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Holt A, Strange JE, Hansen ML, Lamberts M, Rasmussen PV. The Bad Reputation of Digoxin in Atrial Fibrillation-Causality or Bias? Nationwide Nested Case-Control Study. AMERICAN JOURNAL OF MEDICINE OPEN 2025; 13:100093. [PMID: 40166486 PMCID: PMC11957803 DOI: 10.1016/j.ajmo.2025.100093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 02/03/2025] [Indexed: 04/02/2025]
Abstract
Aims Studies have reported excess risk of mortality associated with digoxin in atrial fibrillation (AF).This study sought to investigate if these findings could be replicated and whether a potential association could be explained by bias. Methods Using Danish Nationwide registers, a nested-case control study from 2012 to 2022 was conducted in a cohort of patients with AF. Cases were defined as death of any cause and the exposure was treatment with digoxin compared with beta blockers/verapamil. To investigate bias, additional analyses with negative control outcomes as case definitions-in which we would not expect a plausible association (eg, nursing home admission)-were employed. Associations were reported as hazard ratios (HRs) with 95% confidence intervals (95% CI). Results A total of 59,748 cases were identified and matched 1:10 with controls (53% men, median age: 84 [IQR: 77-89]). Digoxin was associated with increased rates of mortality in the entire cohort (HR 1.85, 95% CI 1.78-1.92) as well as subgroups such as patients with heart failure (HR 1.84, 95% CI 1.65-2.06), diabetes (HR 1.85, 95% CI 1.6-2.14), and kidney disease (HR 1.37, 95% CI 1.04-1.8). Significant associations with all negative control outcomes were also found, most notably nursing home admissions (HR 1.79, 95% CI 1.67-1.93). Conclusion Digoxin use was associated with increased mortality in AF. However, negative control outcomes were also associated with digoxin use indicating that the described association between digoxin and mortality is likely not causal and being prescribed digoxin is merely a marker of more advanced disease and frailty.
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Affiliation(s)
- Anders Holt
- Department of Cardiology, Herlev-Gentofte University Hospital, Copenhagen, Denmark
| | - Jarl Emanuel Strange
- Department of Cardiology, Herlev-Gentofte University Hospital, Copenhagen, Denmark
| | - Morten Lock Hansen
- Department of Cardiology, Herlev-Gentofte University Hospital, Copenhagen, Denmark
| | - Morten Lamberts
- Department of Cardiology, Herlev-Gentofte University Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Peter Vibe Rasmussen
- Department of Cardiology, Herlev-Gentofte University Hospital, Copenhagen, Denmark
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2
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Gazzaniga G, Menichelli D, Scaglione F, Farcomeni A, Pani A, Pastori D. Effect of digoxin on all-cause and cardiovascular mortality in patients with atrial fibrillation with and without heart failure: an umbrella review of systematic reviews and 12 meta-analyses. Eur J Clin Pharmacol 2023; 79:473-483. [PMID: 36872367 PMCID: PMC10039090 DOI: 10.1007/s00228-023-03470-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 02/27/2023] [Indexed: 03/07/2023]
Abstract
PURPOSE To perform a systematic umbrella review with meta-analysis to evaluate the certainty of evidence on mortality risk associated with digoxin use in patients with atrial fibrillation (AF) with or without heart failure (HF). METHODS We systematically searched MEDLINE, Embase, and Web of Science databases from inception to 19 October 2021. We included systematic reviews and meta-analyses of observational studies investigating digoxin effects on mortality of adult patients with AF and/or HF. The primary outcome was all-cause mortality; secondary outcome was cardiovascular mortality. Certainty of evidence was evaluated by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool and the quality of systematic reviews/meta-analyses by the A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR2) tool. RESULTS Eleven studies accounting for 12 meta-analyses were included with a total of 4,586,515 patients. AMSTAR2 analysis showed a high quality in 1, moderate in 5, low in 2, and critically low in 3 studies. Digoxin was associated with an increased all-cause mortality (hazard ratio [HR] 1.19, 95% confidence interval [95%CI] 1.14-1.25) with moderate certainty of evidence and with an increased cardiovascular mortality (HR 1.19, 95%CI 1.06-1.33) with moderate certainty of evidence. Subgroup analysis showed that digoxin was associated with all-cause mortality both in patients with AF alone (HR 1.23, 95%CI 1.19-1.28) and in those with AF and HF (HR 1.14, 95%CI 1.12-1.16). CONCLUSION Data from this umbrella review suggests that digoxin use is associated with a moderate increased risk of all-cause and cardiovascular mortality in AF patients regardless of the presence of HF. TRIAL REGISTRATION This review was registered in PROSPERO (CRD42022325321).
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Affiliation(s)
- Gianluca Gazzaniga
- Department of Medical Biotechnology and Translational Medicine, Postgraduate School of Clinical Pharmacology and Toxicology, Università degli Studi di Milano, 20122, Milan, Italy
| | - Danilo Menichelli
- Department of General and Specialized Surgery "Paride Stefanini", Sapienza University of Rome, 00185, Rome, Italy
| | - Francesco Scaglione
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, 20122, Milan, Italy
- Department of Chemical-Clinical and Microbiological Analyses, Grande Ospedale Metropolitano Niguarda, 20162, Milan, Italy
| | - Alessio Farcomeni
- Department of Economics and Finance, University of Rome ":Tor Vergata", 00133, Rome, Italy
| | - Arianna Pani
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, 20122, Milan, Italy
| | - Daniele Pastori
- Department of Clinical, Internal, Anesthesiological, and Cardiovascular Sciences, Sapienza University of Rome, 00185, Rome, Italy.
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3
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Wang X, Luo Y, Xu D, Zhao K. Effect of Digoxin Therapy on Mortality in Patients With Atrial Fibrillation: An Updated Meta-Analysis. Front Cardiovasc Med 2021; 8:731135. [PMID: 34660731 PMCID: PMC8517124 DOI: 10.3389/fcvm.2021.731135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 09/06/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Whether digoxin is associated with increased mortality in atrial fibrillation (AF) remains controversial. We aimed to assess the risk of mortality and clinical effects of digoxin use in patients with AF. Methods: PubMed, Embase, and the Cochrane library were systematically searched to identify eligible studies comparing all-cause mortality of patients with AF taking digoxin with those not taking digoxin, and the length of follow-up was at least 6 months. Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted and pooled. Results: A total of 29 studies with 621,478 patients were included. Digoxin use was associated with an increased risk of all-cause mortality in all patients with AF (HR 1.17, 95% CI 1.13–1.22, P < 0.001), especially in patients without HF (HR 1.28, 95% CI 1.11–1.47, P < 0.001). There was no significant association between digoxin and mortality in patients with AF and HF (HR 1.06, 95% CI 0.99–1.14, P = 0.110). In all patients with AF, regardless of concomitant HF, digoxin use was associated with an increased risk of sudden cardiac death (SCD) (HR 1.40, 95% CI 1.23–1.60, P < 0.001) and cardiovascular (CV) mortality (HR 1.27, 95% CI 1.08–1.50, P < 0.001), and digoxin use had no significant association with all-cause hospitalization (HR 1.13, 95% CI 0.92–1.39, P = 0.230). Conclusion: We conclude that digoxin use is associated with an increased risk of all-cause mortality, CV mortality, and SCD, and it does not reduce readmission for AF, regardless of concomitant HF. Digoxin may have a neutral effect on all-cause mortality in patients with AF with concomitant HF. Systematic Review Registration:https://www.crd.york.ac.ukPROSPERO.
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Affiliation(s)
- Xiaoxu Wang
- Department of Cardiovascular Diseases, The First Branch, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Luo
- Department of Cardiovascular Diseases, The First Branch, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dan Xu
- Department of Cardiovascular Diseases, The First Branch, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kun Zhao
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China
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4
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Baker WL, Sobieraj DM, DiDomenico RJ. Influence of digoxin on mortality in patients with atrial fibrillation: Overview of systematic reviews. Pharmacotherapy 2021; 41:394-404. [PMID: 33544894 DOI: 10.1002/phar.2510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/18/2021] [Accepted: 01/24/2021] [Indexed: 11/08/2022]
Abstract
Once a routine part of atrial fibrillation (AF) management, digoxin use has declined. Likely hastening this decline are findings from several studies and systematic reviews identifying a potential association between digoxin use and all-cause mortality in AF populations. However, inconsistency exists within some of these studies potentially leading to confusion among clinicians. To critically evaluate the current literature to contextualize the associations between digoxin and mortality risk in patients with AF by performing an overview of systematic reviews. We searched MEDLINE, Cochrane Central Database of Systematic Reviews, and SCOPUS from their earliest date through October 12, 2020, to identify systematic reviews (SRs) that included studies enrolling patients with AF or atrial flutter and evaluated the association between digoxin use and all-cause mortality. We used the AMSTAR 2 tool to assess the risk of bias for each included SR. Results from reviews are qualitatively synthesized. Our search identified 10 SRs that met our inclusion criteria. Of the 41 unique AF studies included in these SRs, 41% were cohort studies, 29% were post hoc analyses of randomized controlled trials (RCTs), 15% were RCTs, and 15% were registry studies. Based on our AMSTAR 2 assessment, the overall confidence in the results of the 10 reviews was rated as "moderate" in three SRs, "low" in three SRs, and "critically low" in the rest. Except for one review, each included SR shows that digoxin use in AF is associated with a 15 to 38% higher risk of all-cause mortality. This association may be greater when AF-only populations are considered compared with a mix of AF and heart failure populations. Serum digoxin concentration (SDC) data were infrequently considered, but available data suggested a greater association between increasing SDC and all-cause mortality. This overview of reviews found general consistency regarding the association between digoxin use and higher all-cause mortality in AF populations. However, heterogeneity exists among and between SRs and an unmet need exists for additional study in a RCT setting with close monitoring and reporting of SDC to better inform clinical practice.
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Affiliation(s)
- William L Baker
- Department of Pharmacy Practice, University of Connecticut School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA
| | - Diana M Sobieraj
- Department of Pharmacy Practice, University of Connecticut School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA
| | - Robert J DiDomenico
- Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
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5
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Muk B, Vámos M, Bógyi P, Szabó B, Dékány M, Vágány D, Majoros Z, Borsányi T, Duray GZ, Kiss RG, Nyolczas N. The impact of serum concentration-guided digoxin therapy on mortality of heart failure patients: A long-term follow-up, propensity-matched cohort study. Clin Cardiol 2020; 43:1641-1648. [PMID: 33140454 PMCID: PMC7724220 DOI: 10.1002/clc.23500] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Recently published studies suggested that digoxin may increase mortality in heart failure with reduced ejection fraction (HFrEF). However, in the vast majority of former trials serum digoxin concentration (SDC) was not measured and therapy was not SDC-guided. AIM To assess the impact of SDC-guided digoxin therapy on mortality in HFrEF patients. METHODS Data of 580 HFrEF patients were retrospectively analyzed. In patients on digoxin, SDC was measured every 3 months and digoxin dosage was SDC-guided (target SDC: 0.5-0.9 ng/mL). All-cause mortality of digoxin users and nonusers was compared after propensity score matching (PSM). RESULTS After 7.1 ± 4.7 years follow-up period (FUP) all-cause mortality of digoxin users (n = 180) was significantly higher than nonusers (n = 297) (propensity-adjusted HR = 1.430; 95% CI = 1.134-1.804; P = .003). Patients having SDC of 0.9 to 1.1 ng/mL (n = 60) or > 1.1 ng/mL (n = 44) at any time during the FUP had an increased risk of all-cause mortality (HR = 1.750; 95% CI = 1.257-2.436, P = .001 and HR = 1.687; 95% CI = 1.153-2.466, P = .007), while patients having a maximal SDC < 0.9 ng/mL (n = 76) had similar mortality risk (HR = 1.139; 95% CI = 0.827-1.570, P = .426), compared to digoxin nonusers. CONCLUSIONS According to our propensity-matched analysis, SDC-guided digoxin therapy was associated with increased all-cause mortality in optimally treated HFrEF patients, especially with SDC ≥0.9 ng/mL. These results reinforce the expert opinion that digoxin in HFrEF can only be used among carefully selected patients with close SDC monitoring.
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Affiliation(s)
- Balázs Muk
- Dep. of Cardiology, Medical Centre Hungarian Defence Forces, Budapest, Hungary
| | - Máté Vámos
- Department of Medicine and Cardiology Center, University of Szeged, Szeged, Hungary
| | - Péter Bógyi
- Dep. of Cardiology, Medical Centre Hungarian Defence Forces, Budapest, Hungary
| | - Barna Szabó
- Heart-Lung-Physiology Clinic, Örebro University Hospital, Örebro, Sweden
| | - Miklós Dékány
- Dep. of Cardiology, Medical Centre Hungarian Defence Forces, Budapest, Hungary
| | - Dénes Vágány
- Dep. of Cardiology, Medical Centre Hungarian Defence Forces, Budapest, Hungary
| | - Zsuzsanna Majoros
- Dep. of Cardiology, Medical Centre Hungarian Defence Forces, Budapest, Hungary
| | - Tünde Borsányi
- Dep. of Cardiology, Medical Centre Hungarian Defence Forces, Budapest, Hungary
| | - Gábor Zoltán Duray
- Dep. of Cardiology, Medical Centre Hungarian Defence Forces, Budapest, Hungary
| | - Róbert Gábor Kiss
- Dep. of Cardiology, Medical Centre Hungarian Defence Forces, Budapest, Hungary
| | - Noémi Nyolczas
- Dep. of Cardiology, Medical Centre Hungarian Defence Forces, Budapest, Hungary.,Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
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6
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Ferrari F, Santander IRMF, Stein R. Digoxin in Atrial Fibrillation: An Old Topic Revisited. Curr Cardiol Rev 2020; 16:141-146. [PMID: 31237216 PMCID: PMC7460705 DOI: 10.2174/1573403x15666190618110941] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 04/28/2019] [Accepted: 04/29/2019] [Indexed: 12/19/2022] Open
Abstract
Digoxin has been used for more than 50 years in patients with Atrial Fibrillation (AF), with the goal of Controlling Heart Rate (HR) and restoring sinus rhythm. In the last two decades, several studies have correlated therapeutic use of digoxin with increased mortality. However, such studies have potential biases that cannot be disregarded, mainly because they are cross-sectional experiments or post-hoc analyses of Randomized Controlled Trials (RCTs). Despite uncertainties regarding the safety of digoxin in this setting, it remains one of the most prescribed drugs for AF worldwide. On the other hand, the absence of any RCTs designed to evaluate mortality makes a definitive conclusion more difficult to reach; therefore, this medication must be used with care. In this review, we explored the therapeutic use of digoxin in the context of AF, discussed mortality data by means of critical analysis in the light of the best available evidence, and position ourselves in relation to more rigorous control of serum levels of this drug in daily practice.
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Affiliation(s)
- Filipe Ferrari
- Graduate Program in Cardiology and Cardiovascular Sciences, School of Medicine, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,Exercise Cardiology Research Group (CardioEx) HCPA/UFRGS, Porto Alegre, Brazil
| | | | - Ricardo Stein
- Graduate Program in Cardiology and Cardiovascular Sciences, School of Medicine, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,Exercise Cardiology Research Group (CardioEx) HCPA/UFRGS, Porto Alegre, Brazil.,School of Medicine, HCPA/UFRGS, Porto Alegre, Brazil
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7
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Pastori D, Carnevale R, Nocella C, Bartimoccia S, Novo M, Cammisotto V, Piconese S, Santulli M, Vasaturo F, Violi F, Pignatelli P. Digoxin and Platelet Activation in Patients With Atrial Fibrillation: In Vivo and In Vitro Study. J Am Heart Assoc 2019; 7:e009509. [PMID: 30571484 PMCID: PMC6404445 DOI: 10.1161/jaha.118.009509] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Background Digoxin use was shown to be associated with an increased risk of cardiovascular events in atrial fibrillation ( AF ). We hypothesized that digoxin may affect cardiovascular risk by increasing platelet activation. Methods and Results Post hoc analysis of a prospective study of anticoagulated patients with AF . Patients were divided into 2 groups balanced for age, sex, and cardiovascular risk factors: digoxin users (n=132) and nonusers (n=388). Urinary excretion of 11-dehydro-thromboxane B2 (TxB2), a marker of platelet activation, and serum digoxin concentration ( SDC ) were measured. In vitro experiments were performed on platelets from healthy subjects and AF patients, which were incubated with scalar doses of digoxin (0.6-2.4 ng/mL) with or without prestimulation with a sub-threshold of collagen. Median 11-dehydro-TxB2 was 105.0 ( interquartile range, 60.0-190.0) ng/mg creatinine, and median SDC was 0.65 ( interquartile range, 0.40-1.00) ng/mL. Urinary 11-dehydro-TxB2 and SDC were correlated ( rs=0.350, P<0.001). Patients in the upper tertile of SDC showed higher 11-dehydro-TxB2 compared with non-digoxin users ( P=0.019). In vitro study showed an increased basal platelet activation in patients with AF compared with healthy subjects . Digoxin (2.4 ng/mL) induced calcium mobilization, PAC -1 (procaspase-activating compound 1) and platelet aggregation in AF patients but not in healthy subjects . After pretreatment with a sub-threshold of collagen, digoxin dose-dependent induced calcium mobilization, arachidonic acid release, TxB2 biosynthesis, PAC -1 and soluble platelet selectin expression, and platelet aggregation, which were inhibited by antibody against digoxin. Conclusions We found a significant in vivo correlation between SDC and platelet activation. Supratherapeutic SDC increased in vitro platelet aggregation via calcium-related phospholipase A2 phosphorylation. Our findings may have clinical implications for AF patients treated with digoxin.
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Affiliation(s)
- Daniele Pastori
- 1 I Clinica Medica Department of Internal Medicine and Medical Specialties Sapienza University of Rome Italy
| | - Roberto Carnevale
- 2 Department of Medical-Surgical Sciences and Biotechnologies Sapienza University of Rome Latina Italy
| | | | - Simona Bartimoccia
- 1 I Clinica Medica Department of Internal Medicine and Medical Specialties Sapienza University of Rome Italy
| | - Marta Novo
- 1 I Clinica Medica Department of Internal Medicine and Medical Specialties Sapienza University of Rome Italy
| | - Vittoria Cammisotto
- 1 I Clinica Medica Department of Internal Medicine and Medical Specialties Sapienza University of Rome Italy
| | - Silvia Piconese
- 1 I Clinica Medica Department of Internal Medicine and Medical Specialties Sapienza University of Rome Italy
| | - Maria Santulli
- 4 Department of Experimental Medicine Sapienza University of Rome Italy
| | - Fortunata Vasaturo
- 1 I Clinica Medica Department of Internal Medicine and Medical Specialties Sapienza University of Rome Italy
| | - Francesco Violi
- 1 I Clinica Medica Department of Internal Medicine and Medical Specialties Sapienza University of Rome Italy
| | - Pasquale Pignatelli
- 1 I Clinica Medica Department of Internal Medicine and Medical Specialties Sapienza University of Rome Italy
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8
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Qiu R, Hu J, Huang Y, Han S, Zhong C, Li M, He T, Lin Y, Guan M, Chen J, Shang H. Outcome reporting from clinical trials of non-valvular atrial fibrillation treated with traditional Chinese medicine or Western medicine: a systematic review. BMJ Open 2019; 9:e028803. [PMID: 31471437 PMCID: PMC6720335 DOI: 10.1136/bmjopen-2018-028803] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVES To examine variation in outcomes, outcome measurement instruments (OMIs) and measurement times in clinical trials of non-valvular atrial fibrillation (NVAF) and to identify outcomes for prioritisation in developing a core outcome set (COS) in this field. DESIGN This study was a systematic review. DATA SOURCES Clinical trials published between January 2015 and March 2019 were obtained from PubMed, the Cochrane Library, Web of Science, Wanfang Database, the China National Knowledge Infrastructure and SinoMed. ELIGIBILITY CRITERIA Randomised controlled trials (RCTs) and observational studies were considered. Interventions included traditional Chinese medicine and Western medicine. The required treatment duration or follow-up time was ≥4 weeks. The required sample size was ≥30 and≥50 in each group in RCTs and observational studies, respectively. We excluded trials that aimed to investigate the outcome of complications of NVAF, to assess the mechanisms or pharmacokinetics, or for which full text could not be acquired. DATA EXTRACTION AND SYNTHESIS The general information and outcomes, OMIs and measurement times were extracted. The methodological and outcome reporting quality were assessed. The results were analysed by descriptive analysis. RESULTS A total of 218 articles were included from 25 255 articles. For clinical trials of antiarrhythmic therapy, 69 outcomes from 16 outcome domains were reported, and 28 (31.82%, 28/88) outcomes were reported only once; the most frequently reported outcome was ultrasonic cardiogram. Thirty-one outcomes (44.93%, 31/69) were provided definitions or OMIs; the outcome measurement times ranged from 1 to 20 with a median of 3. For clinical trials of anticoagulation therapy, 82 outcomes from 18 outcome domains were reported; 38 (29.23%, 38/130) outcomes were reported only once. The most frequently reported outcome was ischaemic stroke. Forty (48.78%, 40/82) outcomes were provided OMIs or definitions; and the outcome measurement times ranged from 1 to 27 with a median of 8. CONCLUSION Outcome reporting in NVAF is inconsistent. Thus, developing a COS that can be used in clinical trials is necessary.
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Affiliation(s)
- Ruijin Qiu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jiayuan Hu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Ya Huang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Songjie Han
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Changming Zhong
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Min Li
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Tianmai He
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yiyi Lin
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Manke Guan
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jing Chen
- Baokang Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hongcai Shang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Evidence-based Medicine Center, Jiangxi University of Chinese Medicine, Nanchang, China
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9
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Abstract
Atrial fibrillation often occurs as a cause or consequence of heart failure. Clinical outcomes are worse when atrial fibrillation and heart failure coexist. There are important sex-related differences in the incidence, prevalence, pathophysiology, treatment, and outcomes of these patients. Women with heart failure are at greater risk of developing atrial fibrillation than men, and more women with atrial fibrillation develop heart failure. More women die of atrial fibrillation-related strokes. Despite significant morbidity and mortality, current treatments for women are inadequate. This review explores sex differences in atrial fibrillation and heart failure, emphasizing risk stratification and treatments to improve clinical outcomes.
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Affiliation(s)
- Nidhi Madan
- Department of Medicine, Cardiology Division, Rush University Medical Center, 1653 West Congress Parkway, Chicago, IL 60612, USA
| | - Dipti Itchhaporia
- Department of Medicine, Cardiology Division, Hoag Memorial Hospital, University of California, Irvine, 520 Superior Avenue, Newport Beach, CA 92663, USA
| | - Christine M Albert
- Department of Medicine, Cardiology Division, Brigham and Women's Medical Center, 75 Francis Street Towers 3a, Boston, MA 02115, USA
| | - Neelum T Aggarwal
- Department of Neurological Sciences, Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W. Harrison, Suite 1000, Chicago, IL 60612, USA
| | - Annabelle Santos Volgman
- Department of Medicine, Cardiology Division, Rush University Medical Center, 1725 W. Harrison Street, Room 1159, Chicago, IL 60612, USA.
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10
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Abstract
PURPOSE OF REVIEW A number of recent observational analyses have assessed clinical outcomes associated with digoxin use in patients with atrial fibrillation. In this review, we review these data and provide suggestions on the contemporary use of digoxin in patients with atrial fibrillation as supported by the recent evidence. RECENT FINDINGS Observational data from clinical trials and registries have provided variable results on the safety and efficacy of chronic digoxin use in patients with atrial fibrillation. In general, results have been consistent with an associated increase in adverse clinical outcomes with digoxin use in atrial fibrillation patients without heart failure. In atrial fibrillation patients with heart failure, while the weight of evidence suggested an associated risk with digoxin therapy, the results are inconsistent. In patients with atrial fibrillation without heart failure, digoxin should generally be avoided. In atrial fibrillation patients with heart failure, digoxin should generally be reserved for patients that do not achieve adequate rate control or are not tolerant of other rate control therapies.
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11
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Quinn KL, Macdonald EM, Gomes T, Mamdani MM, Huang A, Juurlink DN. Macrolides, Digoxin Toxicity and the Risk of Sudden Death: A Population-Based Study. Drug Saf 2018; 40:835-840. [PMID: 28421551 DOI: 10.1007/s40264-017-0539-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Digoxin is commonly prescribed to elderly patients with heart failure and atrial fibrillation, and macrolide antibiotics markedly increase the risk of digoxin toxicity. OBJECTIVE The aim was to determine whether, in older patients receiving digoxin, macrolide antibiotics are associated with sudden death. METHODS We used a population-based, nested, case-control design from January 1, 1994 to December 31, 2012 in a cohort of Ontario residents aged 66 years or older prescribed digoxin. The primary outcome was the risk of sudden death within 14 days of exposure to one of three antibiotics (erythromycin, clarithromycin, or azithromycin), relative to cefuroxime. RESULTS Among 39,072 Ontarians who died suddenly while receiving digoxin, 586 died within 14 days of receiving a study antibiotic. Relative to cefuroxime, we found no statistically significant increase in the risk of sudden death following treatment with erythromycin [adjusted odds ratio (aOR) 0.98; 95% confidence interval (CI) 0.65-1.48], clarithromycin (aOR 1.25; 95% CI 0.94-1.65), or azithromycin (aOR 1.07; 95% CI 0.75-1.53). CONCLUSION This finding reinforces the cardiovascular safety of macrolide antibiotics in a high-risk population.
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Affiliation(s)
- Kieran L Quinn
- Department of Internal Medicine, University of Toronto, Toronto, ON, Canada. .,Sunnybrook Health Sciences Centre, 2075 Bayview Avenue G106, Toronto, ON, M4N 3M5, Canada.
| | | | - Tara Gomes
- Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.,Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada
| | - Muhammad M Mamdani
- Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.,Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.,King Saud University, Riyadh, Saudi Arabia.,Sunnybrook Research Institute, Toronto, ON, Canada
| | - Anjie Huang
- Institute for Clinical Evaluative Sciences, Toronto, ON, Canada
| | - David N Juurlink
- Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.,Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.,Sunnybrook Health Sciences Centre, 2075 Bayview Avenue G106, Toronto, ON, M4N 3M5, Canada
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12
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Shin JH, Kang KW, Kim JG, Lee SJ. Concurrent renal dysfunction with ischemic heart disease is an important determinant for cardiac and cerebrovascular mortality in patients on chronic digoxin therapy for atrial fibrillation. Kidney Res Clin Pract 2018; 37:130-137. [PMID: 29971208 PMCID: PMC6027812 DOI: 10.23876/j.krcp.2018.37.2.130] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 05/04/2018] [Accepted: 05/06/2018] [Indexed: 12/19/2022] Open
Abstract
Background Major adverse cardiac and cerebrovascular events (MACCEs) are main concerns in patients with atrial fibrillation (AF); however, factors affecting MACCEs remain inconclusive in AF patients chronically treated with digoxin. We investigated the major clinical determinants for fatal MACCEs in AF patients treated with digoxin over a 10-year follow-up period. Methods We analyzed a retrospective cohort of 1,480 AF patients at Eulji University Hospital, Daejeon, South Korea from March 2004 to August 2015. Among this population, 402 consecutive patients receiving chronic digoxin therapy were selected for the study. Data for electrocardiography, medication history, laboratory values including the serum digoxin concentration (SDC) and fatal MACCEs were collected. All data were divided and compared between groups based on the occurrence of MACCEs. Results The overall incidence of fatal MACCEs among the 402 digoxin-treated AF patients (age, 68 ± 11 years; male, 40.3%) was 12.1%. These fatalities resulted from heart failure (46.1%), fatal stroke (26.9%), fatal myocardial infarction (15.3%) and sudden cardiac death (5.7%). A higher prevalence of diabetes, pre-existing ischemic heart disease (IHD), lower estimated glomerular filtration rate (eGFR), higher SDC, and junctional bradycardia were more frequently observed in patients with MACCEs compared to those without MACCEs. Multivariable analysis showed that an eGFR of ≤ 60 mL/min/1.73 m2 and pre-existing IHD had a hazard ratio of 3.35 and a confidence interval of 1.64-6.87 (P < 0.001) for fatal MACCEs. Conclusion Chronic kidney disease stage III-V with pre-existing IHD is significantly associated with increased cardiac and cerebrovascular mortality in AF patients with chronic digoxin use.
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Affiliation(s)
- Jong Ho Shin
- Division of Nephrology, Eulji University Hospital, Eulji University College of Medicine, Daejeon, Korea
| | - Ki-Woon Kang
- Division of Cardiology, Eulji University Hospital, Eulji University College of Medicine, Daejeon, Korea
| | - Jae Guk Kim
- Division of Neurology, Eulji University Hospital, Eulji University College of Medicine, Daejeon, Korea
| | - Soo Joo Lee
- Division of Neurology, Eulji University Hospital, Eulji University College of Medicine, Daejeon, Korea
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13
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Lopes RD, Rordorf R, De Ferrari GM, Leonardi S, Thomas L, Wojdyla DM, Ridefelt P, Lawrence JH, De Caterina R, Vinereanu D, Hanna M, Flaker G, Al-Khatib SM, Hohnloser SH, Alexander JH, Granger CB, Wallentin L. Digoxin and Mortality in Patients With Atrial Fibrillation. J Am Coll Cardiol 2018. [DOI: 10.1016/j.jacc.2017.12.060] [Citation(s) in RCA: 135] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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14
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Predictors of digoxin use and risk of mortality in ED patients with atrial fibrillation. Am J Emerg Med 2017; 35:1589-1594. [DOI: 10.1016/j.ajem.2017.04.070] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 04/26/2017] [Accepted: 04/26/2017] [Indexed: 11/23/2022] Open
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Biteker M, Başaran Ö, Dogan V, Beton O, Tekinalp M, Çağrı Aykan A, Kalaycıoğlu E, Bolat I, TaŞar O, Şafak Ö, Kalçık M, Yaman M, Kırma C. Real-life use of digoxin in patients with non-valvular atrial fibrillation: data from the RAMSES study. J Clin Pharm Ther 2016; 41:711-717. [PMID: 27671101 DOI: 10.1111/jcpt.12460] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 09/04/2016] [Indexed: 02/05/2023]
Abstract
WHAT IS KNOWN AND OBJECTIVE Although inappropriate use of digoxin has been described in various populations, a real-world evaluation of patterns of digoxin prescription has not been well studied in patients with atrial fibrillation (AF). The aim of this study was to identify prevalence, indications and appropriateness of digoxin use in the general population of patients with non-valvular AF (NVAF) in Turkey. METHODS We included and classified patients from the RAMSES (ReAl-life Multicentre Survey Evaluating Stroke prevention strategies in Turkey) study, a prospective registry including 6273 patients with NVAF, on the basis of digoxin use. After excluding the data of 73 patients whose medical history about digoxin use or left ventricle function was absent, 6200 patients were included for the final analysis. Digoxin use was considered inappropriate if patients did not have left ventricular systolic dysfunction or symptomatic heart failure (HF). RESULTS AND DISCUSSION Digoxin was used in 1274 (20·5%) patients. Patients treated with digoxin were older (71·4 ± 9·8 years vs. 69·2 ± 10·9 years, P < 0·001), more likely to be female (58·8% vs. 55·9%, P = 0·019) and had more common comorbidities such as HF (40·2% vs. 17·4%), diabetes (26·4% vs. 21·1%), coronary artery disease (35·3 vs. 27·6%) and persistent/permanent AF (93·4% vs. 78·4%; P < 0·001 for each comparison). Of the 1274 patients, the indication of digoxin use was considered inappropriate in 762 (59·8%). WHAT IS NEW AND CONCLUSION Our findings show that nearly one-fifth of the patients with NVAF were on digoxin therapy and nearly 60% of these patients were receiving digoxin with inappropriate indications in a real-world setting.
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Affiliation(s)
- M Biteker
- Department of Cardiology, Faculty of Medicine, Mugla Sitki Kocman University, Muğla, Turkey
| | - Ö Başaran
- Department of Cardiology, Faculty of Medicine, Mugla Sitki Kocman University, Muğla, Turkey
| | - V Dogan
- Department of Cardiology, Faculty of Medicine, Mugla Sitki Kocman University, Muğla, Turkey.
| | - O Beton
- Department of Cardiology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey
| | - M Tekinalp
- Department of Cardiology, Kahramanmaraş Necip Fazıl State Hospital, Kahramanmaraş, Turkey
| | - A Çağrı Aykan
- Department of Cardiology, Trabzon Ahi Evren Chest Cardiovascular Surgery Education and Research Hospital, Trabzon, Turkey
| | - E Kalaycıoğlu
- Department of Cardiology, Trabzon Ahi Evren Chest Cardiovascular Surgery Education and Research Hospital, Trabzon, Turkey
| | - I Bolat
- Department of Cardiology, Fethiye State Hospital, Muğla, Turkey
| | - O TaŞar
- Department of Cardiology, Elazığ Education and Research Hospital, Elazig, Turkey
| | - Ö Şafak
- Department of Cardiology, Burdur State Hospital, Burdur, Turkey
| | - M Kalçık
- Department of Cardiology, İskilip Atıf Hoca State Hospital, İskilip, Turkey
| | - M Yaman
- Department of Cardiology, Samsun Education and Research Hospital, Samsun, Turkey
| | - C Kırma
- Kartal Kosuyolu Heart Education and Research Hospital, Istanbul, Turkey
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17
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Digoxin and short term mortality after acute STEMI: Results from the MAGIC trial. Int J Cardiol 2016; 218:176-180. [DOI: 10.1016/j.ijcard.2016.05.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 05/12/2016] [Indexed: 11/19/2022]
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18
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Sessa M, Mascolo A, Andersen MP, Rosano G, Rossi F, Capuano A, Torp-Pedersen C. Effect of Chronic Kidney Diseases on Mortality among Digoxin Users Treated for Non-Valvular Atrial Fibrillation: A Nationwide Register-Based Retrospective Cohort Study. PLoS One 2016; 11:e0160337. [PMID: 27467520 PMCID: PMC4965154 DOI: 10.1371/journal.pone.0160337] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 07/18/2016] [Indexed: 12/20/2022] Open
Abstract
PURPOSE This study investigated the impact of chronic kidney disease on all-causes and cardiovascular mortality in patients with atrial fibrillation treated with digoxin. METHODS All patients with non-valvular atrial fibrillation and/or atrial flutter as hospitalization diagnosis from January 1, 1997 to December 31, 2012 were identified in Danish nationwide administrative registries. Cox proportional hazard model was used to compare the adjusted risk of all-causes and cardiovascular mortality among patients with and without chronic kidney disease and among patients with different chronic kidney disease stages within 180 days and 2 years from the first digoxin prescription. RESULTS We identified 37,981 patients receiving digoxin; 1884 patients had the diagnosis of chronic kidney disease. Cox regression analysis showed no statistically significant differences in all-causes (Hazard Ratio, HR 0.89; 95% confident interval, CI 0.78-1.03) and cardiovascular mortality (HR 0.88; 95%CI 0.74-1.05) among patients with and without chronic kidney disease within 180 days of follow-up period. No statistically significant differences was found using a 2 years follow-up period neither for all causes mortality (HR 0.90; 95%CI 0.79-1.03), nor for cardiovascular mortality (HR 0.87; 95%CI 0.74-1.02). No statistically significant differences was found comparing patients with and without estimated Glomerular Filtration Rate <30ml/min/1.73m2 and patients with different stages of chronic kidney disease, for all-causes and cardiovascular mortality within 180 days and 2 years from the first digoxin prescription. CONCLUSIONS This study suggest no direct effect of chronic kidney disease and chronic kidney disease stages on all-causes and cardiovascular mortality within both 180 days and 2 years from the first digoxin prescription in patients treatment-naïve with digoxin for non-valvular atrial fibrillation.
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Affiliation(s)
- Maurizio Sessa
- Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, Naples, Italy
- * E-mail:
| | - Annamaria Mascolo
- Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, Naples, Italy
| | | | - Giuseppe Rosano
- IRCCS San Raffaele Pisana, Rome, Italy
- Cardiovascular and Cell Sciences Research Institute, St. George's University of London, London, United Kingdom
| | - Francesco Rossi
- Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, Naples, Italy
| | - Annalisa Capuano
- Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, Naples, Italy
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19
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Abstract
Since its isolation in the 1930s, digoxin has played a pivotal role in the treatment of cardiac conditions including heart failure and supraventricular tachyarrhythmias. The parasympathomimetic activity makes digoxin a reasonable option for controlling ventricular rate in atrial fibrillation (AF). However, the unique pharmacokinetic properties, electrolyte-dependent effects, and P-glycoprotein drug interactions influence the clinical use of digoxin. In addition, the delayed onset and narrow therapeutic index can make digoxin utilization cumbersome and often necessitates serum drug monitoring. Despite digoxin's extensive history, recent literature has cast doubt on the efficacy and safety of this medication in the population with AF. Large amounts of data suggest digoxin offers no benefit on mortality and may increase the risk of mortality though this was not consistent in all evaluations. While robust, the majority of the available studies are not randomized which limits the ability to draw firm conclusions. The potential risk of mortality must be weighed against the expected benefits of digoxin use to make individualized patient care decisions. Clinicians should refrain from utilizing digoxin monotherapy for rate control in AF when other options are viable.
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Affiliation(s)
- Michael J Scalese
- 1 Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, Mobile, AL, USA
| | - Dominick J Salvatore
- 2 Division of Pharmacy Practice and Administration, University of Missouri-Kansas City, Kansas City, MI, USA
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20
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Walkey AJ, Evans SR, Winter MR, Benjamin EJ. Practice Patterns and Outcomes of Treatments for Atrial Fibrillation During Sepsis: A Propensity-Matched Cohort Study. Chest 2016; 149:74-83. [PMID: 26270396 DOI: 10.1378/chest.15-0959] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Atrial fibrillation (AF) during sepsis is associated with increased morbidity and mortality, but practice patterns and outcomes associated with rate- and rhythm-targeted treatments for AF during sepsis are unclear. METHODS This was a retrospective cohort study using enhanced billing data from approximately 20% of United States hospitals. We identified factors associated with IV AF treatments (?-blockers [BBs], calcium channel blockers [CCBs], digoxin, or amiodarone) during sepsis. We used propensity score matching and instrumental variable approaches to compare mortality between AF treatments. RESULTS Among 39,693 patients with AF during sepsis, mean age was 77 ± 11 years, 49% were women, and 76% were white. CCBs were the most commonly selected initial AF treatment during sepsis (14,202 patients [36%]), followed by BBs (11,290 [28%]), digoxin (7,937 [20%]), and amiodarone (6,264 [16%]). Initial AF treatment selection differed according to geographic location, hospital teaching status, and physician specialty. In propensity-matched analyses, BBs were associated with lower hospital mortality when compared with CCBs (n = 18,720; relative risk [RR], 0.92; 95% CI, 0.86-0.97), digoxin (n = 13,994; RR, 0.79; 95% CI, 0.75-0.85), and amiodarone (n = 5,378; RR, 0.64; 95% CI, 0.61-0.69). Instrumental variable analysis showed similar results (adjusted RR fifth quintile vs first quintile of hospital BB use rate, 0.67; 95% CI, 0.58-0.79). Results were similar among subgroups with new-onset or preexisting AF, heart failure, vasopressor-dependent shock, or hypertension. CONCLUSIONS Although CCBs were the most frequently used IV medications for AF during sepsis, BBs were associated with superior clinical outcomes in all subgroups analyzed. Our findings provide rationale for clinical trials comparing the effectiveness of AF rate- and rhythm-targeted treatments during sepsis.
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Affiliation(s)
- Allan J Walkey
- Division of Pulmonary and Critical Care Medicine, The Pulmonary Center, Boston University School of Medicine, Boston, MA.
| | - Stephen R Evans
- Data Coordinating Center, Boston University School of Public Health, Boston, MA
| | - Michael R Winter
- Data Coordinating Center, Boston University School of Public Health, Boston, MA
| | - Emelia J Benjamin
- Section of Cardiovascular Medicine, Boston University School of Medicine, Boston, MA; Section of Preventive Medicine, Boston University School of Medicine, Boston, MA; Department of Epidemiology, Boston University School of Public Health, Boston, MA
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Chamaria S, Desai AM, Reddy PC, Olshansky B, Dominic P. Digoxin Use to Control Ventricular Rate in Patients with Atrial Fibrillation and Heart Failure Is Not Associated with Increased Mortality. Cardiol Res Pract 2015; 2015:314041. [PMID: 26788401 PMCID: PMC4691628 DOI: 10.1155/2015/314041] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 11/24/2015] [Indexed: 12/25/2022] Open
Abstract
Introduction. Digoxin is used to control ventricular rate in atrial fibrillation (AF). There is conflicting evidence regarding safety of digoxin. We aimed to evaluate the risk of mortality with digoxin use in patients with AF using meta-analyses. Methods. PubMed was searched for studies comparing outcomes of patients with AF taking digoxin versus no digoxin, with or without heart failure (HF). Studies were excluded if they reported only a point estimate of mortality, duplicated patient populations, and/or did not report adjusted hazard ratios (HR). The primary endpoint was all-cause mortality. Adjusted HRs were combined using generic inverse variance and log hazard ratios. A multivariate metaregression model was used to explore heterogeneity in studies. Results. Twelve studies with 321,944 patients were included in the meta-analysis. In all AF patients, irrespective of heart failure status, digoxin is associated with increased all-cause mortality (HR [1.23], 95% confidence interval [CI] 1.16-1.31). However, digoxin is not associated with increased mortality in patients with AF and HF (HR [1.08], 95% CI 0.99-1.18). In AF patients without HF digoxin is associated with increased all-cause mortality (HR [1.38], 95% CI 1.12-1.71). Conclusion. In patients with AF and HF, digoxin use is not associated with an increased risk of all-cause mortality when used for rate control.
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Affiliation(s)
- Surbhi Chamaria
- Division of Cardiology and Center for Cardiovascular Diseases and Science, LSU Health Science Center, Shreveport, LA 71103, USA
| | - Anand M. Desai
- Division of Cardiology and Center for Cardiovascular Diseases and Science, LSU Health Science Center, Shreveport, LA 71103, USA
| | - Pratap C. Reddy
- Division of Cardiology and Center for Cardiovascular Diseases and Science, LSU Health Science Center, Shreveport, LA 71103, USA
| | - Brian Olshansky
- Division of Cardiovascular Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Paari Dominic
- Division of Cardiology and Center for Cardiovascular Diseases and Science, LSU Health Science Center, Shreveport, LA 71103, USA
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Chen Y, Cai X, Huang W, Wu Y, Huang Y, Hu Y. Increased All-Cause Mortality Associated With Digoxin Therapy in Patients With Atrial Fibrillation: An Updated Meta-Analysis. Medicine (Baltimore) 2015; 94:e2409. [PMID: 26717399 PMCID: PMC5291640 DOI: 10.1097/md.0000000000002409] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Revised: 12/07/2015] [Accepted: 12/09/2015] [Indexed: 01/18/2023] Open
Abstract
Digoxin is still commonly used in atrial fibrillation (AF) patients with and without heart failure (HF) for heart rate control. Studies concerning the detrimental effects of digoxin therapy in AF patients are inconsistent. This updated meta-analysis examined the association of digoxin therapy with all-cause mortality in AF patients, stratified by heart function status. We included observational studies with multivariate-adjusted data on digoxin and all-cause mortality in the analysis. The relative risks (RRs) of all-cause mortality were calculated and reported with 95% confidence intervals (95% CIs). Seventeen studies comprising 408,660 patients were included. Overall, in AF patients, digoxin treatment was associated with a significant increase in all-cause mortality after multivariate-adjustment (RR = 1.22; 95% CI 1.15-1.30). When stratified by heart function status, digoxin treatment was associated with a 14% increase in all-cause mortality in AF patients with HF (RR = 1.14, 95% CI 1.04-1.24), and a 36% increase in those without HF (RR = 1.36, 95% CI 1.18-1.56). The increased risk of all-cause mortality was significantly higher in AF patients without HF compared with those with HF (P for interaction = 0.04). This meta-analysis demonstrates that digoxin therapy was associated with a significant increase in all-cause mortality in AF patients, especially in those without HF. Given other available options, digoxin should be avoided as a first-line agent for heart rate control in AF patients.
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Affiliation(s)
- Ying Chen
- From the Department of Cardiology (YC, WH, YW, YH, YH); The Second Out-patient Department, the First People's Hospital of Shunde (YC); and Clinical Medicine Research Institute, the First People's Hospital of Shunde, Foshan, P.R. China (XC, YH, YH)
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Virgadamo S, Charnigo R, Darrat Y, Morales G, Elayi CS. Digoxin: A systematic review in atrial fibrillation, congestive heart failure and post myocardial infarction. World J Cardiol 2015; 7:808-16. [PMID: 26635929 PMCID: PMC4660476 DOI: 10.4330/wjc.v7.i11.808] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/21/2015] [Accepted: 09/16/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To review digoxin use in systolic congestive heart failure, atrial fibrillation, and after myocardial infarction. METHODS A comprehensive PubMed search was performed using the key words "digoxin and congestive heart failure", "digoxin and atrial fibrillation", "digoxin, atrial fibrillation and systolic congestive heart failure", and "digoxin and myocardial infarction". Only articles written in English were included in this study. We retained studies originating from randomized controlled trials, registries and included at least 500 patients. The studies included patients with atrial fibrillation or heart failure or myocardial infarction and had a significant proportion of patients (at least 5%) on digoxin. A table reviewing the different hazard ratios was developed based on the articles selected. Our primary endpoint was the overall mortality in the patients on digoxin vs those without digoxin, among patients with atrial fibrillation and also among patients with atrial fibrillation and systolic heart failure. We reviewed the most recent international guidelines to discuss current recommendations. RESULTS A total of 18 studies were found that evaluated digoxin and overall mortality in different clinical settings including systolic congestive heart failure and normal sinus rhythm (n = 5), atrial fibrillation with and without systolic congestive heart failure (n = 9), and myocardial infarction (n = 4). Overall, patients with systolic congestive heart failure with normal sinus rhythm, digoxin appears to have a neutral effect on mortality especially if close digoxin level monitoring is employed. However, most of the observational studies evaluating digoxin use in atrial fibrillation without systolic congestive heart failure showed an increase in overall mortality when taking digoxin. In the studies evaluated in this systematic review, the data among patients with atrial fibrillation and systolic congestive heart failure, as well as post myocardial infarction were more controversial. The extent to which discrepancies among studies are based on statistical methods is currently unclear, as these studies' findings are generated by retrospective analyses that employed different techniques to address confounding. CONCLUSION Based on the potential risks and benefits, as well as the presence of alternative drugs, there is a limited role for digoxin in the management of patients with normal sinus rhythm and congestive heart failure. Based on the retrospective studies reviewed there is a growing volume of data showing increased mortality in those with only atrial fibrillation. The proper role of digoxin is, however, less certain in other subgroups of patients, such as those with both atrial fibrillation and systolic congestive heart failure or after a myocardial infarction. Further studies may provide helpful information for such subgroups of patients.
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Affiliation(s)
- Sebastiano Virgadamo
- Sebastiano Virgadamo, Richard Charnigo, Yousef Darrat, Gustavo Morales, Claude S Elayi, Department of Cardiology, University of Kentucky Gill Heart Institute and Veterans Affairs Medical Center, Lexington, KY 40536, United States
| | - Richard Charnigo
- Sebastiano Virgadamo, Richard Charnigo, Yousef Darrat, Gustavo Morales, Claude S Elayi, Department of Cardiology, University of Kentucky Gill Heart Institute and Veterans Affairs Medical Center, Lexington, KY 40536, United States
| | - Yousef Darrat
- Sebastiano Virgadamo, Richard Charnigo, Yousef Darrat, Gustavo Morales, Claude S Elayi, Department of Cardiology, University of Kentucky Gill Heart Institute and Veterans Affairs Medical Center, Lexington, KY 40536, United States
| | - Gustavo Morales
- Sebastiano Virgadamo, Richard Charnigo, Yousef Darrat, Gustavo Morales, Claude S Elayi, Department of Cardiology, University of Kentucky Gill Heart Institute and Veterans Affairs Medical Center, Lexington, KY 40536, United States
| | - Claude S Elayi
- Sebastiano Virgadamo, Richard Charnigo, Yousef Darrat, Gustavo Morales, Claude S Elayi, Department of Cardiology, University of Kentucky Gill Heart Institute and Veterans Affairs Medical Center, Lexington, KY 40536, United States
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Al-Zakwani I, Panduranga P, Zubaid M, Sulaiman K, Rashed WA, Alsheikh-Ali AA, AlMahmeed W, Shehab A, Al Qudaimi A, Asaad N, Amin H. Impact of Digoxin on Mortality in Patients With Atrial Fibrillation Stratified by Heart Failure: Findings From Gulf Survey of Atrial Fibrillation Events in the Middle East. J Cardiovasc Pharmacol Ther 2015; 21:273-9. [PMID: 26341119 DOI: 10.1177/1074248415603505] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 07/09/2015] [Indexed: 12/20/2022]
Abstract
OBJECTIVE The use of digoxin in patients having atrial fibrillation (AF) with or without heart failure (HF) is not without controversy. The aim of this study was to examine the impact of digoxin therapy on mortality stratified by HF. METHODS Gulf Survey of Atrial Fibrillation Events was a prospective, multinational, observational registry of consecutive patients with AF recruited from the emergency department of 23 hospitals in 6 countries in the Middle East. Patients were recruited between October 2009 and June 2010 and followed up for 1 year after enrollment. Analyses were performed using univariate and multivariate statistical techniques. RESULTS The study included a total of 1962 patients with AF, with an overall mean age of 56 ± 16 years, and 52% (n = 1026) were males. At hospital discharge, digoxin was prescribed in 36% (n = 709) of the patients, whereas HF was present in 27% (n = 528) of the cohort. A total of 225 (12.1%) patients died during the 12-month follow-up period after discharge (5.3% [n = 104] were lost to follow-up). Patients with HF were consistently associated with higher mortality at 1 month (5.1% vs 2.1%; P < .001), 6 months (17.2% vs 5.0%; P < 0.001), and 12 months (24.3% vs 7.6%; P < .001) when compared to those without HF. When stratified by HF, digoxin therapy was associated with significantly higher mortality in those without HF at 6 months (8.7% vs 3.7%; adjusted odds ratio (aOR), 5.07; P < .001) and 12 months (12.3% vs 6.0%; aOR, 4.22; P < .001) but not in those with HF (6 months: 18.6% vs 14.7%; aOR, 1.62; P = .177 and 12 months: 25.4% vs 22.4%; aOR, 1.37; P = .317). CONCLUSIONS In patients with AF and HF, digoxin did not offer any survival advantages. However, in those without HF, digoxin therapy was, in fact, associated with significantly higher long-term mortality.
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Affiliation(s)
- Ibrahim Al-Zakwani
- Department of Pharmacology & Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman Gulf Health Research, Muscat, Oman
| | - P Panduranga
- Department of Cardiology, Royal Hospital, Muscat, Oman
| | - M Zubaid
- Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait, Kuwait
| | - K Sulaiman
- Department of Cardiology, Royal Hospital, Muscat, Oman
| | - W A Rashed
- Department of Medicine, Mubarak Al-Kabeer Hospital, Ministry of Health, Kuwait, Kuwait
| | - A A Alsheikh-Ali
- Division of Adult Cardiology, Institute of Cardiac Sciences, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - W AlMahmeed
- Heart & Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - A Shehab
- Department of Medicine, Faculty of Medicine, UAE University, Al Ain, United Arab Emirates
| | - A Al Qudaimi
- Cardiac Center, Al Thawra Hospital, Sana'a, Yemen
| | - N Asaad
- Heart Hospital, Hamad Medical Corporation, Doha, Qatar
| | - H Amin
- Department of Cardiology, Mohammed Bin Khalifa Cardiac Centre, Manama, Bahrain
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Ziff OJ, Lane DA, Samra M, Griffith M, Kirchhof P, Lip GYH, Steeds RP, Townend J, Kotecha D. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ 2015; 351:h4451. [PMID: 26321114 PMCID: PMC4553205 DOI: 10.1136/bmj.h4451] [Citation(s) in RCA: 229] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To clarify the impact of digoxin on death and clinical outcomes across all observational and randomised controlled trials, accounting for study designs and methods. DATA SOURCES AND STUDY SELECTION Comprehensive literature search of Medline, Embase, the Cochrane Library, reference lists, and ongoing studies according to a prospectively registered design ( PROSPERO CRD42014010783), including all studies published from 1960 to July 2014 that examined treatment with digoxin compared with control (placebo or no treatment). DATA EXTRACTION AND SYNTHESIS Unadjusted and adjusted data pooled according to study design, analysis method, and risk of bias. MAIN OUTCOME MEASURES Primary outcome (all cause mortality) and secondary outcomes (including admission to hospital) were meta-analysed with random effects modelling. RESULTS 52 studies were systematically reviewed, comprising 621,845 patients. Digoxin users were 2.4 years older than control (weighted difference 95% confidence interval 1.3 to 3.6), with lower ejection fraction (33% v 42%), more diabetes, and greater use of diuretics and anti-arrhythmic drugs. Meta-analysis included 75 study analyses, with a combined total of 4,006,210 patient years of follow-up. Compared with control, the pooled risk ratio for death with digoxin was 1.76 in unadjusted analyses (1.57 to 1.97), 1.61 in adjusted analyses (1.31 to 1.97), 1.18 in propensity matched studies (1.09 to 1.26), and 0.99 in randomised controlled trials (0.93 to 1.05). Meta-regression confirmed that baseline differences between treatment groups had a significant impact on mortality associated with digoxin, including markers of heart failure severity such as use of diuretics (P=0.004). Studies with better methods and lower risk of bias were more likely to report a neutral association of digoxin with mortality (P<0.001). Across all study types, digoxin led to a small but significant reduction in all cause hospital admission (risk ratio 0.92, 0.89 to 0.95; P<0.001; n=29,525). CONCLUSIONS Digoxin is associated with a neutral effect on mortality in randomised trials and a lower rate of admissions to hospital across all study types. Regardless of statistical analysis, prescription biases limit the value of observational data.
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Affiliation(s)
- Oliver J Ziff
- University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK Royal Free London NHS Foundation Trust, London, UK
| | - Deirdre A Lane
- University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK Sandwell and West Birmingham NHS Trust, City Hospital, Birmingham, UK
| | - Monica Samra
- Royal Free London NHS Foundation Trust, London, UK
| | | | - Paulus Kirchhof
- University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK Sandwell and West Birmingham NHS Trust, City Hospital, Birmingham, UK
| | - Gregory Y H Lip
- University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK Sandwell and West Birmingham NHS Trust, City Hospital, Birmingham, UK
| | | | - Jonathan Townend
- University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK University Hospitals Birmingham NHS Trust, Birmingham, UK
| | - Dipak Kotecha
- University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK Sandwell and West Birmingham NHS Trust, City Hospital, Birmingham, UK University Hospitals Birmingham NHS Trust, Birmingham, UK Monash Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Australia
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Pastori D, Farcomeni A, Bucci T, Cangemi R, Ciacci P, Vicario T, Violi F, Pignatelli P. Response to “Digoxin or digoxin prescribed patient? Randomized trials are essential to discriminate the principal risk factor for the association of digoxin and increased mortality”. Int J Cardiol 2015; 189:247-8. [DOI: 10.1016/j.ijcard.2015.04.125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 04/15/2015] [Indexed: 01/17/2023]
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Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mortality: a systematic review and meta-analysis of the literature. Eur Heart J 2015; 36:1831-8. [PMID: 25939649 DOI: 10.1093/eurheartj/ehv143] [Citation(s) in RCA: 186] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 04/08/2015] [Indexed: 12/21/2022] Open
Abstract
There are conflicting data regarding the effect of digoxin use on mortality in patients with atrial fibrillation (AF) or with congestive heart failure (CHF). The aim of this meta-analysis was to provide detailed analysis of the currently available study reports. We performed a MEDLINE and a COCHRANE search (1993-2014) of the English literature dealing with the effects of digoxin on all-cause-mortality in subjects with AF or CHF. Only full-sized articles published in peer-reviewed journals were considered for this meta-analysis. A total of 19 reports were identified. Nine reports dealt with AF patients, seven with patients suffering from CHF, and three with both clinical conditions. Based on the analysis of adjusted mortality results of all 19 studies comprising 326 426 patients, digoxin use was associated with an increased relative risk of all-cause mortality [Hazard ratio (HR) 1.21, 95% confidence interval (CI), 1.07 to 1.38, P < 0.01]. Compared with subjects not receiving glycosides, digoxin was associated with a 29% increased mortality risk (HR 1.29; 95% CI, 1.21 to 1.39) in the subgroup of publications comprising 235 047 AF patients. Among 91.379 heart failure patients, digoxin-associated mortality risk increased by 14% (HR 1.14, 95% CI, 1.06 to 1.22). The present systematic review and meta-analysis of all available data sources suggest that digoxin use is associated with an increased mortality risk, particularly among patients suffering from AF.
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Affiliation(s)
- Mate Vamos
- Department of Cardiology, Division of Clinical Electrophysiology, J.W. Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Julia W Erath
- Department of Cardiology, Division of Clinical Electrophysiology, J.W. Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Stefan H Hohnloser
- Department of Cardiology, Division of Clinical Electrophysiology, J.W. Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
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Bavishi C, Khan AR, Ather S. Digoxin in patients with atrial fibrillation and heart failure: A meta-analysis. Int J Cardiol 2015; 188:99-101. [PMID: 25900519 DOI: 10.1016/j.ijcard.2015.04.031] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 04/03/2015] [Indexed: 12/25/2022]
Affiliation(s)
- Chirag Bavishi
- Mount Sinai St. Luke's & Roosevelt Hospitals, New York, NY, USA.
| | | | - Sameer Ather
- University of Alabama at Birmingham, Birmingham, AL, USA
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Yildiz A, Soydinc S. Digoxin or digoxin prescribed patient? Randomized trials are essential to discriminate the principal risk factor for the association of digoxin and increased mortality. Int J Cardiol 2015; 184:512-513. [DOI: 10.1016/j.ijcard.2015.03.029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 03/02/2015] [Indexed: 11/25/2022]
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