Date Published: March 8, 2018
Publisher: Public Library of Science
Author(s): Naqash J. Sethi, Emil E. Nielsen, Sanam Safi, Joshua Feinberg, Christian Gluud, Janus C. Jakobsen, Nanette H. Bishopric.
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.
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.
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%).
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.
Atrial fibrillation is the most common arrhythmia of the heart with a prevalence of approximately 2% in the western world [1, 2]. Atrial fibrillation and atrial flutter are both associated with an increased risk of morbidity and death [3–9]. The risks of both cerebral stroke and heart failure are increased nearly fivefold in patients with atrial fibrillation and atrial flutter, and about 20% of every stroke may be due to atrial fibrillation [3–8]. Atrial fibrillation and atrial flutter also have a significant impact on healthcare costs and account for approximately 1% of the National Health Service budget in the United Kingdom and approximately 26 billion dollars of annual expenses in the United States [10, 11]. In the management of atrial fibrillation and atrial flutter, it is often necessary to use medical interventions to lower the heart rate and consequently prevent excessive tachycardia and limit symptoms [12, 13]. Lowering the heart rate might also, theoretically, prevent the development of heart failure and tachycardia-mediated cardiomyopathy [14–16].
We conducted this systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA) (S1 Text) , and the updated Cochrane methodology used in this systematic review is described in detail in our protocol (S2 Text) [24–26], which was registered prior to the systematic literature search.
We were able to include 28 randomized clinical trials reported in 32 publications with 37 comparisons including a total of 2223 participants. All trials and outcome results were at high risk of bias and the quality of the evidence according to GRADE was ‘low’ to ‘very low’ (see Summary of Findings table (Table 6)). None of the included trials had long-term follow-up.
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 may increase the risk of a serious adverse event, but no firm evidence was available. Our systematic review could neither confirm nor reject the findings from recent systematic reviews of observational studies showing that digoxin compared to no digoxin increased the risk of death. The increased risk of death found in observational studies might be caused by selection, prescription biases, or due to a longer follow-up [21, 22]. Based on current randomized evidence, digoxin is superior compared with placebo, but inferior compared with beta blockers in controlling the heart rate acutely. Digoxin also seems to be inferior compared with calcium antagonists and with amiodarone in controlling the heart rate acutely, but firm evidence is not available. The long-term effect of digoxin is unclear, as no trials reported long-term follow-up. More randomized clinical trials assessing the clinical effects of digoxin are needed, especially considering that our results indicate that digoxin might increase the risk of serious adverse events.