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Review
. 2018 Mar 8;13(3):e0193924.
doi: 10.1371/journal.pone.0193924. eCollection 2018.

Digoxin for atrial fibrillation and atrial flutter: A systematic review with meta-analysis and trial sequential analysis of randomised clinical trials

Naqash J Sethi  1 , Emil E Nielsen  1 , Sanam Safi  1 , Joshua Feinberg  1 , Christian Gluud  1   2 , Janus C Jakobsen  1   2   3
Affiliations
Review

Digoxin for atrial fibrillation and atrial flutter: A systematic review with meta-analysis and trial sequential analysis of randomised clinical trials

Naqash J Sethi et al. PLoS One. .

Abstract

Background: During recent years, systematic reviews of observational studies have compared digoxin to no digoxin in patients with atrial fibrillation or atrial flutter, and the results of these reviews suggested that digoxin seems to increase the risk of all-cause mortality regardless of concomitant heart failure. Our objective was to assess the benefits and harms of digoxin for atrial fibrillation and atrial flutter based on randomized clinical trials.

Methods: We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-Expanded, BIOSIS for eligible trials comparing digoxin versus placebo, no intervention, or other medical interventions in patients with atrial fibrillation or atrial flutter in October 2016. Our primary outcomes were all-cause mortality, serious adverse events, and quality of life. Our secondary outcomes were heart failure, stroke, heart rate control, and conversion to sinus rhythm. We performed both random-effects and fixed-effect meta-analyses and chose the more conservative result as our primary result. We used Trial Sequential Analysis (TSA) to control for random errors. We used GRADE to assess the quality of the body of evidence.

Results: 28 trials (n = 2223 participants) were included. All were at high risk of bias and reported only short-term follow-up. When digoxin was compared with all control interventions in one analysis, we found no evidence of a difference on all-cause mortality (risk ratio (RR), 0.82; TSA-adjusted confidence interval (CI), 0.02 to 31.2; I2 = 0%); serious adverse events (RR, 1.65; TSA-adjusted CI, 0.24 to 11.5; I2 = 0%); quality of life; heart failure (RR, 1.05; TSA-adjusted CI, 0.00 to 1141.8; I2 = 51%); and stroke (RR, 2.27; TSA-adjusted CI, 0.00 to 7887.3; I2 = 17%). Our analyses on acute heart rate control (within 6 hours of treatment onset) showed firm evidence of digoxin being superior compared with placebo (mean difference (MD), -12.0 beats per minute (bpm); TSA-adjusted CI, -17.2 to -6.76; I2 = 0%) and inferior compared with beta blockers (MD, 20.7 bpm; TSA-adjusted CI, 14.2 to 27.2; I2 = 0%). Meta-analyses on acute heart rate control showed that digoxin was inferior compared with both calcium antagonists (MD, 21.0 bpm; TSA-adjusted CI, -30.3 to 72.3) and with amiodarone (MD, 14.7 bpm; TSA-adjusted CI, -0.58 to 30.0; I2 = 42%), but in both comparisons TSAs showed that we lacked information. Meta-analysis on acute conversion to sinus rhythm showed that digoxin compared with amiodarone reduced the probability of converting atrial fibrillation to sinus rhythm, but TSA showed that we lacked information (RR, 0.54; TSA-adjusted CI, 0.13 to 2.21; I2 = 0%).

Conclusions: The clinical effects of digoxin on all-cause mortality, serious adverse events, quality of life, heart failure, and stroke are unclear based on current evidence. Digoxin seems to be superior compared with placebo in reducing the heart rate, but inferior compared with beta blockers. The long-term effect of digoxin is unclear, as no trials reported long-term follow-up. More trials at low risk of bias and low risk of random errors assessing the clinical effects of digoxin are needed.

Systematic review registration: PROSPERO CRD42016052935.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. PRISMA flow diagram.
We screened 17 003 records and included 32 publications of 28 trials in this systematic review.
Fig 2
Fig 2. Forest plot of the meta-analysis on serious adverse events.
Meta-analysis on serious adverse events suggested that digoxin might have a harmful effect.
Fig 3
Fig 3. Forest plot of the meta-analysis of digoxin versus placebo on heart rate control within 6 hours of treatment onset.
Meta-analysis showed firm evidence of digoxin being superior compared with placebo.
Fig 4
Fig 4. Trial sequential analysis of digoxin versus placebo on heart rate control within 6 hours of treatment onset.
Trial Sequential Analysis (TSA) of digoxin versus placebo on heart rate control within 6 hours of treatment onset showed that the Z-curve (the blue line) crossed the upper trial sequential monitoring boundary for benefit (the upper red line). Hence, we have enough information to confirm that digoxin is superior compared with placebo in controlling the heart rate within 6 hours of treatment onset.
Fig 5
Fig 5. Forest plot of the meta-analysis of digoxin versus beta blockers on heart rate control within 6 hours of treatment onset.
Meta-analysis showed firm evidence of digoxin being inferior compared with beta blockers.
Fig 6
Fig 6. Trial sequential analysis of digoxin versus beta blockers on heart rate control within 6 hours of treatment onset.
Trial Sequential Analysis (TSA) of digoxin versus beta blockers on heart rate control within 6 hours of treatment onset showed that the Z-curve (the blue line) crossed the lower trial sequential monitoring boundary for harm (the lower red line). Hence, we have enough information to confirm that digoxin is inferior compared with beta blockers in controlling the heart rate within 6 hours of treatment onset.
See this image and copyright information in PMC

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MeSH terms

Grants and funding

The Copenhagen Trial Unit paid the salary for all authors during the writing of this review. Otherwise, we have received no funding. The funding source had no role in the design and conduct of the study; the extraction, management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript.