Systematic review and meta-analysis of mortality and digoxin use in atrial fibrillation

Qureshi, Waqas; O’Neal, Wesley T.; Soliman, Elsayed Z.; Al-Mallah, Mouaz

doi:10.5603/cj.a2016.0016

Cited by 29 publications

(33 citation statements)

References 24 publications

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“…Since CTS antagonists such as pNaKitde 41 and rostafuroxin 42 have been developed, it will be interesting to test whether they are effective against atherosclerosis in vivo and therefore provide a novel therapeutic strategy. Finally, our findings may also provide a mechanistic basis for recent clinical reports of increased mortality rates in patients taking digoxin in the setting of chronic heart diseases 43–45 .…”

Section: Discussionsupporting

confidence: 57%

Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase

Chen

Huang

Yang

et al. 2017

ATVB

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Objective Circulating levels of cardiotonic steroids (CTS) are elevated in various chronic inflammatory conditions, but the role of CTS in inflammation remains largely unknown. We have previously shown that the CTS ouabain stimulates pro-inflammatory responses in murine macrophages. In this study, we aim to explore the mechanism how CTS induce pro-inflammatory responses in primary murine and human macrophages. Approach and Results Using both murine peritoneal macrophages and human monocyte-derived macrophages, we demonstrated that ouabain activated NF-κB, leading to pro-inflammatory cytokine (e.g. MCP-1, TNF-α, IL-1β and IL-6) production. By applying siRNA techniques as well as murine peritoneal macrophages isolated from genetically modified mice, we showed that macrophages partially deficient in Na/K-ATPase, the receptor for CTS or fully deficient in the scavenger receptor CD36 or TLR4 were resistant to ouabain-induced NF-κB activation, suggesting an indispensible role of these three receptors in this pathway. Mechanistically, this effect of ouabain was independent of the ion transport function of the Na/K-ATPase. Instead, ouabain stimulated a signaling complex including Na/K-ATPase, CD36 and TLR4. Subsequently, TLR4 recruited MyD88 adaptor protein for NF-κB activation. Furthermore, intraperitoneal injection of ouabain into mice specifically recruited Ly6C+CCR2+ monocyte subtypes to the peritoneal cavities, indicating that the CTS ouabain triggers inflammation in vivo. Conclusions CTS activate NF-κB leading to pro-inflammatory cytokine production in primary macrophages through a signaling complex including CD36, TLR4 and Na/K-ATPase. These findings warrant further studies on endogenous CTS in chronic inflammatory diseases such as atherosclerosis.

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Section: Discussionsupporting

confidence: 57%

Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase

Chen

Huang

Yang

et al. 2017

ATVB

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“…4,26 A recent metaanalysis described a risk of death associated with digoxin, especially in AF patients without HF. 27 In contrast, another one reported a neutral effect on mortality in AF patients with HF related to this drug. The latter study argued that excess in mortality related to digoxin could be due to a worse clinical profile such as more advanced stage of HF.…”

Section: Discussionmentioning

confidence: 98%

Mortality in heart failure with atrial fibrillation: Role of digoxin and diuretics

Gonzalez-Loyola

Abellana

Verdú-Rotellar

et al. 2018

Eur J Clin Investigation

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“…During recent years, systematic reviews of observational studies have compared digoxin versus no digoxin (the latter participants usually receiving some other treatment for heart rate control) in patients with atrial fibrillation or atrial flutter and showed that digoxin seemed to increase the risk of all-cause mortality regardless of concomitant heart failure [53–56]. A systematic review of both observational studies and randomised clinical trials showed similar findings on all-cause mortality when assessing the observational studies.…”

Section: Why Is It Important To Do This Review?mentioning

confidence: 98%

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

et al. 2017

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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.

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Systematic review and meta-analysis of mortality and digoxin use in atrial fibrillation

Cited by 29 publications

References 24 publications

Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase

Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase

Mortality in heart failure with atrial fibrillation: Role of digoxin and diuretics

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

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