Digoxin versus placebo, no intervention, or other medical interventions for atrial fibrillation and atrial flutter: a protocol for a systematic review with meta-analysis and Trial Sequential Analysis

Abstract

BackgroundAtrial fibrillation is the most common arrhythmia of the heart with a prevalence of approximately 2% in the western world. Atrial flutter, another arrhythmia, occurs less often with an incidence of approximately 200,000 new patients per year in the USA. Patients with atrial fibrillation and atrial flutter have an increased risk of death and morbidities. In the management of atrial fibrillation and atrial flutter, it is often necessary to use medical interventions to lower the heart rate. Lowering the heart rate may theoretically prevent the development of heart failure and tachycardia-mediated cardiomyopathy. The evidence on the benefits and harms of digoxin compared with placebo or with other medical interventions is unclear. This protocol for a systematic review aims at identifying the beneficial and harmful effects of digoxin compared with placebo, no intervention, or with other medical interventions for atrial fibrillation and atrial flutter.MethodsThis protocol for a systematic review was conducted following the recommendations of Cochrane and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials comparing digoxin with placebo, no intervention, or with other medical interventions. We plan to search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, Science Citation Index Expanded on Web of Science, and BIOSIS to identify relevant trials. Any eligible trial will be assessed and classified as either at high risk of bias or low risk of bias, and our primary conclusions will be based on trials with low risk of bias. We will perform our meta-analyses of the extracted data using Review Manager 5.3 and Trial Sequential Analysis ver. 0.9.5.5 beta. For both our primary and secondary outcomes, we will create a ‘Summary of Findings’ table based on GRADE assessments of the quality of the evidence.DiscussionThe results of this systematic review have the potential to benefit millions of patients worldwide as well as healthcare economy.Systematic review registrationPROSPERO CRD42016052935Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-017-0470-2) contains supplementary material, which is available to authorized users.

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

“…We conducted this systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA) ( S1 Text ) [ 23 ], 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.…”

“…Additionally, we checked the reference lists of relevant publications for any unidentified trials. Trials were included irrespective of trial design, setting, publication status, publication year, language, and reporting of one of our outcomes [ 25 ].…”

“…If there was substantial discrepancy between the results of the two methods, we reported and discussed the results [ 36 ]. We used Trial Sequential Analysis (TSA) to control for random errors by estimating the diversity-adjusted required information size (DARIS) (that is the number of participants needed in a meta-analysis to detect or reject a certain intervention effect) [ 24 , 25 , 36 , 39 – 48 ]. The DARIS is based on our predefined anticipated intervention effect.…”

“…When analysing dichotomous outcomes, we pragmatically anticipated an intervention effect of 15% risk ratio reduction (RRR). When analysing continuous outcomes, we pragmatically anticipated an intervention effect equal to the MD of the observed standard difference (SD)/2 [ 25 , 49 ]. Based on the DARIS, trial sequential monitoring boundaries were constructed.…”

Should Digoxin Continue To Be Used for the Management of Atrial Fibrillation?

“…For example, in some recent trials of stroke prevention involving patients with atrial fibrillation, rates of digoxin use ranged from 29% to 39%. 10,11 Another meta-analysis on this topic is being planned, 12 but the results will be subject to the limitations of the existing publications. A randomized controlled trial on the effect of digoxin on all-cause mortality in patients who have atrial fibrillation with or without HFrEF (most urgently the latter) would provide better information.…”