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.