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Journal Article

Is there a role for digoxin in atrial fibrillation without heart failure

01 Jan 2009-Cardiology Journal (Cardiol J)-Vol. 16, Iss: 5, pp 483-486
TL;DR: The main indications for digoxin in atrial fibrillation are restoration of sinus rhythm, prevention of recurrence and slowing of the ventricular rate, but none of these effects of digoxin have been confirmed in placebo controlled studies.
Abstract: Digoxin remains one of the most frequently prescribed drugs in the management of atrial fibrillation. The main indications for digoxin in atrial fibrillation are restoration of sinus rhythm, prevention of recurrence and slowing of the ventricular rate. However, none of these effects of digoxin have been confirmed in placebo controlled studies. In addition, recent reports suggest increased mortality in patients with atrial fibrillation without heart failure taking digoxin. The aim of this article is to review the role of digoxin in atrial fibrillation without heart failure.

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Citations
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Journal ArticleDOI
TL;DR: In patients with AF taking digoxin, the risk of death was independently related to serum digoxin concentration and was highest in patients with concentrations ≥1.2 ng/ml, regardless of heart failure.

143 citations

Journal Article
TL;DR: In this paper, the authors investigated the role of structural remodeling in the progression of atrial fibrillation (AF) and proposed new strategies for prevention and termination of AF based on the knowledge of the mechanisms and time course of AF-induced atrial remodeling.
Abstract: The natural history of atrial fibrillation (AF) is characterized by a gradual worsening with time. The recent finding that AF itself produces changes in atrial function and structure has provided a possible explanation for the progressive nature of this arrhythmia. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to an increase in stability of AF. However, 'domestication of AF' must also depend on a 'second factor' since the persistence of AF continues to increase after electrical remodeling has been completed. Atrial contractile remodeling (loss of contractility) leads to a reduced atrial transport function after cardioversion of AF. An important clinical consequence is that during several days after restoration of sinus rhythm, the risk of atrial thrombus formation is still high. In addition, the reduction of atrial contractility during AF may enhance atrial dilatation which may add to the persistence of AF. Tachycardia-induced structural remodeling takes place in a different time domain (weeks to months). Myolysis probably contributes to the loss of atrial contractile force. Although it might explain the loss of efficacy of pharmacological cardioversion and the development of permanent AF, the role of structural remodeling in the progression of AF is still unclear. Atrial structural remodeling also occurs as a result of heart failure and other underlying cardiovascular diseases. The associated atrial fibrosis might explain intra-atrial conduction disturbances and the susceptibility for AF. Thus, both AF itself and the underlying heart disease are responsible for the development of the arrhythmogenic substrate. New strategies for prevention and termination of AF should be build on our knowledge of the mechanisms and time course of AF-induced atrial remodeling.

109 citations

Journal ArticleDOI
TL;DR: This review highlights an overview of development of carbohydrate-based molecules from others and the authors' lab which have shown promising biological activity against front line diseases.
Abstract: In addition to being valuable source of energy, carbohydrates, one of the main dietary components, are integral parts of the cell. As extra- & intracellular molecules they act as cell surface receptor and also as signaling molecules playing predominant role in molecular recognition and many other cellular processes. The clear understanding of their role in the various important biological events has led to the demand for easy access of diverse glycoconjugates for their complete chemical and biological investigations. Several carbohydrate-based molecules both of synthetic and natural origin are known for their wide range of pharmacological activities and even many of them are clinically used to treat different ailments. Due to their structural diversity in terms of functional groups, ring size and linkages they are valuable scaffolds in drug discovery processes. Because of the hydrophilic nature of monosaccharides they offer good water solubility, optimum pharmacokinetics and decreased toxicity. These naturally occurring molecules have therefore been extensively used to access diverse library of compounds with great chemotherapeutic importance. This review highlights an overview of development of carbohydrate-based molecules from others and our lab which have shown promising biological activity against front line diseases.

74 citations

Journal ArticleDOI
TL;DR: Evidence for benefit exists for CHF with reduced ejection fraction (EF), also referred to as heart failure with reduced EF (HFrEF), especially when considering the combination of mortality, morbidity, and decreased hospitalizations.
Abstract: The history of digitalis is rich and interesting, with the first use usually attributed to William Withering and his study on the foxglove published in 1785. However, some knowledge of plants with digitalis-like effects used for congestive heart failure (CHF) was in evidence as early as Roman times. The active components of the foxglove (Digitalis purpurea and Digitalis lanata) are classified as cardiac glycosides or cardiotonic steroids and include the well-known digitalis leaf, digitoxin, and digoxin; ouabain is a rapid-acting glycoside usually obtained from Strophanthus gratus. These drugs are potent inhibitors of cellular membrane sodium–potassium adenosine triphosphatase (Na+/K+-ATPase). For most of the twentieth century, digitalis and its derivatives, especially digoxin, were the available standard of care for CHF. However, as the century closed, many doubts, especially regarding safety, were raised about their use as other treatments for CHF, such as decreasing the preload of the left ventricle, were developed. Careful attention is needed to maintain the serum digoxin level at ≤ 1.0 ng/ml because of the very narrow therapeutic window of the medication. Evidence for benefit exists for CHF with reduced ejection fraction (EF), also referred to as heart failure with reduced EF (HFrEF), especially when considering the combination of mortality, morbidity, and decreased hospitalizations. However, the major support for using digoxin is in atrial fibrillation (AF) with a rapid ventricular response when a rate control approach is planned. The strongest support of all for digoxin is for its use in rate control in AF in the presence of a marginal blood pressure, since all other rate control medications contribute to additional hypotension. In summary, these days, digoxin appears to be of most use in HFrEF and in AF with rapid ventricular response for rate control, especially when associated with hypotension. The valuable history of the foxglove continues; it has been modified but not relegated to the garden or the medical history book, as some would advocate.

60 citations


Cites background from "Is there a role for digoxin in atri..."

  • ...The main indications for digoxin in AF were previously considered to be restoration of sinus rhythm and prevention of AF recurrence, but this is certainly not the case, and the only potential benefit in AF is rate control via slowing of the ventricular response rate [97]....

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Book ChapterDOI
TL;DR: In this article, the cardinal developments in the synthesis and analysis of biologically significant carbohydrate-based molecules from the leading laboratories, highlighting the certainty of carbohydrates in creating an ideal therapeutic platform for drug discovery and development.
Abstract: Carbohydrates, one of the most abundant classes of biomolecules, are the structural building blocks of genetic materials and vital source of energy. They are integral part of the living cells as they play key roles in many cellular and intracellular interactions in the form of cell surface receptors, signaling molecules, and bacterial adhesives. These roles of carbohydrates underlie their potential as pharmaceutical and diagnostic agents and therefore stimulate the synthetic chemists to develop various facile ways to synthesize diverse eccentric glycoconjugates. Many carbohydrates and their derivatives of natural and synthetic origin are clinically used for treatment of various diseases. The immense structural diversity in terms of functional groups, linkages, and number of rings offers these molecules as a valuable tool for design and development of biologically active glycoconjugates. The promising biological activity of carbohydrate-based entities makes them valuable molecular scaffold after their thorough chemical and biological investigations. The carbohydrate moieties in glycoconjugates impart properties like hydrophilicity and decreased toxicity, which enhance the bioavailability to give the optimum pharmacokinetics. This chapter will abridge the cardinal developments in the synthesis and analysis of biologically significant carbohydrate-based molecules from the leading laboratories, highlighting the certainty of carbohydrates in creating an ideal therapeutic platform for drug discovery and development.

32 citations

References
More filters
Journal ArticleDOI
TL;DR: Artificial maintenance of AF leads to a marked shortening of AERP, a reversion of its physiological rate adaptation, and an increase in rate, inducibility and stability of AF.
Abstract: Background In this study we tested the hypothesis that atrial fibrillation (AF) causes electrophysiological changes of the atrial myocardium which might explain the progressive nature of the arrhythmia. Methods and Results Twelve goats were chronically instrumented with multiple electrodes sutured to the epicardium of both atria. Two to 3 Weeks after implantation, the animals were connected to a fibrillation pacemaker which artificially maintained AF. Whereas during control episodes of AF were short lasting (6±3 seconds), artificial maintenance of AF resulted in a progressive increase in the duration of AF to become sustained (>24 hours) after 7.1±4.8 days (10 of 11 goats). During the first 24 hours of AF the median fibrillation interval shortened from 145±18 to 108±8 ms and the inducibility of AF by a single premature stimulus increased from 24% to 76%. The atrial effective refractory period (AERP) shortened from 146±19 to 95±20 ms (−35%) (S1S1, 400 ms). At high pacing rates the shortening was less (−12%...

3,430 citations


"Is there a role for digoxin in atri..." refers background in this paper

  • ...This suggests that D is associated with a higher rate of recurrence of AF and could be the first step in the development of chronic AF [11, 16]....

    [...]

Journal Article
TL;DR: Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization both overall and for worsening heart failure, which defines more precisely the role of digoxin in the management of chronic heart failure.
Abstract: Background The role of cardiac glycosides in treating patients with chronic heart failure and normal sinus rhythm remains controversial. We studied the effect of digoxin on mortality and hospitalization in a randomized, double-blind clinical trial.Methods In the main trial, patients with left ventricular ejection fractions of 0.45 or less were randomly assigned to digoxin (3397 patients) or placebo (3403 patients) in addition to diuretics and angiotensin-converting-enzyme inhibitors (median dose of digoxin, 0.25 mg per day; average follow-up, 37 months). In an ancillary trial of patients with ejection fractions greater than 0.45, 492 patients were randomly assigned to digoxin and 496 to placebo.Results In the main trial, mortality was unaffected. There were 1181 deaths (34.8 percent) with digoxin and 1194 deaths (35.1 percent) with placebo (risk ratio when digoxin was compared with placebo, 0.99; 95 percent confidence interval, 0.91 to 1.07; P = 0.80). In the digoxin group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure (risk ratio, 0.88; 95 percent confidence interval, 0.77 to 1.01; P = 0.06). There were 6 percent fewer hospitalizations overall in that group than in the placebo group, and fewer patients were hospitalized for worsening heart failure (26.8 percent vs. 34.7 percent; risk ratio, 0.72; 95 percent confidence interval, 0.66 to 0.79; P < 0.001). In the ancillary trial, the findings regarding the primary combined outcome of death or hospitalization due to worsening heart failure were consistent with the results of the main trial.Conclusions Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization both overall and for worsening heart failure. These findings define more precisely the role of digoxin in the management of chronic heart failure. (C) 1997, Massachusetts Medical Society.

2,401 citations

Journal ArticleDOI
TL;DR: Both AF itself and the underlying heart disease are responsible for the development of the arrhythmogenic substrate, and the role of structural remodeling in the progression of AF is still unclear.
Abstract: The natural history of atrial fibrillation (AF) is characterized by a gradual worsening with time. The recent finding that AF itself produces changes in atrial function and structure has provided a possible explanation for the progressive nature of this arrhythmia. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to an increase in stability of AF. However, 'domestication of AF' must also depend on a 'second factor' since the persistence of AF continues to increase after electrical remodeling has been completed. Atrial contractile remodeling (loss of contractility) leads to a reduced atrial transport function after cardioversion of AF. An important clinical consequence is that during several days after restoration of sinus rhythm, the risk of atrial thrombus formation is still high. In addition, the reduction of atrial contractility during AF may enhance atrial dilatation which may add to the persistence of AF. Tachycardia-induced structural remodeling takes place in a different time domain (weeks to months). Myolysis probably contributes to the loss of atrial contractile force. Although it might explain the loss of efficacy of pharmacological cardioversion and the development of permanent AF, the role of structural remodeling in the progression of AF is still unclear. Atrial structural remodeling also occurs as a result of heart failure and other underlying cardiovascular diseases. The associated atrial fibrosis might explain intra-atrial conduction disturbances and the susceptibility for AF. Thus, both AF itself and the underlying heart disease are responsible for the development of the arrhythmogenic substrate. New strategies for prevention and termination of AF should be build on our knowledge of the mechanisms and time course of AF-induced atrial remodeling.

1,339 citations


"Is there a role for digoxin in atri..." refers background in this paper

  • ...This suggests that D is associated with a higher rate of recurrence of AF and could be the first step in the development of chronic AF [11, 16]....

    [...]

Journal ArticleDOI
TL;DR: An “on-treatment” analysis of the relationship of survival to cardiac rhythm and treatment as they changed over time suggests that any beneficial antiarrhythmic effects of AADs are offset by their adverse effects.
Abstract: Background The AFFIRM Study showed that treatment of patients with atrial fibrillation and a high risk for stroke or death with a rhythm-control strategy offered no survival advantage over a rate-control strategy in an intention-to-treat analysis This article reports an "on-treatment" analysis of the relationship of survival to cardiac rhythm and treatment as they changed over time Methods and results Modeling techniques were used to determine the relationships among survival, baseline clinical variables, and time-dependent variables The following baseline variables were significantly associated with an increased risk of death: increasing age, coronary artery disease, congestive heart failure, diabetes, stroke or transient ischemic attack, smoking, left ventricular dysfunction, and mitral regurgitation Among the time-dependent variables, the presence of sinus rhythm (SR) was associated with a lower risk of death, as was warfarin use Antiarrhythmic drugs (AADs) were associated with increased mortality only after adjustment for the presence of SR Consistent with the original intention-to-treat analysis, AADs were no longer associated with mortality when SR was removed from the model Conclusions Warfarin use improves survival SR is either an important determinant of survival or a marker for other factors associated with survival that were not recorded, determined, or included in the survival model Currently available AADs are not associated with improved survival, which suggests that any beneficial antiarrhythmic effects of AADs are offset by their adverse effects If an effective method for maintaining SR with fewer adverse effects were available, it might be beneficial

1,154 citations


"Is there a role for digoxin in atri..." refers background or result in this paper

  • ...In the AFFIRM sub-study [8], patients taking D had a higher mortality than non-digitalized ones (hazard ratio 1....

    [...]

  • ...According to the authors, the lower survival rate in patients taking D was more likely due to an increased risk of death, rather than an adverse D effect [8]....

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Journal ArticleDOI
19 Feb 2003-JAMA
TL;DR: It is demonstrated that higher SDCs were associated with increased mortality and suggested that the effectiveness of digoxin therapy in men with heart failure and a left ventricular ejection fraction of 45% or less may be optimized in the SDC range of 0.5 to 0.8 ng/mL.
Abstract: ContextThe Digitalis Investigation Group (DIG) trial reported that digoxin provided no overall mortality benefit and only a modest reduction in hospitalizations among patients with heart failure and depressed left ventricular systolic function. The clinical outcomes associated with digoxin therapy at different serum concentrations in the DIG trial have not been assessed.ObjectiveTo assess variations in serum digoxin concentration (SDC) and their association with mortality and hospitalization in patients with heart failure.Design, Setting, and PatientsPost hoc analysis of the randomized, double-blinded, placebo-controlled DIG trial, conducted from August 1991 to December 1995, with the main analysis restricted to men with a left ventricular ejection fraction of 45% or less (n = 3782). Patients randomly assigned to receive digoxin were divided into 3 groups based on SDC at 1 month (0.5-0.8 ng/mL, n = 572; 0.9-1.1 ng/mL, n = 322; and ≥1.2 ng/mL, n = 277) and compared with patients randomly assigned to receive placebo (n = 2611).Main Outcome MeasureAll-cause mortality at a mean follow-up of 37 months.ResultsHigher SDCs were associated with increased crude all-cause mortality rates (0.5-0.8 ng/mL, 29.9%; 0.9-1.1 ng/mL, 38.8%; and ≥1.2 ng/mL, 48.0%; P = .006 for trend). Patients with SDCs of 0.5 to 0.8 ng/mL had a 6.3% (95% confidence interval [CI], 2.1%-10.5%) lower mortality rate compared with patients receiving placebo. Digoxin was not associated with a reduction in mortality among patients with SDCs of 0.9 to 1.1 ng/mL (2.6% increase; 95% CI, − 3.0% to 8.3%), whereas patients with SDCs of 1.2 ng/mL and higher had an 11.8% (95% CI, 5.7%-18.0%) higher absolute mortality rate than patients receiving placebo. The association between SDC and mortality persisted after multivariable adjustment (SDC 0.5-0.8 ng/mL hazard ratio [HR] 0.80, 95% CI, 0.68-0.94; SDC 0.9-1.1 ng/mL HR 0.89, 95% CI, 0.74-1.08; SDC ≥1.2 ng/mL HR 1.16, 95% CI, 0.96-1.39; and HR of 1.00 [referent] for placebo).ConclusionsOur findings demonstrate that higher SDCs were associated with increased mortality and suggest that the effectiveness of digoxin therapy in men with heart failure and a left ventricular ejection fraction of 45% or less may be optimized in the SDC range of 0.5 to 0.8 ng/mL.

633 citations


"Is there a role for digoxin in atri..." refers background in this paper

  • ...This assumption, however, was recently challenged by reports suggesting that D has adverse effects on survival in patients with higher than 1.2 ng/mL serum D concentration (SDC) [6] and in those with AF without heart failure [6–10]....

    [...]

  • ...Also, the indications for D, mechanism of heart failure and SDC were unknown....

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  • ...Among important limitations of this study were: SDC was not available, probably not all confounders could be included, and there was no information on renal and left ventricular function....

    [...]

  • ...2 ng/mL serum D concentration (SDC) [6] and in those with AF without heart failure [6–10]....

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