Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data

Ziff, Oliver J.; Lane, Deirdre A.; Samra, Monica; Griffith, Michael; Kirchhof, Paulus; Lip, Gregory Y.H.; Steeds, Richard P.; Townend, Jonathan N.; Kotecha, Dipak

doi:10.1136/bmj.h4451

Cited by 282 publications

(249 citation statements)

References 107 publications

(162 reference statements)

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“…As demonstrated in this study and others,1, 9, 14 in patients with HF, digoxin is prescribed to patients with more advanced HF, lower LVEF, worse New York Heart Association functional class, and greater burden of other comorbidities. As such, the association between digoxin use and clinical outcomes in patients with HF may be biased by residual confounding caused by the baseline medical condition and concomitant medications 15. Adjusting for multiple confounders, propensity matching, and IPTW may not fully account for this difference.…”

Section: Discussionmentioning

confidence: 99%

“…Conflicting data exist regarding adverse outcomes that are associated with digoxin use in patients with AF 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. While several retrospective studies and meta‐analyses have demonstrated an association between digoxin use and all‐cause mortality, cardiovascular death, and sudden cardiac death (SCD),6, 7, 8, 9, 10, 11, 12, 13 other studies have not found a compelling association 14, 15, 16.…”

Section: Introductionmentioning

confidence: 99%

“…While several retrospective studies and meta‐analyses have demonstrated an association between digoxin use and all‐cause mortality, cardiovascular death, and sudden cardiac death (SCD),6, 7, 8, 9, 10, 11, 12, 13 other studies have not found a compelling association 14, 15, 16. These contradictory results can be attributed to the nature of observational studies and to digoxin prescription biases.…”

Section: Introductionmentioning

confidence: 99%

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Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF‐TIMI 48 Trial

Eisen

Ruff

Braunwald

et al. 2017

JAHA

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BackgroundDigoxin is widely used in patients with atrial fibrillation despite the lack of randomized controlled trials. Observational studies report conflicting results regarding its association with mortality, perhaps because of residual confounding by the presence of heart failure (HF).Methods and ResultsIn the ENGAGE AF‐TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation‐Thrombolysis in Myocardial Infarction 48) trial, clinical outcomes of patients with atrial fibrillation with and without HF were examined by baseline digoxin use during a median follow‐up of 2.8 years. HF was defined at baseline as prior or current clinical stage C or D HF. Of 21 105 patients enrolled, 6327 (30%) were treated with digoxin at baseline. Among patients without HF (n=8981), digoxin use (20%) was independently associated with sudden cardiac death (adjusted hazard ratio, 1.51; 95% CI, 1.10–2.08), with no significant interaction by age, sex, left ventricular ejection fraction, renal function, or concomitant medications (P>0.05 for each). Consistent results were observed using propensity matching (adjusted hazard ratio for sudden cardiac death, 1.90; 95% CI, 1.36–2.65). Among patients with HF (n=12 124), digoxin use (37%) was associated with an increase in all‐cause death, cardiovascular death, sudden cardiac death, and death caused by HF/cardiogenic shock (P<0.01 for each), but not with noncardiovascular death, stroke/systemic embolism, or myocardial infarction.ConclusionsIn this observational analysis of patients with atrial fibrillation without investigator‐reported HF, digoxin use was significantly associated with sudden cardiac death. While residual confounding cannot be excluded, the association between digoxin use and worse clinical outcomes highlights the need to examine digoxin use, particularly when prescribed to control heart rate in patients with atrial fibrillation in a randomized trial.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF‐TIMI 48 Trial

Eisen

Ruff

Braunwald

et al. 2017

JAHA

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“…W praktyce klinicznej często przepisuje się digoksynę, ale nie przeprowadzono bezpośrednich porównawczych RCT u pacjentów z AF. W metaanalizie badań obserwacyjnych digoksyna wywierała neutralny wpływ na umieralność u pacjentów z AF i współistniejącą niewydolnością serca [badania obserwacyjne skorygowane względem ryzyka: ryzyko względne (RR) 0,90; 95% CI 0,70-1,16; badania obserwacyjne z doborem z wykorzystaniem skali skłonności: RR 1,08; 95% CI 0,93-1,26) [225]. Początkowe i skojarzone leczenie w celu kontroli częstości rytmu komór u pacjentów z AF i HFrEF powinno więc być wybierane z uwzględnieniem charakterystyki poszczególnych chorych oraz występujących u nich objawów.…”

Section: Pacjenci Z Migotaniem Przedsionków Oraz Niewydolnością Sercaunclassified

“…Nie przeprowadzono żadnych bezpośrednich porównawczych RCT, w których oceniono by digoksynę u pacjentów z AF [546]. W badaniach obserwacyjnych wiązano jej stosowanie ze zwiększoną umieralnością wśród pacjentów z AF [547][548][549], ale ten związek wynikał prawdopodobnie z błędów doboru i odmiennej charakterystyki pacjentów, którym przepisywano ten lek, a nie z rzeczywistej szkodliwości digoksyny [550][551][552][553], zwłaszcza dlatego, że digoksynę często stosuje się u ciężej chorych pacjentów [225]. W krzyżowej próbie klinicznej w celu oceny mechanizmów działania, przeprowadzonej w grupie 47 pacjentów z HFrEF i AF, nie stwierdzono różnic pod względem częstości rytmu komór, ciśnienia tętniczego, dystansu chodu i LVEF między leczonymi karwedilolem a leczonymi digoksyną, choć podawanie beta-adrenolityku wiązało się z większym stężeniem peptydu natriuretycznego typu B, to podczas skojarzonego leczenia karwedilolem i digoksyną nastąpił wzrost LVEF, a odstawienie digoksyny spowodowało zmniejszenie LVEF [554].…”

Section: Naparstnicaunclassified

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

Kirchhof

Benussi

Kotecha³

et al. 2016

Kardiol Pol

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4,206

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Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life

Kotecha

Bunting

Gill

et al. 2020

JAMA

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143

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for the Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF) Team IMPORTANCE There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation, in particular those with coexisting heart failure.OBJECTIVE To compare low-dose digoxin with bisoprolol (a β-blocker). DESIGN, SETTING, AND PARTICIPANTSRandomized, open-label, blinded end-point clinical trial including 160 patients aged 60 years or older with permanent atrial fibrillation (defined as no plan to restore sinus rhythm) and dyspnea classified as New York Heart Association class II or higher. Patients were recruited from 3 hospitals and primary care practices in England from 2016 through 2018; last follow-up occurred in October 2019. INTERVENTIONS Digoxin (n = 80; dose range, 62.5-250 μg/d; mean dose, 161 μg/d) or bisoprolol (n = 80; dose range, 1.25-15 mg/d; mean dose, 3.2 mg/d). MAIN OUTCOMES AND MEASURESThe primary end point was patient-reported quality of life using the 36-Item Short Form Health Survey physical component summary score (SF-36 PCS) at 6 months (higher scores are better; range, 0-100), with a minimal clinically important difference of 0.5 SD. There were 17 secondary end points (including resting heart rate, modified European Heart Rhythm Association [EHRA] symptom classification, and N-terminal pro-brain natriuretic peptide [NT-proBNP] level) at 6 months, 20 end points at 12 months, and adverse event (AE) reporting.RESULTS Among 160 patients (mean age, 76 [SD, 8] years; 74 [46%] women; mean baseline heart rate, 100/min [SD, 18/min]), 145 (91%) completed the trial and 150 (94%) were included in the analysis for the primary outcome. There was no significant difference in the primary outcome of normalized SF-36 PCS at 6 months (mean, 31.9 [SD, 11.7] for digoxin vs 29.7 [11.4] for bisoprolol; adjusted mean difference, 1.4 [95% CI, −1.1 to 3.8]; P = .28). Of the 17 secondary outcomes at 6 months, there were no significant between-group differences for 16 outcomes, including resting heart rate (a mean of 76.9/min [SD, 12.1/min] with digoxin vs a mean of 74.8/min [SD, 11.6/min] with bisoprolol; difference, 1.5/min [95% CI, −2.0 to 5.1/min]; P = .40). The modified EHRA class was significantly different between groups at 6 months; 53% of patients in the digoxin group reported a 2-class improvement vs 9% of patients in the bisoprolol group (adjusted odds ratio, 10.3 [95% CI, 4.0 to 26.6]; P < .001). At 12 months, 8 of 20 outcomes were significantly different (all favoring digoxin), with a median NT-proBNP level of 960 pg/mL (interquartile range, 626 to 1531 pg/mL) in the digoxin group vs 1250 pg/mL (interquartile range, 847 to 1890 pg/mL) in the bisoprolol group (ratio of geometric means, 0.77 [95% CI, 0.64 to 0.92]; P = .005). Adverse events were less common with digoxin; 20 patients (25%) in the digoxin group had at least 1 AE vs 51 patients (64%) in the bisoprolol group (P < .001). There were 29 treatment-related AEs and 16 serious AEs in the digoxin group vs 142 and 37, ...

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Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data

Abstract: ObjeCtiveTo clarify the impact of digoxin on death and clinical outcomes across all observational and randomised controlled trials, accounting for study designs and methods.

Cited by 282 publications

References 107 publications

Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF‐TIMI 48 Trial

Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF‐TIMI 48 Trial

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life

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