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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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Frommeyer G, Lange PS, Kleemann T, Stellbrink C, Ince H, Brachmann J, Lewalter T, Hochadel M, Senges J, Eckardt L. Digitalis Therapy Is Associated With an Increased Risk of ICD Shock Delivery and Device Revision. Ann Noninvasive Electrocardiol 2025; 30:e70080. [PMID: 40189742 PMCID: PMC11972923 DOI: 10.1111/anec.70080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/28/2025] [Accepted: 03/30/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Digitalis glycosides are employed for rate control of atrial fibrillation and treatment of heart failure. Previous studies suggested potential harmful effects of digitalis therapy. The aim of the present study was to assess the prevalence and potential impact of digitalis therapy on outcomes in patients with systolic failure who were implanted with an ICD- or CRT-ICD system. METHODS AND RESULTS The German Device Registry is a nationwide, prospective registry with a 1-year follow-up investigating 4384 patients receiving either ICD or CRT systems in 52 German centers. The present analysis focused on the presence of digitalis therapy in 3826 patients undergoing device implantation. Patients receiving digitalis therapy (n = 800) presented a more severely impaired left ventricular function, higher NYHA class, and an increased incidence of left bundle branch block. Consequently, the implantation of CRT systems was more common in this group. One-year mortality did not significantly differ between both groups (9.1% vs. 7.4%, p = 0.14). Similar results were obtained for the combined endpoint, including death, myocardial infarction, and stroke. ICD shock delivery (19.7% vs. 15.0%, p = 0.006) and device revision (11.4% vs. 7.5%, p < 0.004) were more common in digitalis-treated patients. CONCLUSION In this study in patients undergoing ICD or CRT implantation, an association of digitalis therapy with an increased risk of device revision was observed. Of note, mortality or severe cardiovascular events did not differ between both groups. Furthermore, an increased risk of ICD shock delivery was observed in digitalis-treated patients.
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Affiliation(s)
- Gerrit Frommeyer
- Clinic for Cardiology II – ElectrophysiologyUniversity of MünsterMünsterGermany
| | - Philipp S. Lange
- Clinic for Cardiology II – ElectrophysiologyUniversity of MünsterMünsterGermany
| | - Thomas Kleemann
- Department of CardiologyKlinikum der Stadt LudwigshafenLudwigshafenGermany
| | | | - Hüseyin Ince
- Department of CardiologyVivantes Klinikum Am Urban and NeuköllnBerlinGermany
- Rostock UniversityRostockGermany
| | - Johannes Brachmann
- Medical School REGIOMED, University of Split School of MedicineSplitCroatia
| | | | | | - Jochen Senges
- Stiftung Institut für Herzinfarktforschung (IHF)LudwigshafenGermany
| | - Lars Eckardt
- Clinic for Cardiology II – ElectrophysiologyUniversity of MünsterMünsterGermany
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3
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Ahuja T, Saadi R, Papadopoulos J, Bernard S, Pashun R, Horowitz J, Yuriditsky E, Merchan C. Digoxin Loading Doses and Serum Digoxin Concentrations for Rate Control of Atrial Arrhythmias in Critically Ill Patients. J Cardiovasc Pharmacol 2025; 85:211-216. [PMID: 39531271 DOI: 10.1097/fjc.0000000000001648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 10/19/2024] [Indexed: 11/16/2024]
Abstract
ABSTRACT Intravenous (IV) digoxin loading dose (LD) recommendations for rate control of atrial arrhythmias in critically ill patients are not well studied. When using digoxin in the setting of atrial fibrillation/atrial flutter (AF/AFL), a LD in either a fixed-dose regimen, weight-based dose, or pharmacokinetic-based calculation to target a serum digoxin concentration (SDC) of 0.8-1.5 ng/mL is recommended. The objective of this study was to assess the safety and effectiveness of digoxin LD used in critically ill patients for rate control of AF/AFL and to assess the SDC achieved. This single-center retrospective cohort study included patients, who received IV digoxin and had a SDC drawn. The primary endpoint was the median SDC achieved after a digoxin LD. Secondary outcomes included the frequency of SDCs ≥1.5 ng/mL and heart rate control. A total of 92 patients were included. The median total LD of digoxin for the entire cohort was 11 μg/kg (750 μg). For 61% of the cohort, the LD was distributed over 6-hour intervals. The median SDC after completion of the IV digoxin LD was 1.3 ng/mL (0.9-1.7). The incidence of supratherapeutic SDC was 36% for the total cohort. A target heart rate <110 beats per minute within 24 hours from digoxin LD was achieved in 60% of the cohort. In conclusion, a median total digoxin LD of 750 μg in critically ill patients with AF/AFL, targeting a SDC <1.5 ng/mL, may be considered for acute rate control, taking into account drug-drug interactions in the cardiac intensive care unit. Future studies are necessary to confirm our findings.
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Affiliation(s)
- Tania Ahuja
- Department of Pharmacy, NYU Langone Health, New York, NY; and
- Division of Cardiology, Department of Medicine, NYU Langone Health, New York, NY
| | - Raghad Saadi
- Department of Pharmacy, Morristown Medical Center, Atlantic Health System, Morristown, NJ
| | | | - Samuel Bernard
- Division of Cardiology, Department of Medicine, NYU Langone Health, New York, NY
| | - Raymond Pashun
- Division of Cardiology, Department of Medicine, NYU Langone Health, New York, NY
| | - James Horowitz
- Division of Cardiology, Department of Medicine, NYU Langone Health, New York, NY
| | - Eugene Yuriditsky
- Division of Cardiology, Department of Medicine, NYU Langone Health, New York, NY
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Stulberg EL, Delic A, Zheutlin AR, Steinberg BA, Yaghi S, Sharma R, de Havenon A. Modelling anticoagulation and health-related quality of life in those with atrial fibrillation: a secondary analysis of AFFIRM. Clin Res Cardiol 2024; 113:1200-1210. [PMID: 37962572 PMCID: PMC11785410 DOI: 10.1007/s00392-023-02335-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023]
Abstract
Associations of anticoagulation with primary endpoints in longitudinal studies are impacted by selection bias and time-varying covariates (e.g. comorbidities). We demonstrate how time-varying covariates and selection bias influence association estimates between anticoagulation and health-related quality of life (HRQoL) in patients with atrial fibrillation. We performed a secondary analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management trial quality of life substudy. Dichotomized warfarin use was ascertained at the study baseline, 2 months later, and annually for up to 6 years. HRQoL was measured at every time point using a self-reported ordinal 5-point Likert-scale (lower score and lower odds ratio represents better health-related quality of life). Static and time-varying covariates were ascertained throughout the study period. Confounder-adjusted generalized mixed model and generalized estimating equation regressions were used to demonstrate traditional association estimates between anticoagulation and HRQoL. Inverse probability of treatment and censorship weights were used to ascertain the influence of time-varying confounding and selection bias. Age-stratified analysis (age ≥ 70 years) evaluated for effect modification. 656 individuals were included in the analysis, 601 on warfarin at baseline. The association of warfarin use with better HRQoL over time strengthened when accounting for time-varying confounding and selection bias (OR 0.30, 95% CI 0.14-0.55) compared to traditional analyses (OR 0.61, 95% CI 0.38-0.97), and was most pronounced in those ≥ 70 years upon stratified analysis. Anticoagulation is associated with higher HRQoL in patients with atrial fibrillation, with time-varying confounding and selection bias likely influencing longitudinal estimates in anticoagulation-HRQoL research.
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Affiliation(s)
- Eric L Stulberg
- Department of Neurology, University of Utah School of Medicine, 175 Medical Dr N, Salt Lake City, UT, 84132, USA.
| | - Alen Delic
- Department of Neurology, University of Utah School of Medicine, 175 Medical Dr N, Salt Lake City, UT, 84132, USA
| | - Alexander R Zheutlin
- Department of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, USA
| | - Benjamin A Steinberg
- Department of Cardiology, University of Utah School of Medicine, Salt Lake City, USA
| | - Shadi Yaghi
- Department of Neurology, Brown Alpert School of Medicine, Providence, USA
| | - Richa Sharma
- Department of Neurology, Yale School of Medicine, New Haven, USA
| | - Adam de Havenon
- Department of Neurology, University of Utah School of Medicine, 175 Medical Dr N, Salt Lake City, UT, 84132, USA
- Department of Neurology, Yale School of Medicine, New Haven, USA
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5
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Menezes MS, Doria GAA, Valença-Feitosa F, Pereira SN, Silvestre CC, de Oliveira Filho AD, Lobo IMF, Quintans-Júnior LJ. Incidence of drug-related adverse events related to the use of high-alert drugs: A systematic review of randomized controlled trials. EXPLORATORY RESEARCH IN CLINICAL AND SOCIAL PHARMACY 2024; 14:100435. [PMID: 38646469 PMCID: PMC11031819 DOI: 10.1016/j.rcsop.2024.100435] [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: 02/08/2024] [Revised: 03/28/2024] [Accepted: 04/01/2024] [Indexed: 04/23/2024] Open
Abstract
Background High-alert medication (HAM) is more predictable to cause significant harm to the patient, even when used as intended. The damage related to the HAM lead not only suffering to the patient, but also raise the additional costs associated with care. Objective Evaluate the incidence of drug-related adverse events related to the use of high-alert medications. Methods It was conducted an active search for information through COCHRANE databases, LILACS, SciELO, SCOPUS, PubMed/MEDLINE and WEB OF SCIENCE. The search strategy included the following terms: "Patient safety", "Medication errors" and "Hospital" and "High Alert Medications" or "Dangerous Drugs" in different combinations. Then two reviewers independently conducted a preliminary evaluation of relevant titles, abstracts and finally full-text. Studies quality was evaluated according to PRISMA declaration. Results The systematic review evaluated seven articles, which showed that only 11 HAM identified in the literature could have serious events. The most frequently cited were warfarin (22.2%) which progressed from deep vein thrombosis to gangrene, suggesting lower initial doses, followed by cyclophosphamide (22.2%) and cyclosporine (22.2%) which presented invasive fungal infection and death. In addition to these, morphine was compared with its active metabolite (M6G), with M6G causing fewer serious clinical events related to nausea and vomiting, reducing the need for concomitant use of antiemetics. Conclusions The most reported drug classes in the articles included that were related to incidence of drug-related adverse events in use of high-alert medications: morphine, M6G-glucuronide, haloperidol, promethazine, ivabradine, digoxin, warfarin, ximelagatran, cyclophosphamide, cyclosporine, and ATG. The formulate protocols for the use of these medications, with importance placed on evaluating, among the classes, the medication that causes the least harm.
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Affiliation(s)
- Michelle Santos Menezes
- Federal University of Sergipe (UFS), Cidade Universitária “Prof. José Aloísio Campos”, Jardim Rosa Elze, São Cristóvão, CEP: 49100-000, Brazil
| | - Grace Anne Azevedo Doria
- Federal University of Sergipe (UFS), Cidade Universitária “Prof. José Aloísio Campos”, Jardim Rosa Elze, São Cristóvão, CEP: 49100-000, Brazil
| | - Fernanda Valença-Feitosa
- Laboratory of Teaching and Research in Social Pharmacy (LEPFS), Department of Pharmacy, Federal University of Sergipe, Cidade Universitária “Prof. José Aloísio Campos”, Jardim Rosa Elze, São Cristóvão, CEP: 49100-000, Brazil
| | - Sylmara Nayara Pereira
- Laboratory of Teaching and Research in Social Pharmacy (LEPFS), Department of Pharmacy, Federal University of Sergipe, Cidade Universitária “Prof. José Aloísio Campos”, Jardim Rosa Elze, São Cristóvão, CEP: 49100-000, Brazil
| | - Carina Carvalho Silvestre
- Federal University of Juiz de Fora - Governador Valadares Campus, Minas Gerais, University Campus, Rua José Lourenço Kelmer, s/n - São Pedro, Juiz de Fora, MG, 36036-900, Brazil
| | - Alfredo Dias de Oliveira Filho
- Laboratory of Teaching and Research in Social Pharmacy (LEPFS), Department of Pharmacy, Federal University of Sergipe, Cidade Universitária “Prof. José Aloísio Campos”, Jardim Rosa Elze, São Cristóvão, CEP: 49100-000, Brazil
| | - Iza Maria Fraga Lobo
- Federal University of Bahia (2003). Infectologist, Head of the Risk Management Unit (UGRA) and Risk Manager of the University Hospital of the Federal University of Sergipe, R. Cláudio Batista - Palestine, Aracaju - SE, 49060-676, Brazil
| | - Lucindo José Quintans-Júnior
- Physiology Department, Federal University of Sergipe (DFS/UFS)
- Laboratory of Neurosciences and Pharmacological Tests (LANEF), Federal University of Sergipe, Rua Marechal Rondon, s/n. University City "Prof. José Aloísio Campos ", Jardim Rosa Elze, São Cristóvão, CEP: 49100-000, Brazil
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6
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Newman JD, O'Meara E, Böhm M, Savarese G, Kelly PR, Vardeny O, Allen LA, Lancellotti P, Gottlieb SS, Samad Z, Morris AA, Desai NR, Rosano GMC, Teerlink JR, Giraldo CS, Lindenfeld J. Implications of Atrial Fibrillation for Guideline-Directed Therapy in Patients With Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol 2024; 83:932-950. [PMID: 38418008 DOI: 10.1016/j.jacc.2023.12.033] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/29/2023] [Accepted: 12/18/2023] [Indexed: 03/01/2024]
Abstract
Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular conditions that frequently coexist. Among patients with HF, more than one-half also have AF. Both are associated with significant morbidity and mortality. Moreover, the prevalence of each is increasing globally, and this trend is expected to continue owing to an aging population and increased life expectancy. Diagnosis of AF in a patient with HF is associated with greater symptom burden, more frequent hospitalizations, and a worse prognosis. Guideline-directed medical therapy (GDMT) for HF can affect the incidence of AF. Once present, AF can influence the efficacy of some components of GDMT for HF. In this review, we discuss the effect of GDMT for HF across the spectrum of ejection fraction on prevention of AF as well as the benefit of GDMT in patients with vs without AF.
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Affiliation(s)
| | - Eileen O'Meara
- Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada
| | - Michael Böhm
- University of the Saarland, Homberg/Saar, Germany
| | - Gianluigi Savarese
- Division of Cardiology, Department of Medicine, Karolinska Institute, Stockholm, Sweden; Heart and Vascular and Neuro Theme, Karolinska University Hospital, Stockholm, Sweden
| | | | - Orly Vardeny
- University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Larry A Allen
- Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
| | | | - Stephen S Gottlieb
- Division of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA; Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA
| | | | | | - Nihar R Desai
- Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Giuseppe M C Rosano
- Center for Clinical and Basic Research, IRCCS San Raffaele Pisana, Rome, Italy
| | | | | | - JoAnn Lindenfeld
- Vanderbilt Heart and Vascular Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
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7
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See C, Wheelock KM, Caraballo C, Khera R, Annapureddy A, Mahajan S, Lu Y, Krumholz HM, Murugiah K. Patterns of Digoxin Prescribing for Medicare Beneficiaries in the United States 2013-2019. AMERICAN JOURNAL OF MEDICINE OPEN 2023; 10:100048. [PMID: 38213879 PMCID: PMC10783702 DOI: 10.1016/j.ajmo.2023.100048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/13/2024]
Abstract
Background Studies show that digoxin use is declining but is still prevalent. Recent data on digoxin prescription and characteristics of digoxin prescribers are unknown, which can help understand its contemporary use. Methods Using Medicare Part D data from 2013 to 2019, we studied the change in number and proportion of digoxin prescriptions and digoxin prescribers, overall and by specialty. Using logistic regression, we identified prescriber characteristics associated with digoxin prescription. Results From 2013 to 2019, total digoxin prescriptions (4.6 to 1.8 million) and proportion of digoxin prescribers decreased (9.1% to 4.3% overall; 26.6% to 11.8% among General Medicine prescribers and 65.4% to 48.9% among Cardiology). Of digoxin prescribers from 2013 practicing in 2019 (91.2% remained active), 59.1% did not prescribe digoxin at all, 31.7% reduced, and 9.2% maintained or increased prescriptions. The proportion of all digoxin prescriptions that were prescribed by General Medicine prescribers declined from 59.7% to 48.2% and increased for Cardiology (29% to 38.5%). Among new prescribers in 2019 (N = 85,508), only 1.9% prescribed digoxin. Digoxin prescribers when compared to non-digoxin prescribers were more likely male, graduated from medical school earlier, were located in the Midwest or South, and belonged to Cardiology (all P < .001). Conclusions Digoxin prescriptions continue to decline with over half of 2013 prescribers no longer prescribing digoxin in 2019. This may be a result of the increasing availability of newer heart failure therapies. The decline in digoxin prescription was greater among general medicine physicians than cardiologists, suggesting a change in digoxin use to a medication prescribed increasingly by specialists.
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Affiliation(s)
- Claudia See
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
| | - Kevin M. Wheelock
- Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
| | - César Caraballo
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn
| | - Rohan Khera
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn
| | - Amarnath Annapureddy
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
| | - Shiwani Mahajan
- Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn
| | - Yuan Lu
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn
| | - Harlan M. Krumholz
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn
- Department of Health Policy and Management, Yale School of Public Health, New Haven, Conn
| | - Karthik Murugiah
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn
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8
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Clark JL, Jacobs JA, Watanabe AH, Catino AB, Dechand JA. Evaluation of Safety and Efficacy of Intravenous Digoxin Loading Doses Based on Ideal Body Weight. Ann Pharmacother 2023; 57:1154-1161. [PMID: 36642982 DOI: 10.1177/10600280221146530] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Intravenous digoxin loading dose recommendations differ between clinical guidelines and Food and Drug Administration packaging for acute rate control. OBJECTIVE The objective of this study was to assess the safety and efficacy of intravenous digoxin loading in patients who received ≤12 µg/kg and >12 µg/kg of digoxin using ideal body weight (IBW). METHODS This single center retrospective cohort study with exempt status from the local Institutional Review Board included patients who received intravenous digoxin and had a serum digoxin concentration (SDC) drawn. Digoxin doses >36 hours after the first dose were excluded. Patients who received a total of >12 µg/kg and ≤12 µg/kg IBW were compared. The primary endpoint was frequency of SDCs ≥1.2 ng/mL, which have been shown to be associated with increased mortality. RESULTS A total of 244 patients were included (144 receiving >12 µg/kg and 100 receiving ≤12 µg/kg). There were significantly more SDC ≥1.2 ng/mL in the >12 µg/kg group than the ≤12 µg/kg group (50.6% vs. 30.0%; adjusted odds ratio, 3.19; 95% confidence interval [CI]: 1.79-5.84), with no difference in rate control failure. Major limitations of the study include retrospective nature and possible selection bias. CONCLUSION AND RELEVANCE Compared to patients who received digoxin doses ≤12 µg/kg IBW, patients who received >12 µg/kg IBW had higher rates of SDC ≥1.2 ng/mL. This suggests that appropriate weight-based dosing with 8 to 12 µg/kg IBW has the potential to be a safer approach to digoxin loading, rather than frequently used dosing strategies that result in doses >12 µg/kg.
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Affiliation(s)
- Jessi L Clark
- Department of Pharmacy, University of Utah Health, Salt Lake City, UT, USA
- Department of Pharmacy, University of Kentucky HealthCare, Lexington, KY, USA
| | - Joshua A Jacobs
- Department of Pharmacy, University of Utah Health, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | | | - Anna B Catino
- Department of Cardiology, University of Utah Health, Salt Lake City, UT, USA
| | - John A Dechand
- Department of Pharmacy, University of Utah Health, Salt Lake City, UT, USA
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9
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Triska J, Uretsky BF, Pitt B, Birnbaum Y. Closing the Digitalis Divide: Back to the Basics of Randomized Controlled Trials. Cardiovasc Drugs Ther 2023; 37:807-813. [PMID: 34748147 DOI: 10.1007/s10557-021-07287-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/01/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE Publishe d decades after several randomized controlled trials (RCT) demonstrating decreased hospitalizations and no effect on all-cause mortality with digoxin use, a series of meta-analyses linking digoxin treatment and mortality have contributed to a narrower application of this medication for the management of heart failure (HF) and atrial fibrillation (AF). Given the conflicting data from the earlier RCTs and more recent meta-analyses, there is a growing polarization among providers for and against the use of digoxin in managing these conditions. METHODS To help close this divide, we provide a perspective on the literature with special attention to the quality of both older and more recent studies on this subject. RESULTS The data from the highest quality studies we have, RCTs, suggest that digoxin use in patients with HF and/or AF is associated with improvement in several areas of outcomes including functional capacity, symptom management, reduced hospitalizations, fewer deaths due to HF, and treatment of refractory chronic heart failure with rEF, and may even have overall mortality benefit when serum digoxin concentrations are within therapeutic range. These effects are more pronounced in patients with EF < 25% and NYHA Class II-IV and at highest risk for hospitalization. CONCLUSION As the risk of confounding factors was minimized by the study design, the likelihood that positive outcomes were identified with digoxin use increased. Clinicians and researchers need further adequately designed and powered RCTs exploring the connection between digoxin therapy and mortality, hospitalizations, and symptom management.
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Affiliation(s)
- J Triska
- Internal Medicine Residency, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
| | - B F Uretsky
- University of Arkansas for Medical Sciences, Central Arkansas Veterans Health System, Little Rock, AR, 72205, USA
| | - B Pitt
- University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA
| | - Y Birnbaum
- John S. Dunn Chair in Cardiology Research and Education, The Department of Medicine, Section of Cardiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
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10
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Banaag AL, Pollard HB, Koehlmoos TP. Digoxin and Standard-of-Care Therapy for Heart Failure Patients with COVID-19: Analysis of Data from the US Military Health System (MHS) Data Repository. Drugs Real World Outcomes 2023; 10:299-307. [PMID: 36933173 PMCID: PMC10024520 DOI: 10.1007/s40801-023-00360-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2023] [Indexed: 03/19/2023] Open
Abstract
BACKGROUND Cardiac glycosides such as digoxin, digitoxin and ouabain are still used around the world to treat patients with chronic heart failure with reduced ejection fraction (HFrEF) and/or atrial fibrillation (AF). However, in the US, only digoxin is licensed for treating these illnesses, and the use of digoxin for this group of patients is increasingly being replaced in the US by a new standard of care with groups of more expensive drugs. However, ouabain and digitoxin, and less potently digoxin, have also recently been reported to inhibit SARS-CoV-2 virus penetration into human lung cells, thus blocking COVID-19 infection. COVID-19 is known to be a more aggressive disease in patients with cardiac comorbidities, including heart failure. OBJECTIVE We therefore considered the possibility that digoxin might provide at least a measure of relief from COVID-19 in digoxin-treated heart failure patients. To this end, we hypothesized that treatment with digoxin rather than standard of care might equivalently protect heart failure patients with regard to diagnosis of COVID-19, hospitalization and death. METHODS To test this hypothesis, we conducted a cross-sectional study by using the US Military Health System (MHS) Data Repository to identify all MHS TRICARE Prime and Plus beneficiaries aged 18-64 years with a heart failure (HF) diagnosis during the period April 2020 to August 2021. In the MHS, all patients receive equal, optimal care without regard to rank or ethnicity. Analyses included descriptive statistics on patient demographics and clinical characteristics, and logistic regressions to determine likelihood of digoxin use. RESULTS We identified 14,044 beneficiaries with heart failure in the MHS during the study period. Of these, 496 were treated with digoxin. However, we found that both digoxin-treated and standard-of-care groups were equivalently protected from COVID-19. We also noted that younger active duty service members and their dependents with HF were less likely to receive digoxin compared with older, retired beneficiaries with more comorbidities. CONCLUSION The hypothesis of equivalent protection by digoxin treatment of HF patients in terms of susceptibility to COVID-19 infection appears to be supported by the data.
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Affiliation(s)
- Amanda L Banaag
- Center for Health Services Research (CHSR), School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, 20817, USA
| | - Harvey B Pollard
- Department of Anatomy, Physiology and Genetics; Military and Emergency Medicine; and Pediatrics, Uniformed Services University School of Medicine, Uniformed Services University of the Health Sciences (USUHS), 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
- Consortium for Health and Military Performance (CHAMP), School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
| | - Tracey P Koehlmoos
- Center for Health Services Research (CHSR), School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA
- Department of Preventive Medicine and Biometrics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA
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11
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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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12
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Harfouche MN, Nigam R, Efron DT, Diaz JJ. Surgical Stabilization of Rib Fractures in Severe Injury Is Not Associated With Worse Outcomes. J Surg Res 2023; 284:106-113. [PMID: 36563451 DOI: 10.1016/j.jss.2022.11.053] [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: 03/01/2022] [Revised: 11/17/2022] [Accepted: 11/20/2022] [Indexed: 12/24/2022]
Abstract
INTRODUCTION This study aimed to determine whether surgical stabilization of rib fractures (SSRF) is associated with worse outcomes in individuals with multicompartmental injuries. MATERIALS AND METHODS A retrospective review of a prospective trauma registry was performed for adult blunt trauma patients (aged ≥ 18 y) with Injury Severity Score ≥ 15 and radiographic evidence of rib fractures (2015-2020). Individuals without concomitant head, abdomen/pelvis, or lower extremity Abbreviated Injury Scale scores ≥ 3 were excluded. Propensity match on demographic and clinical variables was performed comparing patients treated nonoperatively (NO) to those undergoing SSRF. A chart review was performed for additional data. Primary outcome was hospital length of stay (LOS). Secondary outcomes were in-hospital mortality, intensive care unit LOS, and duration of mechanical ventilation. RESULTS One thousand nine hundred ninety three patients fit the inclusion criteria (NO = 1,951, SSRF = 42). After matching, there were 98 in the NO group and 42 in the SSRF group. Mean age was 51 y, 61.4% were male, and 71.4% were of White race. Median time to fixation was 5 d. The SSRF group had more severe chest trauma as evidenced by a higher RibScore (3.2 versus 1.7, P < 0.001) and had a longer LOS (18 versus 9 d, P < 0.001), intensive care unit LOS (13 versus 3 d, P = 0.007), and duration of mechanical ventilation (8 versus 2 d, P = 0.013) on univariate analysis. Multivariable regression analysis demonstrated no association between SSRF and these short-term outcomes. CONCLUSIONS Despite delayed average time to intervention, SSRF in a trauma-patient population with multicompartmental injuries and competing management priorities is not associated with worse short-term outcomes.
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Affiliation(s)
- Melike N Harfouche
- R Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, Maryland.
| | | | - David T Efron
- R Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, Maryland
| | - Jose J Diaz
- R Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, Maryland
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13
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Kapelios CJ, Lund LH, Benson L, Dahlström U, Rosano GMC, Hauptman PJ, Savarese G. Digoxin use in contemporary heart failure with reduced ejection fraction: an analysis from the Swedish Heart Failure Registry. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2022; 8:756-767. [PMID: 34921603 PMCID: PMC9716867 DOI: 10.1093/ehjcvp/pvab079] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/05/2021] [Accepted: 11/17/2021] [Indexed: 02/07/2023]
Abstract
AIMS Digoxin is included in some heart failure (HF) guidelines but controversy persists about the true role for and impact of treatment with this drug, particularly in the absence of atrial fibrillation (AF). The aim of this study was to assess the association between clinical characteristics and digoxin use and between digoxin use and mortality/morbidity in a large, contemporary cohort of patients with HF with reduced ejection fraction (HFrEF) stratified by history of AF. METHODS AND RESULTS Patients with HFrEF (EF < 40%) enrolled in the Swedish HF registry between 2005 and 2018 were analysed. The independent association between digoxin use and patient characteristics was assessed by logistic regression, and between digoxin use and outcomes [composite of all-cause mortality or HF hospitalization (HFH), all-cause mortality, and HFH] by Cox regressions in a 1:1 propensity score matched population. Digoxin use was analysed at baseline and as a time-dependent variable. Of 42 456 patients with HFrEF, 16% received digoxin, 29% in the AF group and 2.8% in the non-AF group. The main independent predictors of use were advanced HF, higher heart rate, history of AF, preserved renal function, and concomitant use of beta blockers. Digoxin use was associated with lower risk of all-cause death/HFH [hazard ratio (HR): 0.95; 95% confidence interval (CI): 0.91-0.99] in AF, but with higher risk in non-AF (HR: 1.24; 95% CI: 1.09-1.43). Consistent results were observed when digoxin use was analysed as a time-dependent variable. CONCLUSION The great majority of digoxin users had a history of AF. Digoxin use was associated with lower mortality/morbidity in patients with AF, but with higher mortality/morbidity in patients without AF.
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Affiliation(s)
- Chris J Kapelios
- Cardiology Department, Royal Brompton Hospital, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Lars H Lund
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
| | - Lina Benson
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ulf Dahlström
- Department of Cardiology and Department of Health, Medicine and Caring Sciences, Linköping University, Linkoping, Sweden
| | - Giuseppe M C Rosano
- Cardiovascular Clinical Academic Group, St George's Hospitals NHS Trust, University of London, Cranmer Terrace, London, UK
- IRCCS San Raffaele, Pisana, Roma, Italy
| | - Paul J Hauptman
- Graduate School of Medicine, University of Tennessee, Knoxville, TN, USA
| | - Gianluigi Savarese
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
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14
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Botis M, Kartas A, Samaras A, Akrivos E, Vrana E, Liampas E, Papazoglou AS, Moysidis DV, Papanastasiou A, Baroutidou A, Karvounis H, Tzikas A, Parissis J, Drakos SG, Giannakoulas G. Clinical Outcomes in Patients with Atrial Fibrillation treated with Digoxin, according to the presence of Heart Failure: Insights from the MISOAC- AF trial. Hellenic J Cardiol 2022; 68:25-32. [PMID: 36037999 DOI: 10.1016/j.hjc.2022.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 08/12/2022] [Accepted: 08/21/2022] [Indexed: 11/18/2022] Open
Affiliation(s)
- Michail Botis
- First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Anastasios Kartas
- First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Athanasios Samaras
- First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Evangelos Akrivos
- Laboratory of Computing, Medical Informatics and Biomedical Imaging Technologies, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Elena Vrana
- First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Evangelos Liampas
- First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Andreas S Papazoglou
- First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Dimitrios V Moysidis
- First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Anastasios Papanastasiou
- First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Amalia Baroutidou
- First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Haralambos Karvounis
- First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Apostolos Tzikas
- First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece; Interbalkan European Medical Center, Asklipiou 10, Pylaia, Thessaloniki, Greece
| | - John Parissis
- Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavros G Drakos
- Division of Cardiovascular Medicine & Nora Eccles Harrison Cardiovascular Research & Training Institute, University of Utah, Salt Lake City, UT, USA
| | - George Giannakoulas
- First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece.
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15
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Doshchitsin VL, Tarzimanova AI. Historical Aspects of the Use of Antiarrhythmic Drugs in Clinical Practice. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2022; 18:350-358. [DOI: 10.20996/1819-6446-2022-06-07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025] Open
Abstract
Heart rhythm disorders are one of the most urgent problems in cardiology. The first reports on the possibility of using drugs in the treatment of cardiac arrhythmias began to appear in the scientific literature from the middle of the 18th century. This pharmacotherapeutic direction has been developed since the second half of the 20th century, when new antiarrhythmic drugs began to be used in clinical practice. The introduction of new drugs and modern methods of treating arrhythmias into clinical practice has significantly improved the prognosis and quality of life of patients. Combination antiarrhythmic therapy, including antiarrhythmic drugs and radiofrequency ablation, seems to be the most promising and successful tactic for treating patients in the future. A historical review of the literature on the clinical use of antiarrhythmic drugs both in past years and at present is presented in the article.
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Affiliation(s)
| | - A. I. Tarzimanova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
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16
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Kytö V, Saraste A, Rautava P, Tornio A. Digoxin use and outcomes after myocardial infarction in patients with atrial fibrillation. Basic Clin Pharmacol Toxicol 2022; 130:655-665. [PMID: 35420260 PMCID: PMC9321089 DOI: 10.1111/bcpt.13733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/27/2022] [Accepted: 04/11/2022] [Indexed: 12/04/2022]
Abstract
Digoxin is used for rate control in atrial fibrillation (AF), but evidence for its efficacy and safety after myocardial infarction (MI) is scarce and mixed. We studied post-MI digoxin use effects on AF patient outcomes in a nationwide registry follow-up study in Finland. Digoxin was used by 18.6% of AF patients after MI, with a decreasing usage trend during 2004-2014. Baseline differences in digoxin users (n = 881) and controls (n = 3898) were balanced with inverse probability of treatment weight adjustment. The median follow-up was 7.4 years. Patients using digoxin after MI had a higher cumulative all-cause mortality (77.4% vs. 72.3%; hazard ratio [HR]: 1.19; confidence interval [CI]: 1.07-1.32; p = 0.001) during a 10-year follow-up. Mortality differences were detected in a subgroup analysis of patients without baseline heart failure (HF) (HR: 1.23; p = 0.019) but not in patients with baseline HF (HR: 1.05; p = 0.413). Cumulative incidences of HF hospitalizations, stroke and new MI were similar between digoxin group and controls. In conclusion, digoxin use after MI is associated with increased mortality but not with HF hospitalizations, new MI or stroke in AF patients. Increased mortality was detected in patients without baseline HF. Results suggest caution with digoxin after MI in AF patients, especially in the absence of HF.
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Affiliation(s)
- Ville Kytö
- Heart CenterTurku University Hospital and University of TurkuTurkuFinland
- Research Center of Applied and Preventive Cardiovascular MedicineUniversity of TurkuTurkuFinland
- Center for Population Health ResearchTurku University Hospital and University of TurkuTurkuFinland
- Administrative CenterHospital District of Southwest FinlandTurkuFinland
- Department of Public HealthUniversity of HelsinkiHelsinkiFinland
| | - Antti Saraste
- Heart CenterTurku University Hospital and University of TurkuTurkuFinland
| | - Päivi Rautava
- Department of Public HealthUniversity of TurkuTurkuFinland
- Turku Clinical Research CentreTurku University HospitalTurkuFinland
| | - Aleksi Tornio
- Integrative Physiology and Pharmacology, Institute of BiomedicineUniversity of TurkuTurkuFinland
- Unit of Clinical PharmacologyTurku University HospitalTurkuFinland
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17
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Koniari I, Artopoulou E, Velissaris D, Mplani V, Anastasopoulou M, Kounis N, de Gregorio C, Tsigkas G, Karunakaran A, Plotas P, Ikonomidis I. Pharmacologic Rate versus Rhythm Control for Atrial Fibrillation in Heart Failure Patients. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:743. [PMID: 35744006 PMCID: PMC9228123 DOI: 10.3390/medicina58060743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/25/2022] [Accepted: 05/26/2022] [Indexed: 11/24/2022]
Abstract
Atrial fibrillation (AF) and Heart failure (HF) constitute two frequently coexisting cardiovascular diseases, with a great volume of the scientific research referring to strategies and guidelines associated with the best management of patients suffering from either of the two or both of these entities. The common pathophysiological paths, the adverse outcomes, the hospitalization rates, and the mortality rates that occur from various reports and trials indicate that a targeted therapy to the common background of these cardiovascular conditions may reverse the progression of their interrelating development. Among other optimal treatments concerning the prevalence of both AF and HF, the introduction of rhythm and rate control strategies in the guidelines has underlined the importance of sinus rhythm and heart rate control in the prevention of deleterious complications. The use of these strategies in the clinical practice has led to a debate about the superiority of rhythm versus rate control. The current guidelines as well as the published randomized trials and studies have not proved that rhythm control is more beneficial than the rate control treatments in the terms of survival, all-cause mortality, hospitalization rates, and quality of life. Therefore, the current therapeutic strategy is based on the therapy guidelines and the clinical judgment and experience. The aim of this review was to elucidate the endpoints of pharmacologic randomized clinical trials and the clinical data of each antiarrhythmic or rate-limiting medication, so as to promote their effective, individualized, evidence-based clinical use.
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Affiliation(s)
- Ioanna Koniari
- Department of Cardiology, University Hospital of South Manchester NHS Foundation Trust, Manchester M23 9LT, UK; (I.K.); (A.K.)
| | - Eleni Artopoulou
- Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (E.A.); (D.V.)
| | - Dimitrios Velissaris
- Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (E.A.); (D.V.)
| | - Virginia Mplani
- Department of Cardiology, University Hospital of Patras, 26504 Patras, Greece; (V.M.); (M.A.); (N.K.); (G.T.)
| | - Maria Anastasopoulou
- Department of Cardiology, University Hospital of Patras, 26504 Patras, Greece; (V.M.); (M.A.); (N.K.); (G.T.)
| | - Nicholas Kounis
- Department of Cardiology, University Hospital of Patras, 26504 Patras, Greece; (V.M.); (M.A.); (N.K.); (G.T.)
| | - Cesare de Gregorio
- Department of Clinical and Experimental Medicine Cardiology Unit, University Hospital of Messina, 98125 Messina, Italy;
| | - Grigorios Tsigkas
- Department of Cardiology, University Hospital of Patras, 26504 Patras, Greece; (V.M.); (M.A.); (N.K.); (G.T.)
| | - Arun Karunakaran
- Department of Cardiology, University Hospital of South Manchester NHS Foundation Trust, Manchester M23 9LT, UK; (I.K.); (A.K.)
| | - Panagiotis Plotas
- Laboratory Primary Health Care, School of Health Rehabilitation Sciences, University of Patras, 26504 Patras, Greece;
| | - Ignatios Ikonomidis
- Second Cardiology Department, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
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Abstract
The majority of cardiovascular randomized controlled trials (RCTs) test interventions in selected patient populations under explicitly protocol-defined settings. Although these ‘explanatory’ trial designs optimize conditions to test the efficacy and safety of an intervention, they limit the generalizability of trial findings in broader clinical settings. The concept of ‘pragmatism’ in RCTs addresses this concern by providing counterbalance to the more idealized situation underpinning explanatory RCTs and optimizing effectiveness over efficacy. The central tenets of pragmatism in RCTs are to test interventions in routine clinical settings, with patients who are representative of broad clinical practice, and to reduce the burden on investigators and participants by minimizing the number of trial visits and the intensity of trial-based testing. Pragmatic evaluation of interventions is particularly important in cardiovascular diseases, where the risk of death among patients has remained fairly stable over the past few decades despite the development of new therapeutic interventions. Pragmatic RCTs can help to reveal the ‘real-world’ effectiveness of therapeutic interventions and elucidate barriers to their implementation. In this Review, we discuss the attributes of pragmatism in RCT design, conduct and interpretation as well as the general need for increased pragmatism in cardiovascular RCTs. We also summarize current challenges and potential solutions to the implementation of pragmatism in RCTs and highlight selected ongoing and completed cardiovascular RCTs with pragmatic trial designs. In this Review, Khan and colleagues discuss the benefits and challenges of including pragmatism in the design, conduct and interpretation of randomized controlled trials (RCTs) for cardiovascular disease and highlight selected ongoing and completed cardiovascular RCTs that incorporate a pragmatic design.
Most cardiovascular randomized controlled trials (RCTs) conducted to date have been ‘explanatory’, that is, designed to study the intervention in optimized conditions with selected patient populations and frequent protocolized assessments. Although explanatory RCT designs increase validity, they limit the generalizability of trial findings, whereas a ‘pragmatic’ approach to RCTs yields findings more relevant to real-world practice. In pragmatic RCTs, interventions are tested in patients who are broadly representative of the condition being studied, and the study is aligned with routine clinical care to reduce costs and organizational burden. Although pragmatic RCTs tend to attenuate estimates of treatment effects, they do provide a more realistic understanding of population-level effectiveness and costs than explanatory trials. Pragmatic trials can highlight barriers to the implementation of therapies and are better suited than explanatory RCTs to assessing the effects of implementation strategies and health-care policies at the population level. Widespread implementation of pragmatic trials would require the development of technological infrastructure to collect and share data as well as regulatory guidelines amenable to findings derived from routinely collected data.
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19
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Digoxin Use in Atrial Fibrillation; Insights from National Ambulatory Medical Care Survey. Curr Probl Cardiol 2022:101209. [PMID: 35460684 DOI: 10.1016/j.cpcardiol.2022.101209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 04/13/2022] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To evaluate the characteristics and trends of digoxin use during outpatient visits with atrial fibrillation in the US from 2006 to 2015. METHODS We conducted a retrospective analysis of adult (age ≥18) patient visits to office-based physicians from National Ambulatory Medical Care Survey (NAMCS) database between 2006-2015. The International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify patients with atrial fibrillation. Visits in which digoxin was listed as a medication were analyzed with descriptive statistics. Multivariable logistic regression analysis was used to identify the predictors of digoxin usage. RESULTS Of a weighted sample of 108,113,894 patient visits, 17,617,853 (16.3%) visits included use of digoxin. Patients who used digoxin had a mean age of 75 ± 0.7 years and were predominantly Caucasian (92.56%). Among the patients who used digoxin, 24% had a diagnosis of heart failure. Multivariate analysis showed that the increased likelihood of digoxin utilization was associated with female sex (adjusted odds ratio [aOR] 1.34, 95% CI 1.05-1.71, p = .019), heart failure (aOR 1.51, 95% CI 1.05-1.17, p = .025), and usage of ³5 medications (aOR 5.32, 95% CI 3.67-7.71, p = <0.001). Among the visits with atrial fibrillation, the percentage of visits with digoxin usage decreased from 23% in 2006 to 9% in 2013 and then again increased to 14% in 2015(P-trend <0.001). CONCLUSION This is the first study to examine the use of digoxin in atrial fibrillation patients in a large outpatient setting. During 2006-2015, the percentage of digoxin prescriptions in atrial fibrillation patients has declined. Predictors of digoxin use in atrial fibrillation patients are female sex, congestive heart failure, and higher number of concurrent medications.
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20
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Gerakaris A, Mulita F, Koniari I, Artopoulou E, Mplani V, Tsigkas G, Abo-Elseoud M, Kounis N, Velissaris D. Digoxin Impact on Heart Failure Patients with Atrial Fibrillation. Med Arch 2022; 76:23-28. [PMID: 35422570 PMCID: PMC8976896 DOI: 10.5455/medarh.2022.76.23-28] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 02/25/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Digoxin is a cardiac glycoside, derived from the plant Digitalis purpurea. For many years digitalis has been widely used in the treatment of heart failure (HF), owing to its cardiotonic and neurohormonal effects and atrial fibrillation (AF), due to its parasympathomimetic effect on the AV node. OBJECTIVE The aim of this paper is to evaluate the available evidence on the safety and efficacy of digoxin in patients with HF and AF, by reviewing the pertinent literature. METHODS We conducted a PubMed/MEDLINE and SCOPUS search to evaluate the currently available evidence on the administration of digoxin and its association with all-cause mortality risk in patients with AF and HF. RESULTS Several observational analyses of clinical trials and meta-analyses have shown conflicting results on the safety and efficacy of digoxin administration in patients with AF and HF. According to these results, digoxin should be avoided in patients without HF, as it is associated with worse outcomes. On the other hand, in patients with AF and HF digoxin should be used with caution. CONCLUSION The impact of digoxin on all-cause mortality and adverse effects in these patients remains unclear based on the current evidence. More trials at low risk of bias evaluating the effects of digoxin are needed.
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Affiliation(s)
- Andreas Gerakaris
- Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Francesk Mulita
- Department of Surgery, University Hospital of Patras, Patras, Greece
| | - Ioanna Koniari
- Manchester Heart Institute, Manchester University Foundation Trust, Manchester, United Kingdom
| | - Eleni Artopoulou
- Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Virginia Mplani
- Department of Cardiology, University Hospital of Patras, Patras, Greece
| | - Grigorios Tsigkas
- Department of Cardiology, University Hospital of Patras, Patras, Greece
| | - Mohammed Abo-Elseoud
- Manchester Heart Institute, Manchester University Foundation Trust, Manchester, United Kingdom
| | - Nicholas Kounis
- Department of Cardiology, University Hospital of Patras, Patras, Greece
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21
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Singkham N, Wongsalap Y, Poolpun D, Phetnoo S, Somkhon C. Utilization of Digoxin among Hospitalized Older Patients with Heart Failure and Atrial Fibrillation in Thailand: Prevalence, Associated Factors, and Clinical Outcomes. Ann Geriatr Med Res 2021; 25:260-268. [PMID: 34958732 PMCID: PMC8749041 DOI: 10.4235/agmr.21.0098] [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: 09/03/2021] [Accepted: 12/07/2021] [Indexed: 11/29/2022] Open
Abstract
Background Digoxin is used to control heart rate in patients with heart failure (HF) and atrial fibrillation (AF). However, its use is often limited in older patients, as they are prone to digoxin toxicity. This study aimed to determine the prevalence of digoxin use, investigate the factors associated with digoxin use, and explore the association between digoxin use and clinical outcomes in older Thai patients with HF and AF. Methods This cross-sectional study used data obtained from an electronic medical records database. We performed logistic regression analysis to determine the prevalence of digoxin use at index discharge and the factors associated with its use. The Cox proportional hazard model was used to determine the association of all-cause mortality and HF rehospitalization with digoxin use. Results Of the 640 patients assessed, 107 (16.72%) were prescribed digoxin before discharge. The factors negatively associated with digoxin use included high serum creatinine level (adjusted odds ratio [AOR]=0.38; 95% confidence interval [CI], 0.22–0.65) and ischemic heart disease (IHD) (AOR=0.52; 95% CI, 0.30–0.88). The factors positively associated with digoxin use were the use of diuretics (AOR=2.65; 95% CI, 1.60–4.38) and mineralocorticoid receptor antagonists (MRAs) (AOR=2.24; 95% CI, 1.18–4.27). We observed no significant association between digoxin use and clinical outcomes (adjusted hazard ratio=1.00; 95% CI, 0.77–1.30). Conclusion Digoxin use was prevalent among older patients with HF and AF. Patients with high serum creatinine or IHD were less likely to be prescribed digoxin, whereas those using diuretics or MRAs were more likely to be prescribed digoxin. Although digoxin use was not uncommon among older patients, it was prescribed with caution among Thai patients hospitalized with HF and AF.
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Affiliation(s)
- Noppaket Singkham
- Division of Pharmacy Practice, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,Unit of Excellence on Pharmacogenomic Pharmacokinetic and Pharmacotherapeutic Researches (UPPER), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | - Yuttana Wongsalap
- Division of Pharmacy Practice, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,Unit of Excellence on Pharmacogenomic Pharmacokinetic and Pharmacotherapeutic Researches (UPPER), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | | | - Sirichok Phetnoo
- Division of Pharmacy Practice, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | - Chuthalak Somkhon
- Division of Pharmacy Practice, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
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22
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Abstract
Atrial fibrillation (AF) is one of the main cardiac arrhythmias associated with higher risk of cardiovascular morbidity and mortality. AF can cause adverse symptoms and reduced quality of life. One of the strategies for the management of AF is rate control, which can modulate ventricle rate, alleviate adverse associated symptoms and improve the quality of life. As primary management of AF through rate control or rhythm is a topic under debate, the purpose of this review is to explore the rationale for the rate control approach in managing AF by considering the guidelines, recommendations and determinants for the choice of rate control drugs, including beta blockers, digoxin and non- dihydropyridine calcium channel blockers for patients with AF and other comorbidities and atrioventricular nodal ablation and pacing. Despite the limitations of rate control treatment, which may not be effective in preventing disease progression or in reducing symptoms in highly symptomatic patients, it is widely used for almost all patients with atrial fibrillation. Although rate control is one of the first line management of all patient with atrial fibrillation, several issues remain debateable.
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Affiliation(s)
- Muath Alobaida
- Department of Basic Sciences, Prince Sultan bin Abdulaziz College for Emergency Medical Services, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Abdullah Alrumayh
- Department of Basic Sciences, Prince Sultan bin Abdulaziz College for Emergency Medical Services, King Saud University, Riyadh, Kingdom of Saudi Arabia
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23
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Safety of digoxin in nonagenarian patients with atrial fibrillation: lessons from the Spanish Multicenter Registry. JOURNAL OF GERIATRIC CARDIOLOGY : JGC 2021; 18:809-815. [PMID: 34754292 PMCID: PMC8558738 DOI: 10.11909/j.issn.1671-5411.2021.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND The association between digoxin and mortality is an unclear issue. In older patients with atrial fibrillation (AF), where use of digoxin is frequent, the evidence of its safety is scarce. Our aim is to assess the safety of digoxin in nonagenarian patients with AF. METHODS We evaluated data from 795 nonagenarian patients with non-valvular AF from the Spanish Multicenter Registry. We analyzed the relationship between digoxin and all-cause mortality with the Cox proportional-hazards model. RESULTS Follow-up was 27.7 ± 18.3 months. Mean age was 92.5 ± 3.8 years, and 71% of nonagenarian patients were female. Digoxin was not associated with increased risk of mortality [adjusted hazard ratio (aHR) = 1.16, 95% CI: 0.96−1.41,P = 0.130]. However, we found a significant increase in mortality in the subgroup with estimated glomerular filtration rate (eGFR) < 30 mL/min per 1.73 m 2 (aHR = 2.01, 95% CI: 1.13−3.57,P = 0.018), but not in the other subgroups of eGFR (30−59 mL/min per 1.73 m2 and ≥ 60 mL/min per 1.73 m2). When exploring the risk of mortality according to sex, male subgroup was associated with an increase in mortality (aHR = 1.48, 95% CI: 1.02−2.14,P = 0.041). This was not observed in females subgroup (aHR = 1.03, 95% CI: 0.81−1.29,P = 0.829). Based on the presence or absence of heart failure, we did not find significant differences (aHR = 1.20, 95% CI: 0.87−1.65,P = 0.268 vs. aHR = 1.15, 95% CI: 0.90−1.47,P = 0.273, respectively).
CONCLUSIONS In our large registry of nonagenarian patients with AF, we did not find an association between digoxin and mortality in the total sample. However, in the subgroup analyses, we found an increase in mortality with the use of digoxin in men and in patients with an eGFR < 30 mL/min per 1.73 m 2.
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24
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Ding WY, Boriani G, Marin F, Blomström-Lundqvist C, Potpara TS, Fauchier L, Lip GYH. Outcomes of digoxin vs. beta-blocker in AF: report from ESC-EHRA EORP-AF Long-Term General Registry. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2021; 8:372-382. [PMID: 34665249 DOI: 10.1093/ehjcvp/pvab076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/15/2021] [Accepted: 10/12/2021] [Indexed: 11/13/2022]
Abstract
BACKGROUND The safety of digoxin therapy in atrial fibrillation (AF) remains ill-defined. We aimed to evaluate the effects of digoxin over beta-blocker therapy in AF. METHODS Patients with AF who were treated with either digoxin or beta-blocker from the ESC-EHRA EORP-AF General Long-Term Registry were included. Outcomes of interest were all-cause mortality, cardiovascular (CV) mortality, non-CV mortality, quality of life and number of patients with unplanned hospitalisations. RESULTS Of 6377 patients, 549(8.6%) were treated with digoxin. Over 24 months, there were 550(8.6%) all-cause mortality events and 1304(23.6%) patients with unplanned emergency hospitalisations. Compared to beta-blocker, digoxin therapy was associated with increased all-cause mortality (HR 1.90 [95%CI,1.48-2.44], CV mortality (HR 2.18 [95%CI,1.47-3.21] and non-CV mortality (HR 1.68 [95%CI,1.02-2.75] with reduced quality of life (Health Utility Score 0.555[±0.406] vs. 0.705[±0.346], P<0.001) but no differences in emergency hospitalisations (HR 1.00 [95%CI,0.56-1.80]) or AF-related hospitalisations (HR 0.95 [95%CI,0.60-1.52]).On multivariable analysis, there were no differences in any of the outcomes between both groups, after accounting for potential confounders. Similar results were obtained in the subgroups of patients with permanent AF and coexisting heart failure. There was no differences in outcomes between AF patients receiving digoxin with and without chronic kidney disease. CONCLUSION Poor outcomes related to the use of digoxin over beta-blocker therapy in terms of excess mortality and reduced quality of life are associated with the presence of other risk factors rather than digoxin per se. The choice of digoxin or beta-blocker therapy had no influence on the incidence of unplanned hospitalisations.
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Affiliation(s)
- Wern Yew Ding
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom
| | - Giuseppe Boriani
- Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy
| | - Francisco Marin
- Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, University of Murcia, CIBERCV, Murcia, Spain
| | | | - Tatjana S Potpara
- School of Medicine, University of Belgrade, Belgrade, Serbia.,Intensive Arrhythmia Care, Cardiology Clinic, Clinical Center of Serbia, Belgrade, Serbia
| | - Laurent Fauchier
- Service de Cardiologie, Centre Hospitalier Universitaire Trousseau, Tours, France
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom.,Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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25
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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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26
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Review of the 2020 ESC Guidelines for the Diagnosis and Management of Atrial Fibrillation-What Has Changed and How Does This Affect Daily Practice. J Clin Med 2021; 10:jcm10173922. [PMID: 34501370 PMCID: PMC8432123 DOI: 10.3390/jcm10173922] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/18/2021] [Accepted: 08/27/2021] [Indexed: 01/01/2023] Open
Abstract
The high prevalence of atrial fibrillation (AF) in the overall population and its association with substantial morbidity, increased mortality and health care cost has instigated significant basic and clinical research efforts over recent years. The publication of multiple new high-quality randomized multi-center trials in the area of AF management and the rapidly evolving technological progress in terms of diagnostic possibilities and catheter ablation in recent years demanded a revision of the previous ESC AF Guidelines from 2016. The 2020 guidelines provide up-to-date, evidence-based guidance for the management of AF. One of the most important innovations is the presentation of a new concept for structural characterization of AF (the “4S AF scheme”) replacing the traditional classification based on its temporal pattern alone (paroxysmal-persistent-permanent). The 4S-AF-scheme highlights the importance of systematic assessment of stroke risk, severity of symptoms, total AF burden and underlying substrate as the foundation for effective and individualized AF treatment for each and every patient. Further novelties relate to the presentation of an easy and intuitive management pathway (“ABC pathway”) and strengthening the recommendations for early rhythm control, in particular the role of first line catheter ablation in heart failure. Another core component of the guidelines is the focus on patient involvement to achieve optimal outcomes. Patient education, shared decision making and incorporation of patient values and patient reported outcome of treatment interventions as well as integrated care by a multidisciplinary team all have a central role in the proposed management pathway for AF.
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27
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Kempf T, Bauersachs J, Bavendiek U. Eisen und Digitalis bei Herzinsuffizienz. AKTUELLE KARDIOLOGIE 2021. [DOI: 10.1055/a-1472-0114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
ZusammenfassungNeben der medikamentösen Standardtherapie der Herzinsuffizienz (HI) gilt es, Patienten zu identifizieren, die von einer Eisensupplementation oder Therapie mit Digitalis profitieren können. Wir haben die aktuelle Evidenz für diese Therapien zusammengestellt und beschreiben, wie die HI-Therapie mit Eisen und Digitalis individualisiert werden kann. Eine Eisensupplementation verbessert Leistungsfähigkeit, Symptome und Lebensqualität bei Patienten mit symptomatischer Herzinsuffizienz und Eisenmangel. Die Daten aus der unlängst publizierten AFFIRM-AHF-Studie zeigen, dass eine Eisentherapie mit Eisencarboxymaltose zudem HI-Hospitalisationen verhindert. Die Therapie mit Digitalis sollte bei fortgeschrittenen Stadien der Herzinsuffizienz mit reduzierter systolischer Funktion trotz leitliniengerechter Pharmako- und Devicetherapie in Erwägung gezogen werden, insbesondere, wenn diese aufgrund von Komorbiditäten nur eingeschränkt möglich ist. Auch bei koexistentem Vorhofflimmern
ist Digitalis zur Herzfrequenzkontrolle von großem Wert. Serumkonzentrationen von Digitalis im niedrigen therapeutischen Bereich sind anzustreben.
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Affiliation(s)
- Tibor Kempf
- Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Johann Bauersachs
- Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Udo Bavendiek
- Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Deutschland
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28
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Kitaoka H, Tsutsui H, Kubo T, Ide T, Chikamori T, Fukuda K, Fujino N, Higo T, Isobe M, Kamiya C, Kato S, Kihara Y, Kinugawa K, Kinugawa S, Kogaki S, Komuro I, Hagiwara N, Ono M, Maekawa Y, Makita S, Matsui Y, Matsushima S, Sakata Y, Sawa Y, Shimizu W, Teraoka K, Tsuchihashi-Makaya M, Ishibashi-Ueda H, Watanabe M, Yoshimura M, Fukusima A, Hida S, Hikoso S, Imamura T, Ishida H, Kawai M, Kitagawa T, Kohno T, Kurisu S, Nagata Y, Nakamura M, Morita H, Takano H, Shiga T, Takei Y, Yuasa S, Yamamoto T, Watanabe T, Akasaka T, Doi Y, Kimura T, Kitakaze M, Kosuge M, Takayama M, Tomoike H. JCS/JHFS 2018 Guideline on the Diagnosis and Treatment of Cardiomyopathies. Circ J 2021; 85:1590-1689. [PMID: 34305070 DOI: 10.1253/circj.cj-20-0910] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Hiroaki Kitaoka
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | | | - Toru Kubo
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Tomomi Ide
- Department of Cardiovascular Medicine, Kyushu University
| | | | - Keiichi Fukuda
- Department of Cardiology, Keio University School of Medicine
| | - Noboru Fujino
- Department of Cardiovascular and Internal Medicine, Kanazawa University, Graduate School of Medical Science
| | - Taiki Higo
- Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences
| | | | - Chizuko Kamiya
- Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center
| | - Seiya Kato
- Division of Pathology, Saiseikai Fukuoka General Hospital
| | | | | | | | - Shigetoyo Kogaki
- Department of Pediatrics and Neonatology, Osaka General Medical Center
| | - Issei Komuro
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
| | | | - Minoru Ono
- Department of Cardiac Surgery, The University of Tokyo Hospital
| | - Yuichiro Maekawa
- Division of Cardiology, Internal Medicine III, Hamamatsu University School of Medicine
| | - Shigeru Makita
- Department of Cardiac Rehabilitation, Saitama International Medical Center, Saitama Medical University
| | - Yoshiro Matsui
- Department of Cardiac Surgery, Hanaoka Seishu Memorial Hospital
| | | | - Yasushi Sakata
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
| | - Yoshiki Sawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine
| | - Wataru Shimizu
- Department of Cardiovascular Medicine, Nippon Medical School
| | | | | | | | - Masafumi Watanabe
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine
| | - Michihiro Yoshimura
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine
| | | | - Satoshi Hida
- Department of Cardiovascular Medicine, Tokyo Medical University
| | - Shungo Hikoso
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
| | | | | | - Makoto Kawai
- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine
| | - Toshiro Kitagawa
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences
| | - Takashi Kohno
- Department of Cardiovascular Medicine, Kyorin University School of Medicine
| | - Satoshi Kurisu
- Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences
| | - Yoji Nagata
- Division of Cardiology, Fukui CardioVascular Center
| | - Makiko Nakamura
- Second Department of Internal Medicine, University of Toyama
| | - Hiroyuki Morita
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
| | - Hitoshi Takano
- Department of Cardiovascular Medicine, Nippon Medical School Hospital
| | - Tsuyoshi Shiga
- Department of Clinical Pharmacology and Therapeutics, The Jikei University School of Medicine
| | | | - Shinsuke Yuasa
- Department of Cardiology, Keio University School of Medicine
| | - Teppei Yamamoto
- Department of Cardiovascular Medicine, Nippon Medical School
| | - Tetsu Watanabe
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine
| | - Takashi Akasaka
- Department of Cardiovascular Medicine, Wakayama Medical University
| | | | - Takeshi Kimura
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
| | | | - Masami Kosuge
- Division of Cardiology, Yokohama City University Medical Center
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29
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Bode N, Hochadel M, Andresen D, Zahn R, Spitzer SG, Brachmann J, Stellbrink C, Jung W, Gonska BD, Reinke F, Senges J, Eckardt L. Cardiac glycosides are not associated with increased mortality or hospitalization rates in ICD and CRT-ICD patients after adjustment for baseline-characteristics at one-year follow-up: Results from the German DEVICE registry. Int J Cardiol 2021; 338:109-114. [PMID: 34087337 DOI: 10.1016/j.ijcard.2021.05.047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/23/2021] [Accepted: 05/26/2021] [Indexed: 12/28/2022]
Abstract
AIMS Despite lacking supporting randomized trials, cardiac glycosides (CGs) are widely used in heart failure and/or atrial fibrillation. Moreover, several pro- and retrospective studies and registry-data have recently raised serious concerns in terms of efficacy and safety of CGs in this field. We have therefore examined the association between CGs and clinical outcome of implantable cardioverter-defibrillator (ICD) and cardiac resynchronization (CRT-ICD) patients of the large German DEVICE registry. METHODS AND RESULTS Between 2007 and 2014, 3782 ICD and 1529 CRT-ICD patients were enrolled in the German DEVICE registry. Those two groups were analyzed independently according to medication with or without CGs. After adjustment for patient characteristics, CGs were not significantly associated with increased one-year mortality (HR 1.27, 95%-CI 0.91-1.76, p = 0.162), major adverse cardiac and cerebrovascular events (OR 1.36, 95%-CI 0.98-1.89, p = 0.063), ICD-shocks (OR 1.29, 95%-CI 0.95-1.74, p = 0.104) or the need for rehospitalization in ICD patients at one-year-follow-up. Similar findings were obtained in CRT-ICD patients. Regarding possible determinants for glycoside treatment, atrial fibrillation at enrollment was found to be most strongly associated with the prescription of glycosides in ICD (adjusted OR 3.25, 95%-CI 2.63-4.02) and CRT-ICD patients (adjusted OR 3.17, 95%-CI 2.39-4.19). CONCLUSION Overall harmful effects of CGs in ICD- and CRT-ICD patients could not be confirmed in DEVICE. Further large and randomized-controlled trials that investigate dose-dependent effects of CGs in addition to contemporary therapy of heart failure and atrial fibrillation are needed.
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Affiliation(s)
- Niklas Bode
- Clinic for Cardiology II - Electrophysiology, University Hospital Münster, Münster, Germany.
| | - Matthias Hochadel
- Stiftung Institut für Herzinfarktforschung (IHF), Ludwigshafen am Rhein, Germany
| | - Dietrich Andresen
- Department of Cardiology, Evangelisches Krankenhaus Hubertus, Berlin, Germany
| | - Ralf Zahn
- Department of Cardiology, Klinikum Ludwigshafen, Ludwigshafen, Germany
| | - Stefan G Spitzer
- Praxisklinik Herz und Gefäße, Dresden, Germany; Brandenburgische Technische Universität Cottbus-Senftenberg, Institut für Medizintechnologie, Senftenberg, Germany
| | | | | | - Werner Jung
- Department of Cardiology, Schwarzwald-Baar Klinikum, Villingen-Schwenningen, Germany
| | | | - Florian Reinke
- Clinic for Cardiology II - Electrophysiology, University Hospital Münster, Münster, Germany
| | - Jochen Senges
- Stiftung Institut für Herzinfarktforschung (IHF), Ludwigshafen am Rhein, Germany
| | - Lars Eckardt
- Clinic for Cardiology II - Electrophysiology, University Hospital Münster, Münster, Germany
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30
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Koniari I, Artopoulou E, Velissaris D, Kounis N, Tsigkas G. Atrial fibrillation in patients with systolic heart failure: pathophysiology mechanisms and management. J Geriatr Cardiol 2021; 18:376-397. [PMID: 34149826 PMCID: PMC8185445 DOI: 10.11909/j.issn.1671-5411.2021.05.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023] Open
Abstract
Heart failure (HF) and atrial fibrillation (AF) demonstrate a constantly increasing prevalence during the 21st century worldwide, as a result of the aging population and the successful interventions of the clinical practice in the deterioration of adverse cardiovascular outcomes. HF and AF share common risk factors and pathophysiological mechanisms, creating the base of a constant interrelation. AF impairs systolic and diastolic function, resulting in the increasing incidence of HF, whereas the structural and neurohormonal changes in HF with preserved or reduced ejection fraction increase the possibility of the AF development. The temporal relationship of the development of either condition affects the diagnostic algorithms, the prognosis and the ideal therapeutic strategy that leads to euvolaemia, management of non-cardiovascular comorbidities, control of heart rate or restoration of sinus rate, ventricular synchronization, prevention of sudden death, stroke, embolism, or major bleeding and maintenance of a sustainable quality of life. The indicated treatment for the concomitant HF and AF includes rate or/and rhythm control as well as thromboembolism prophylaxis, while the progress in the understanding of their pathophysiological interdependence and the introduction of the genetic profiling, create new paths in the diagnosis, the prognosis and the prevention of these diseases.
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Affiliation(s)
- Ioanna Koniari
- Manchester Heart Institute, Manchester University Foundation Trust, Manchester, United Kingdom
| | - Eleni Artopoulou
- Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | | | - Nicholas Kounis
- Department of Cardiology, University Hospital of Patras, Patras, Greece
| | - Grigorios Tsigkas
- Department of Cardiology, University Hospital of Patras, Patras, Greece
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Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, Meir ML, Lane DA, Lebeau JP, Lettino M, Lip GY, Pinto FJ, Neil Thomas G, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL. Guía ESC 2020 sobre el diagnóstico y tratamiento de la fibrilación auricular, desarrollada en colaboración de la European Association of Cardio-Thoracic Surgery (EACTS). Rev Esp Cardiol 2021. [DOI: 10.1016/j.recesp.2020.10.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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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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33
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Abdel Jalil M, Abdullah N, Alsous M, Abu-Hammour K. Population Pharmacokinetic Studies of Digoxin in Adult Patients: A Systematic Review. Eur J Drug Metab Pharmacokinet 2021; 46:325-342. [PMID: 33616855 DOI: 10.1007/s13318-021-00672-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
BACKGROUND Digoxin is a cardiac glycoside that was introduced to cardiovascular medicine more than 200 years ago. Its use is associated with large variability, which complicates achieving the desired therapeutic outcomes. OBJECTIVES To present a synthesis of the available literature on the population pharmacokinetics of digoxin in adults and to identify the sources of variability in its pharmacokinetics. METHODS This is a PROSPERO registered systematic review (CRD42018105300). A literature search was conducted using the ISI Web of Science, Science Direct, PubMed, and SCOPUS databases to identify digoxin population pharmacokinetic studies of adults that utilized the nonlinear mixed-effect modeling approach. RESULTS Sixteen articles were included in the present analysis. Only two studies were conducted in elderly subjects as a separate population. Both the pharmacokinetics and pharmacodynamics of digoxin were investigated in one study. Furthermore, the reviewed studies were mostly conducted in East Asian populations (68.8%). Digoxin's pharmacokinetics were usually described by a one-compartment model because of the nature of the collected data. Weight, age, kidney function, presence of heart failure, and co-administered medications such as calcium channel blockers were the most commonly identified predictors of digoxin clearance. The value of apparent clearance in a typical study individual ranged from 0.005 to 0.2 l/h/kg, while the value of the apparent volume of distribution ranged from 3.14 to 15.2 l/kg. The quality of model evaluation was deemed excellent only in 31.3% of the studies. CONCLUSION This review provides information about variables that need to be considered when prescribing digoxin. The results highlight the need for prospective studies that allow two-compartment pharmacokinetic/pharmacodynamic models to be established, with a special focus on the elderly subpopulation.
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Affiliation(s)
- Mariam Abdel Jalil
- Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, University of Jordan, Amman, 11942, Jordan.
| | - Noura Abdullah
- Department of Pharmacology, Faculty of Medicine, University of Jordan, Amman, Jordan
| | - Mervat Alsous
- Department of Pharmacy Practice, Faculty of Pharmacy, Yarmouk University, Irbid, Jordan
| | - Khawla Abu-Hammour
- Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, University of Jordan, Amman, 11942, Jordan
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Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373-498. [PMID: 32860505 DOI: 10.1093/eurheartj/ehaa612] [Citation(s) in RCA: 6352] [Impact Index Per Article: 1588.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Zaman N, Naccarelli G, Foy A. A Comparison of Rate Control Agents for the Treatment of Atrial Fibrillation: Follow-Up Investigation of the AFFIRM Study. J Cardiovasc Pharmacol Ther 2021; 26:328-334. [PMID: 33514292 DOI: 10.1177/1074248420987451] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
There are limited data from randomized controlled trials comparing rate control agents in atrial fibrillation. Patient-level data from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial was used to compare outcomes in patients randomized to the rate control arm who were treated with a single rate control agent at baseline. The rate control agents used were beta-blockers, non-dihydropyridine calcium channel blockers, and digoxin. The independent variable for this analysis was the initial study drug used and the dependent variables were time to first hospitalization and time to death from any cause. We analyzed 1,144 out of 2,027 participants assigned to the rate control group who were on a single rate control agent at the start of the trial. There were 485 (42.5%) participants in the beta-blocker group, 344 (30%) in the calcium channel blocker group, and 315 (27.5%) in the digoxin group. All hospitalization and all-cause mortality occurred in 55.9% and 12.5% of those in the beta-blocker group, 58.4% and 16.7% in the calcium channel blocker group, and 55.2% and 21.1% in the digoxin group, respectively. After adjustment for differences in baseline characteristics, there were no significant differences in time to hospitalization or death for any group. In the AFFIRM trial, the initial rate control drug used was not associated with statistically significant differences in time to hospitalization or death after controlling for differences in baseline characteristics. There is limited data at present to guide the selection of rate control agents in patients with atrial fibrillation.
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Affiliation(s)
- Ninad Zaman
- Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA, USA
| | - Gerald Naccarelli
- Division of Cardiology & The Heart and Vascular Institute, Pennsylvania State College of Medicine, Hershey, PA, USA
| | - Andrew Foy
- Division of Cardiology & The Heart and Vascular Institute, Pennsylvania State College of Medicine, Hershey, PA, USA
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36
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Singh S, Moore H, Karasik PE, Lam PH, Wopperer S, Arundel C, Tummala L, Anker MS, Faselis C, Deedwania P, Morgan CJ, Zeng Q, Allman RM, Fonarow GC, Ahmed A. Digoxin Initiation and Outcomes in Patients with Heart Failure (HFrEF and HFpEF) and Atrial Fibrillation. Am J Med 2020; 133:1460-1470. [PMID: 32603789 DOI: 10.1016/j.amjmed.2020.05.030] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND Digoxin reduces the risk of heart failure hospitalization but has no effect on mortality in patients with heart failure without atrial fibrillation in the randomized controlled trial setting. Observational studies of digoxin use in patients with atrial fibrillation have suggested a higher risk for poor outcomes. Less is known about this association in patients with heart failure and atrial fibrillation, the examination of which was the objective of the current study. METHODS We conducted an observational propensity score-matched study of predischarge digoxin initiation in 1768 hospitalized patients with heart failure and atrial fibrillation in the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry, balanced on 56 baseline characteristics (mean age, 79 years; 55% women; 7% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were estimated for the 884 patients initiated on digoxin compared with 884 not initiated on digoxin. RESULTS HRs (95% CIs) for 30-day, 2-year, and 4-year all-cause mortality were 0.80 (0.55-1.18; P = .261), 0.94 (0.87-1.16; P = .936), and 1.01 (0.90-1.14; P = .729), respectively. Respective HRs (95% CIs) for heart failure readmission were 0.67 (0.49-0.92; P = .014), 0.81 (0.69-0.94; P = .005), and 0.85 (0.74-0.97; P = .022), and those for all-cause readmission were 0.78 (0.64-0.96; P = .016), 0.90 (0.81-1.00; P = .057), and 0.91 (0.83-1.01; P = .603). These associations were homogeneous between patients with left ventricular ejection fraction ≤45% vs >45%. CONCLUSIONS Among hospitalized older patients with heart failure (HFrEF and HFpEF) and atrial fibrillation, initiation of digoxin was associated with a lower risk of heart failure readmission but had no association with mortality.
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Affiliation(s)
- Steven Singh
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC.
| | - Hans Moore
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC
| | - Pamela E Karasik
- Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC
| | - Phillip H Lam
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC; MedStar Washington Hospital Center, Washington, DC
| | - Samuel Wopperer
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC
| | - Cherinne Arundel
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC; George Washington University, Washington, DC
| | - Lakshmi Tummala
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC; George Washington University, Washington, DC
| | - Markus S Anker
- Charité Campus Virchow Klinikum, Berlin, Germany; Charité Campus Benjamin Franklin, Berlin, Germany; Berlin Institute of Health Center for Regenerative Therapies, Germany; German Centre for Cardiovascular Research, Berlin, Germany
| | - Charles Faselis
- Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC
| | - Prakash Deedwania
- Veterans Affairs Medical Center, Washington, DC; University of California, San Francisco
| | - Charity J Morgan
- Veterans Affairs Medical Center, Washington, DC; University of Alabama at Birmingham
| | - Qing Zeng
- Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC
| | - Richard M Allman
- George Washington University, Washington, DC; University of Alabama at Birmingham
| | | | - Ali Ahmed
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC; George Washington University, Washington, DC.
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37
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Wang QC, Wang ZY. Big Data and Atrial Fibrillation: Current Understanding and New Opportunities. J Cardiovasc Transl Res 2020; 13:944-952. [PMID: 32378163 DOI: 10.1007/s12265-020-10008-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 04/16/2020] [Indexed: 10/24/2022]
Abstract
Atrial fibrillation (AF) is the most common arrhythmia with diverse etiology that remarkably relates to high morbidity and mortality. With the advancements in intensive clinical and basic research, the understanding of electrophysiological and pathophysiological mechanism, as well as treatment of AF have made huge progress. However, many unresolved issues remain, including the core mechanisms and key intervention targets. Big data approach has produced new insights into the improvement of the situation. A large amount of data have been accumulated in the field of AF research, thus using the big data to achieve prevention and precise treatment of AF may be the direction of future development. In this review, we will discuss the current understanding of big data and explore the potential applications of big data in AF research, including predictive models of disease processes, disease heterogeneity, drug safety and development, precision medicine, and the potential source for big data acquisition. Grapical abstract.
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Affiliation(s)
- Qian-Chen Wang
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, China
| | - Zhen-Yu Wang
- Department of Cardiovascular Medicine, the Second Xiangya Hospital, Central South University, No.139 Renmin Road, Changsha, Hunan, China.
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38
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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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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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40
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Shao XH, Yang YM, Zhu J, Yu LT, Liu LS. Increased mortality in patients with secondary diagnosis of atrial fibrillation: Report from Chinese AF registry. Ann Noninvasive Electrocardiol 2020; 25:e12774. [PMID: 32667718 PMCID: PMC7507354 DOI: 10.1111/anec.12774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/10/2020] [Accepted: 04/21/2020] [Indexed: 11/29/2022] Open
Abstract
Background The relationship between mortality and the primary diagnosis in AF patients is poorly recognized. The purpose of the study is to compare the differences on mortality in patients with a primary or secondary diagnosis of AF and to identify risk factors amenable to treatment. Methods This was a prospective cohort study using data from the Chinese AF registry. For admitted patients, a follow‐up was completed to obtain the outcomes during 1 year. Results A total of 2015 patients with confirmed AF were included. AF was the primary diagnosis in 40.9% (n = 825) of them. 78.9% (n = 939) of the secondary AF diagnosis patients and 55.5% (n = 458) of the primary AF diagnosis patients were sustained AF. Compared with primary AF diagnosis group, the secondary AF diagnosis group was older with more comorbidities. At 1 year, the unadjusted mortality was much higher in the secondary AF diagnosis groups compared with the primary AF diagnosis groups. In Cox regression analysis with adjustment for confounding factors, patients with secondary AF diagnosis were associated with an increased mortality (relative risk 1.723; 95% CI: 1.283 to 2.315, p < .001). On multivariate analysis, age ≥ 75, LVSD, COPD, and diabetes were independent predictors of mortality in patients with primary AF diagnosis, while for the secondary AF diagnosis group, the risk factors were age ≥ 75, heart failure, and previous history of stroke. Conclusions Patients presenting to ED with secondary diagnosis of AF were suffering from higher mortality risks compared with primary AF diagnosis patients. Physicians should distinguish these two groups in clinical practice.
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Affiliation(s)
- Xing-Hui Shao
- Emergency and Intensive Care Center, Fuwai Hospital, Chinese Academy Of Medical Sciences, Beijing, China
| | - Yan-Min Yang
- Emergency and Intensive Care Center, Fuwai Hospital, Chinese Academy Of Medical Sciences, Beijing, China
| | - Jun Zhu
- Emergency and Intensive Care Center, Fuwai Hospital, Chinese Academy Of Medical Sciences, Beijing, China
| | - Li-Tian Yu
- Emergency and Intensive Care Center, Fuwai Hospital, Chinese Academy Of Medical Sciences, Beijing, China
| | - Li-Sheng Liu
- Emergency and Intensive Care Center, Fuwai Hospital, Chinese Academy Of Medical Sciences, Beijing, China
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Grubb A, Mentz RJ. Pharmacological management of atrial fibrillation in patients with heart failure with reduced ejection fraction: review of current knowledge and future directions. Expert Rev Cardiovasc Ther 2020; 18:85-101. [PMID: 32066285 DOI: 10.1080/14779072.2020.1732210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: Both heart failure with reduced ejection fraction (HFrEF) and atrial fibrillation (AF) independently cause significant morbidity and mortality. The two conditions commonly coexist and AF in the setting of HFrEF is associated with worse mortality, hospitalizations, and quality of life compared to HFrEF without AF. Despite the large burden of these conditions, there is no clear optimal management strategy for when they occur together.Areas covered: This review focuses on the pharmacological management of AF in HFrEF. Studies were identified through PubMed search of relevant keywords. The authors review key clinical trials that have influenced management strategies and guidelines. The authors focus on the classes of drugs used to treat AF for both rate and rhythm control strategies including beta-blockers, digoxin, amiodarone, and dofetilide. Additionally, the authors discuss select non-antiarrhythmic medications that affect AF in HFrEF. The authors highlight the strengths and weakness of the data supporting the use of these medications and suggest future directions.Expert opinion: The pharmacological treatment of AF in HFrEF will need further refinement alongside the emerging role of catheter ablation. Novel HF medications and antiarrhythmics offer new tools to prevent the development of AF, as well as for rate and rhythm control strategies.
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Affiliation(s)
- Alex Grubb
- Department of Medicine, Duke University Hospital, Durham, NC, USA
| | - Robert J Mentz
- Division of Cardiology, Department of Medicine, Duke University Hospital, Durham NC, USA.,Duke Clinical Research Institute, Durham NC, USA
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Correa A, Rochlani Y, Aronow WS. Current pharmacotherapeutic strategies for cardiac arrhythmias in heart failure. Expert Opin Pharmacother 2020; 21:339-352. [PMID: 31928092 DOI: 10.1080/14656566.2019.1703950] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 12/09/2019] [Indexed: 12/27/2022]
Abstract
Introduction: Heart failure (HF) affects over 6 million Americans and is the most common cause of hospital readmissions in the United States. Cardiac arrhythmias are common comorbidities seen in patients with HF and are associated with an increase in morbidity and mortality. Pharmacotherapeutic agents along with device and ablation therapies are the mainstays of treatment for cardiac arrhythmias in HF.Areas covered: An extensive literature review of articles and clinical trials on PUBMED on the topic of pharmacotherapy for cardiac arrhythmias in heart failure was conducted. This review article summarizes the above literature to describe the prevalence of the various types of arrhythmias in HF, the recommended pharmacotherapies for the treatment of these arrhythmias in HF and the evidence that supports these recommendations.Expert opinion: Cardiac arrhythmias are common in HF and are the leading cause of death in this patient population. The management of cardiac arrhythmias in HF is challenging. Pharmacotherapy is the primary though increasingly adjunctive therapy for most cardiac arrhythmias. Further, antiarrhythmic drugs must be used with caution in this patient population due to their potential adverse effects.
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Affiliation(s)
- Ashish Correa
- Division of Cardiology, Mount Sinai St. Luke's and Mount Sinai West, New York, NY, USA
| | - Yogita Rochlani
- Division of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
| | - Wilbert S Aronow
- Division of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
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Gao Y, Chang S, Du X, Dong J, Xu X, Zhou Y, Lip GYH, Ma C. Association Between Digoxin Use and Adverse Outcomes Among Patients in the Chinese Atrial Fibrillation Registry. Am J Cardiovasc Drugs 2019; 19:579-587. [PMID: 31077081 DOI: 10.1007/s40256-019-00350-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Digoxin is widely used in patients with atrial fibrillation (AF), but its association with adverse outcomes remains controversial. OBJECTIVE We aimed to assess the association between digoxin and adverse outcomes in Chinese patients with AF. METHODS We used data from the Chinese Atrial Fibrillation Registry, a prospective, multicenter, hospital-based registry study involving 31 hospitals. In total, 10,472 eligible patients with AF, enrolled from August 2011 to December 2016, were included in this study. The association between digoxin use and all-cause mortality, cardiovascular death, and cardiovascular hospitalization were investigated using Cox proportional hazards models. RESULTS In total, 1152 (11%) patients were treated with digoxin at baseline. Patients receiving digoxin were older (mean age 69.7 vs. 66.5 years) and had a higher heart rate (92.4 vs. 79.7 beats/min). A higher proportion of patients receiving digoxin therapy had a history of heart failure (62.5 vs. 15.6%), diabetes mellitus (34.4 vs. 24.4%), and persistent AF (67.9 vs. 38.4%). Digoxin use was independently associated with increased all-cause mortality (adjusted hazard ratio (aHR) 1.21; 95% confidence interval (CI) 1.02-1.43; p = 0.031), cardiovascular death (aHR 1.25; 95% CI 1.01-1.55; p = 0.043), and cardiovascular hospitalization (aHR 1.21; 95% CI 1.05-1.39; p = 0.007). The associations were also homogeneous across various subgroups except in patients with and without renal dysfunction (p value for interaction = 0.029). DISCUSSION In this Chinese AF cohort, for patients who had not undergone ablation, digoxin use was associated with a significant increase in adverse outcomes. Although residual confounders may exist, and serum concentrations of digoxin were unavailable, digoxin should be used with caution in clinical practice, and its effects need to be critically evaluated in randomized trials. CLINICAL TRIAL REGISTRATION URL: http://www.chictr.org.cn/showproj.aspx?proj=5831. Unique identifier: ChiCTR-OCH-13003729.
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Aguirre Dávila L, Weber K, Bavendiek U, Bauersachs J, Wittes J, Yusuf S, Koch A. Digoxin-mortality: randomized vs. observational comparison in the DIG trial. Eur Heart J 2019; 40:3336-3341. [PMID: 31211324 PMCID: PMC6801940 DOI: 10.1093/eurheartj/ehz395] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 03/18/2019] [Accepted: 06/03/2019] [Indexed: 11/12/2022] Open
Abstract
AIMS The Digitalis Investigation Group (DIG) trial, the only large randomized trial of digoxin in heart failure, reported a neutral effect on mortality and a significant reduction in heart failure hospitalizations. Recent observational studies reported increased mortality with digoxin treatment. We present further analyses of the DIG trial displaying the inability to control bias in observational treatment comparisons despite extensive statistical adjustments. METHODS AND RESULTS Forty-four percent of the 6800 patients in the DIG trial had been treated with digoxin before randomization, and half of them were randomly withdrawn from digoxin treatment. We contrast the main randomization-based result of the DIG trial with the observational non-randomized comparison of patients pre-treated or not pre-treated with digoxin. Mortality [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.12-1.34; P < 0.001] and heart failure hospitalizations (HR 1.47, 95% CI 1.33-1.61; P < 0.001) were significantly higher in patients pre-treated with digoxin even after adjustment for baseline population differences. The higher risks for both outcomes in those who had previously received digoxin persisted even if they received placebo during the trial (HR 1.24, 95% CI 1.10-1.40; P < 0.001). This sharply contradicts the neutral effect on mortality and the significant reduction in heart failure hospitalizations observed in the randomized comparison. CONCLUSION Prescription of digoxin is an indicator of disease severity and worse prognosis, which cannot be fully accounted for by covariate adjustments in the DIG trial where patients were well-characterized. It is unlikely that weaker research approaches (observational studies of administrative data or registries) can provide more reliable estimates of the effects of cardiac glycosides.
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Affiliation(s)
- Lukas Aguirre Dávila
- Institute for Biostatistics, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
| | - Kristina Weber
- Institute for Biostatistics, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
| | - Udo Bavendiek
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
| | - Johann Bauersachs
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
| | - Janet Wittes
- Statistics Collaborative, Inc., Washington, DC, USA
| | - Salim Yusuf
- Population Health Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada
| | - Armin Koch
- Institute for Biostatistics, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
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Kodani E, Inoue H, Atarashi H, Okumura K, Yamashita T, Origasa H. Impact of Digitalis Use on Mortality in Japanese Patients With Non-Valvular Atrial Fibrillation - A Subanalysis of the J-RHYTHM Registry. Circ J 2019; 83:1644-1652. [PMID: 31217399 DOI: 10.1253/circj.cj-19-0267] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Because the influence of digitalis use on the death of patients with non-valvular atrial fibrillation (NVAF) remains controversial, a subanalysis of the J-RHYTHM Registry was performed. METHODS AND RESULTS A consecutive series of outpatients with AF from 158 institutions was enrolled and followed for 2 years or until the occurrence of an event. Among 7,406 patients with NVAF, 7,018 (age, 69.7±10.0 years; men, 71.1%) with information on antiarrhythmic drug and digitalis use at baseline were divided into 2 groups based on digitalis use. The influence of digitalis on death was investigated using a propensity score-matching model. In 802 patients treated with digitalis, all-cause death was significantly higher than in 6,216 patients with no digitalis use during the 2-year follow-up period (4.4% vs. 2.4%, unadjusted P<0.001). Digitalis use was significantly associated with all-cause death in the crude model (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.28-2.68, P=0.001). However, after propensity score-matching, the association was not significant (HR 1.31, 95% CI 0.70-2.46, P=0.405). Older age, male sex, heart failure, coronary artery disease, and lower body mass index were significantly associated with all-cause death in NVAF patients treated with digitalis. CONCLUSIONS Digitalis use was not independently associated with all-cause death, and several clinical confounding factors might contribute to increased mortality in NVAF patients treated with digitalis.
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Affiliation(s)
- Eitaro Kodani
- Department of Internal Medicine and Cardiology, Nippon Medical School Tama-Nagayama Hospital
| | | | - Hirotsugu Atarashi
- Department of Internal Medicine and Cardiology, Nippon Medical School Tama-Nagayama Hospital
| | | | | | - Hideki Origasa
- Division of Biostatistics and Clinical Epidemiology, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences
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Atrial Fibrillation Ablation Should Be First-Line Therapy in Heart Failure Patients: CON. Cardiol Clin 2019; 37:197-206. [PMID: 30926021 DOI: 10.1016/j.ccl.2019.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Heart failure (HF) and atrial fibrillation (AF) are the epidemics of the twenty-first century. These often coexist and are the cause of major morbidity and mortality. Management of these patients has posed a significant challenge to the medical community. Guideline-directed pharmacologic therapy for heart failure is important; however, there is no clear consensus on how best to treat AF with concomitant HF. In this article, we provide an in-depth review of the management of AF in patients with HF and provide insight as to why catheter ablation should not be the first line of therapy in this population.
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Stokes MB, Sanders P. Does Left Ventricular Systolic Function Matter? Treating Atrial Fibrillation in HFrEF Versus HFpEF. Cardiol Clin 2019; 37:157-166. [PMID: 30926017 DOI: 10.1016/j.ccl.2019.01.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Atrial fibrillation (AF) and heart failure (HF) pose international health care challenges that contribute significantly to hospitalizations, morbidity, mortality, and significant health care costs. Both AF and HF contribute to the development of each other and both are associated with a worsened prognosis when they occur together. Assessment of systolic function via transthoracic echocardiography is essential in the investigation of the AF patient. Clinical and echocardiographic assessment may classify AF patients with HF into HF with reduced ejection fraction (HF-rEF) and HF with preserved ejection fraction (HF-pEF). Such classification can assist in numerous important management decisions in AF.
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Affiliation(s)
- Michael B Stokes
- Department of Cardiology, South Australian Health and Medical Research Institute, University of Adelaide, Royal Adelaide Hospital, Port Road, Adelaide, South Australia 5000, Australia
| | - Prashanthan Sanders
- Department of Cardiology, Centre for Heart Rhythm Disorders, South Australian Health and Medical Research Institute, University of Adelaide, Royal Adelaide Hospital, Port Road, Adelaide, South Australia 5000, Australia.
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Digitalis therapy is associated with higher comorbidities and poorer prognosis in patients undergoing ablation of atrial arrhythmias: data from the German Ablation Registry. Clin Res Cardiol 2019; 108:1083-1092. [PMID: 30798346 DOI: 10.1007/s00392-019-01442-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 02/18/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Digitalis glycosides are employed for rate control of atrial fibrillation. Recent studies suggested potential harmful effects of digitalis monotherapy and combination with antiarrhythmic drugs. The aim of the present study was to assess the prevalence and potential impact of digitalis therapy on outcome in patients undergoing catheter ablation of supraventricular arrhythmias. METHODS AND RESULTS The German Ablation Registry is a nationwide, prospective registry with a 1-year follow-up investigating 12,566 patients receiving catheter ablations of supraventricular arrhythmias in 52 German centres. The present analysis focussed on pharmacotherapy in 8608 patients undergoing catheter ablation of atrial tachycardia, atrial fibrillation, or atrial flutter. Patients receiving digitalis therapy (n = 417) were older and presented a significantly increased prevalence of comorbidities including coronary artery disease, heart failure, diabetes, and pulmonary disease. One-year mortality was significantly higher in digitalis-treated patients (4.7% vs. 1.3%, p < 0.001), most strikingly in patients undergoing ablation of atrial flutter. This effect was maintained after adjustment for important risk factors. Similar results were obtained for as the combined endpoint of death, myocardial infarction, stroke and major bleeding (6.6% vs. 2.7%, p < 0.001), and non-fatal rehospitalisations (54.1% vs. 45.1%, p = 0.001). CONCLUSION In the present study of patients undergoing catheter ablation of supraventricular arrhythmias, an association of digitalis therapy with increased mortality and an increased rate of other severe adverse events were observed. The results from this 'real-life' registry are consistent with previously published studies. However, whether digitalis therapy promotes a poorer prognosis or may just serve as a marker for this aspect cannot be thoroughly interpreted.
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Beiert T, Schrickel JW. Overexpression of the Na +/Ca 2+exchanger influences ouabain-mediated spontaneous Ca 2+activity but not positive inotropy. Fundam Clin Pharmacol 2019; 33:41-42. [DOI: 10.1111/fcp.12441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Thomas Beiert
- Department of Internal Medicine II; University Hospital Bonn; Sigmund-Freud-Str. 25 53127 Bonn Germany
| | - Jan W. Schrickel
- Department of Internal Medicine II; University Hospital Bonn; Sigmund-Freud-Str. 25 53127 Bonn Germany
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Aguilar M, Nattel S. Clarity and controversy around rate control in AF, the orphan child in AF therapeutics. Int J Cardiol 2018; 287:189-194. [PMID: 30501984 DOI: 10.1016/j.ijcard.2018.11.024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 11/07/2018] [Accepted: 11/08/2018] [Indexed: 12/21/2022]
Abstract
The vast majority of clinical arrhythmia-management research over the past couple of decades has focused on catheter-based therapeutic advances. There has been much less emphasis on rate-control strategies; however, the majority of patients with atrial fibrillation (AF) will require some form of rate-control management, making AF rate-control the single most widely used therapeutic component in AF-patients. While the general principles governing AF rate-control have remained largely unchanged, they are often underappreciated. In addition, a number of important controversies make optimal rate-control therapy sometimes difficult to choose. In this review, we aim to address a number of important areas of controversy in the application of AF rate-control, as well as to discuss aspects that are well understood but often underappreciated. Specific areas of focus include the following: (i) heart rate-targets in patients with preserved left-ventricular ejection fraction and concomitant AF; (ii) the clinical implications of differences in pharmacological mechanisms of action between beta-adrenoceptor and Ca2+-channel blockers; (iii) controversies regarding the safety and use of digoxin in AF; (iv) the implications cardiac resynchronization therapy for rate-control in AF; and (v) controversies surrounding the benefits of rate-control with beta-blockers in patients with reduced left-ventricular ejection fraction and AF.
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Affiliation(s)
- Martin Aguilar
- Research Center, Montreal Heart Institute and Université de Montréal, Canada; Department of Pharmacology and Physiology, Université de Montréal, Canada; Institute of Biomedical Engineering, Université de Montréal, Canada
| | - Stanley Nattel
- Research Center, Montreal Heart Institute and Université de Montréal, Canada; Department of Pharmacology and Therapeutics, McGill University, Canada; Institute of Pharmacology, West German Heart and Vascular Center, University of Duisburg-, Essen, Germany; LIRYC Institute, Bordeaux, France.
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