to ECG recordings, Paulo Foundation, the Finnish Cultural Foundation, and
and presence of AF was based on ICD-10 coding. Fur- the State Research Funding (VTR).
thermore, we did not have information regarding the AF
type (e.g., new onset, paroxysmal, persistent or perma- CONFLICT OF INTEREST
nent), but because there appear to be no significant dif- None.
ferences in outcome between AF types after MI,38 we
consider this limitation to be unlikely to cause significant ORCID
bias. In addition, we did not have data on ejection frac- Ville Kytö https://orcid.org/0000-0002-4521-1093
tion, preventing the subclassification of HF into HFrEF Aleksi Tornio https://orcid.org/0000-0001-5713-5692
and HFpEF.18 Inaccuracies in administrative databases
are a limitation that is likely to affect digoxin users and RE FER EN CES
controls in a similar fashion and are thus not expected to 1. Ehle M, Patel C, Giugliano RP. Digoxin: clinical highlights: a
have major influence over the key findings of this study. review of digoxin and its use in contemporary medicine. Crit
Our study was designed as intention-to-treat-type analy- Pathw Cardiol. 2011;10:93-98. doi:10.1097/HPC.0b013e31822
sis and the persistence with digoxin gradually decreased 1e7dd
2. Whayne TF Jr. Clinical Use of Digitalis: A State of the Art
during the follow-up. Therefore, our results may differ
Review. Am J Cardiovasc Drugs. 2018;18(6):427-440. doi:10.
from the on-treatment impact of digoxin in long-term 1007/s40256-018-0292-1
follow-up. As previously noted, RCTs are the golden stan- 3. Digitalis Investigation G. The effect of digoxin on mortality
dard of drug studies, and observational studies must and morbidity in patients with heart failure. N Engl J Med.
always be interpreted with caution.24,39 1997;336(8):525-533. doi:10.1056/NEJM199702203360801
Our results have clinical implications regarding post- 4. Ziff OJ, Lane DA, Samra M, et al. Safety and efficacy of
MI medication in AF patients. Digoxin is currently used digoxin: systematic review and meta-analysis of observational
and controlled trial data. Bmj. 2015;351:h4451. doi:10.1136/
mainly for rate control in AF patients. Current results,
bmj.h4451
along with older studies, suggest that rate control in AF
5. Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mor-
after MI should be handled by beta blockers rather than tality: a systematic review and meta-analysis of the literature.
digoxin. In addition to lowering the baseline heart rate, Eur Heart J. 2015;36(28):1831-1838. doi:10.1093/eurheartj/
beta blockers limit the abrupt heart rate increases that ehv143
occur during exercise, unlike digoxin, and most impor- 6. Leor J, Goldbourt U, Behar S, et al. Digoxin and mortality in
tantly, beta blockers improve outcomes after MI.20,22,23 In survivors of acute myocardial infarction: observations in
addition, digoxin and beta blockers have comparable patients at low and intermediate risk. The SPRINT Study
Group. Secondary Prevention Reinfarction Israeli Nifedipine
impacts on quality of life in AF patients with rate con-
Trial. Cardiovasc Drugs Ther. 1995;9(4):609-617. doi:10.1007/
trol.40 In clinical reality, however, there are situations in BF00878094
which beta blockers alone or combined with calcium 7. Reicher-Reiss H, Jonas M, Boyko V, Shotan A, Goldbourt U,
channel blockers are not effective enough, or adverse Behar S. Are coronary patients at higher risk with digoxin
drug effects prevent their use, and digoxin usage is thus therapy? An ongoing controversy. Int J Cardiol. 1999;68(2):
unavoidable. 137-143. doi:10.1016/S0167-5273(98)00364-7
664 KYTÖ ET AL.

8. Kober L, Torp-Pedersen C, Gadsboll N, Hildebrandt P, 21. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS
Hoilund-Carlsen PF. Is digoxin an independent risk factor for guideline for the management of patients with atrial fibrilla-
long-term mortality after acute myocardial infarction? Eur tion: a report of the American College of Cardiology/American
Heart J. 1994;15:382-388. Heart Association Task Force on practice guidelines and the
9. Garcia-Rubira JC, Calvo-Taracido M, Francisco-Aparicio F, Heart Rhythm Society. Circulation. 2014;130(23):e199-e267.
et al. The previous use of digoxin does not worsen early out- doi:10.1161/CIR.0000000000000041
come of acute coronary syndromes: an analysis of the ARIAM 22. Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for
Registry. Intern Emerg Med. 2014;9:759-765. doi:10.1007/ the management of acute myocardial infarction in patients
s11739-013-1032-9 presenting with ST-segment elevation: The Task Force for the
10. Metawee M, Charnigo R, Morales G, et al. Digoxin and short management of acute myocardial infarction in patients pre-
term mortality after acute STEMI: Results from the MAGIC senting with ST-segment elevation of the European Society of
trial. Int J Cardiol. 2016;218:176-180. doi:10.1016/j.ijcard.2016. Cardiology (ESC). Eur Heart J. 2018;39:119-177. doi:10.1093/
05.022 eurheartj/ehx393
11. Kyto V, Nuotio M, Rautava P. Sex difference in the case 23. Collet JP, Thiele H, Barbato E, et al. 2020 ESC Guidelines for
fatality of older myocardial infarction patients. J Gerontol A the management of acute coronary syndromes in patients pre-
Biol Sci Med Sci. 2021;77(3):614-620. doi:10.1093/gerona/ senting without persistent ST-segment elevation. Eur Heart J.
glab152 2020;42:2021. doi:10.1093/eurheartj/ehaa909
12. Palomaki A, Kerola AM, Malmberg M, Rautava P, Kyto V. 24. Aguirre Davila L, Weber K, Bavendiek U, et al.
Patients with rheumatoid arthritis have impaired long-term Digoxin-mortality: randomized vs. observational comparison
outcomes after myocardial infarction—a nationwide case- in the DIG trial. Eur Heart J. 2019;40:3336-3341. doi:10.1093/
control registry study. Rheumatology (Oxford). 2021;60(11): eurheartj/ehz395
5205-5215. doi:10.1093/rheumatology/keab204 25. Gheorghiade M, Fonarow GC, van Veldhuisen DJ, et al. Lack
13. Tveden-Nyborg P, Bergmann TK, Jessen N, Simonsen U, of evidence of increased mortality among patients with atrial
Lykkesfeldt J. BCPT policy for experimental and clinical stud- fibrillation taking digoxin: findings from post hoc propensity-
ies. Basic Clin Pharmacol Toxicol. 2021;128:4-8. doi:10.1111/ matched analysis of the AFFIRM trial. Eur Heart J. 2013;34:
bcpt.13492 1489-1497. doi:10.1093/eurheartj/eht120
14. Malmberg M, Gunn J, Rautava P, Sipila J, Kyto V. Outcome of 26. Coiro S, Girerd N, Rossignol P, et al. Association of digitalis
acute myocardial infarction versus stable coronary artery dis- treatment with outcomes following myocardial infarction in
ease patients treated with coronary bypass surgery. Ann Med. patients with heart failure or evidence of left ventricular dys-
2021;53:70-77. doi:10.1080/07853890.2020.1818118 function: an analysis from the High-Risk Myocardial Infarc-
15. VanderWeele TJ, Ding P. Sensitivity analysis in observational tion Database Initiative. Clin Res Cardiol. 2017;106(9):722-733.
research: introducing the E-value. Ann Intern Med. 2017; doi:10.1007/s00392-017-1116-z
167(4):268-274. doi:10.7326/M16-2607 27. Hallberg P, Lindback J, Lindahl B, Stenestrand U, Melhus H.
16. Altman DG, Andersen PK. Calculating the number needed to Digoxin and mortality in atrial fibrillation: a prospective
treat for trials where the outcome is time to an event. BMJ. cohort study. Eur J Clin Pharmacol. 2007;63(10):959-971. doi:
1999;319(7223):1492-1495. doi:10.1136/bmj.319.7223.1492 10.1007/s00228-007-0346-9
17. Bavendiek U, Berliner D, Davila LA, et al. Rationale and 28. Manolis AA, Manolis TA, Apostolopoulos EJ, Apostolaki NE,
design of the DIGIT-HF trial (DIGitoxin to Improve ouTcomes Melita H, Manolis AS. The role of the autonomic nervous sys-
in patients with advanced chronic heart failure): a random- tem in cardiac arrhythmias: The neuro-cardiac axis, more foe
ized, double-blind, placebo-controlled study. Eur J Heart Fail. than friend? Trends Cardiovasc Med. 2021;31:290-302.
2019;21(5):676-684. doi:10.1002/ejhf.1452 29. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM.
18. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Association of serum digoxin concentration and outcomes in
Guidelines for the diagnosis and treatment of acute and patients with heart failure. Jama. 2003;289(7):871-878. doi:10.
chronic heart failure: The Task Force for the diagnosis and 1001/jama.289.7.871
treatment of acute and chronic heart failure of the European 30. Leor J, Goldbourt U, Rabinowitz B, et al. Digoxin and
Society of Cardiology (ESC)Developed with the special increased mortality among patients recovering from acute
contribution of the Heart Failure Association (HFA) of the myocardial infarction: importance of digoxin dose. Cardiovasc
ESC. Eur Heart J. 2016;37(27):2129-2200. doi:10.1093/ Drugs Ther. 1995;9(5):723-729. doi:10.1007/BF00878556
eurheartj/ehw128 31. Lopes RD, Rordorf R, de Ferrari GM, et al. Digoxin and Mor-
19. Writing Committee M, Yancy CW, Jessup M, et al. 2013 tality in Patients With Atrial Fibrillation. J Am Coll Cardiol.
ACCF/AHA guideline for the management of heart failure: a 2018;71:1063-1074. doi:10.1016/j.jacc.2017.12.060
report of the American College of Cardiology 32. Angraal S, Nuti SV, Masoudi FA, et al. Digoxin Use and Asso-
Foundation/American Heart Association Task Force on prac- ciated Adverse Events Among Older Adults. Am J Med. 2019;
tice guidelines. Circulation. 2013;128:e240-e327. 132(10):1191-1198. doi:10.1016/j.amjmed.2019.04.022
20. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines 33. Eisen A, Ruff CT, Braunwald E, et al. Digoxin use and
for the diagnosis and management of atrial fibrillation devel- subsequent clinical outcomes in patients with atrial fibrillation
oped in collaboration with the European Association of with or without heart failure in the ENGAGE AF-TIMI
Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2021;42(5): 48 trial. J am Heart Assoc. 2017;(7):6. doi:10.1161/JAHA.117.
373-498. doi:10.1093/eurheartj/ehaa612 006035
KYTÖ ET AL. 665

34. Chao TF, Liu CJ, Chen SJ, et al. Does digoxin increase 39. Rush CJ, Campbell RT, Jhund PS, Petrie MC, McMurray JJV.
the risk of ischemic stroke and mortality in atrial Association is not causation: treatment effects cannot be esti-
fibrillation? A nationwide population-based cohort study. mated from observational data in heart failure. Eur Heart J.
Can J Cardiol. 2014;30(10):1190-1195. doi:10.1016/j.cjca.2014. 2018;39(37):3417-3438. doi:10.1093/eurheartj/ehy407
05.009 40. Kotecha D, Bunting KV, Gill SK, et al. Effect of digoxin vs bis-
35. Sund R. Quality of the Finnish Hospital Discharge Register: a oprolol for heart rate control in atrial fibrillation on patient-
systematic review. Scand J Public Health. 2012;40(6):505-515. reported quality of life: the RATE-AF randomized clinical trial.
doi:10.1177/1403494812456637 Jama. 2020;324:2497-2508. doi:10.1001/jama.2020.23138
36. Vuori MA, Laukkanen JA, Pietila A, et al. The validity of heart
failure diagnoses in the Finnish Hospital Discharge Register. SU PP O R TI N G I N F O RMA TI O N
Scand J Public Health. 2020;48(1):20-28. doi:10.1177/
Additional supporting information may be found in the
1403494819847051
online version of the article at the publisher’s website.
37. Kyto V, Prami T, Khanfir H, Hasvold P, Reissell E,
Airaksinen J. Usage of PCI and long-term cardiovascular risk
in post-myocardial infarction patients: a nationwide registry
How to cite this article: Kytö V, Saraste A,
cohort study from Finland. BMC Cardiovasc Disord. 2019;19:
Rautava P, Tornio A. Digoxin use and outcomes
123. doi:10.1186/s12872-019-1101-8
38. Batra G, Svennblad B, Held C, et al. All types of atrial fibrilla- after myocardial infarction in patients with atrial
tion in the setting of myocardial infarction are associated with fibrillation. Basic Clin Pharmacol Toxicol. 2022;
impaired outcome. Heart. 2016;102(12):926-933. doi:10.1136/ 130(6):655‐665. doi:10.1111/bcpt.13733
heartjnl-2015-308678