title: Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. Digoxin in patients with permanent atrial fibrillation: data from the RACE II study. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. The effect of digoxin on mortality and morbidity in patients with heart failure. Digoxin reduces 30-day all-cause hospital admission in older patients with chronic systolic heart failure. Digoxin treatment is associated with increased total and cardiovascular mortality in anticoagulated patients with atrial fibrillation. Effects of Digoxin on Morbidity and Mortality in Diastolic Heart Failure: The Ancillary Digitalis Investigation Group Trial Outcomes of a contemporary sample of patients with atrial fibrillation taking digoxin: results from the AFBAR study. Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial. Association of serum digoxin concentration and outcomes in patients with heart failure. The effect of gender on outcome in digitalis-treated heart failure patients. Interaction Between Digoxin and Dronedarone in the PALLAS Trial Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data Relation of digoxin use in atrial fibrillation and the risk of all-cause mortality in patients ≥65 years of age with versus without heart failure. Effect of oral digoxin in high-risk heart failure patients: a pre-specified subgroup analysis of the DIG trial. Sex-based differences in the effect of digoxin for the treatment of heart failure. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. Digoxin in atrial fibrillation: report from the Stockholm Cohort study of Atrial Fibrillation (SCAF)
abstract: BACKGROUND Although digoxin is effective in the treatment of patients with chronic heart failure who are receiving diuretic agents  , it is not clear whether the drug has a role when patients are receiving angiotensin-converting-enzyme inhibitors , as is often the case in current practice . METHODS We studied 178 patients with New York Heart Association class II or III heart failure and left ventricular ejection fractions of 35 percent or less in normal sinus rhythm who were clinical ly stable while receiving digoxin , diuretics , and an angiotensin-converting-enzyme inhibitor ( captopril or enalapril ) .  The patients were r and omly assigned in a double-blind fashion either to continue receiving digoxin ( 85 patients ) or to be switched to placebo ( 93 patients ) for 12 weeks . Otherwise , their medical therapy for heart failure was not changed . RESULTS Worsening heart failure necessitating withdrawal from the study developed in 23 patients switched to placebo , but in only 4 patients who continued to receive digoxin ( P < 0.001 ) . The relative risk of worsening heart failure in the placebo group as compared with the digoxin group was 5.9 ( 95 percent confidence interval , 2.1 to 17.2 ) . All measures of functional capacity deteriorated in the patients receiving placebo as compared with those continuing to receive digoxin ( P = 0.033 for maximal exercise tolerance , P = 0.01 for submaximal exercise endurance , and P = 0.019 for New York Heart Association class ) . In addition , the patients switched from digoxin to placebo had lower quality -of-life scores ( P = 0.04 ) , decreased ejection fractions ( P = 0.001 ) , and increases in heart rate ( P = 0.001 ) and body weight ( P < 0.001 ) . CONCLUSIONS These findings indicate that the withdrawal of digoxin carries considerable risks for patients with chronic heart failure and impaired systolic function who have remained clinical ly stable while receiving digoxin and angiotensin-converting-enzyme inhibitors BACKGROUND The Atrial Fibrillation Follow-up Investigation of Rhythm Management trial showed that digoxin was associated with increased mortality in patients with atrial fibrillation . OBJECTIVES To assess the association of digoxin with cardiovascular ( CV ) morbidity and mortality in patients with permanent atrial fibrillation enrolled in the Dutch Rate Control Efficacy in Permanent AF : A Comparison Between Lenient Versus Strict Rate Control II trial as well as to assess the role of digoxin to achieve heart rate targets . METHODS The primary outcome was a composite of CV morbidity and mortality . Secondary outcomes included CV hospitalization and all-cause mortality or heart failure ( HF ) hospitalization . Of the 614 patients , 608 ( 99 % ) completed the dose-adjustment phase . Outcome events were analyzed from the end of the dose-adjustment phase until the end of follow-up . The median follow-up period was 2.9 years ( interquartile range 2.7 - 3.0 years ) . RESULTS In total , 284 patients ( 46.7 % ) used digoxin after the dose-adjustment phase ( median dosage 0.250 mg ; interquartile range 0.0625 - 0.750 mg ) . These patients were more often women , previously admitted for HF , had an increased left ventricular end-systolic diameter , and more often r and omized to strict rate control . By using Cox proportional hazards regression analysis , the use of digoxin was not associated with an increased risk for the primary and secondary outcomes . For the primary outcome , the 3-year estimated cumulative incidence was 12.9 % vs 13.4 % in the digoxin group vs the no-digoxin group ( unadjusted hazard ratio [ HR ] 0.97 ; 95 % confidence interval [ CI ] 0.62 - 1.52 ) . Incidence was 19.4 % vs. 19.5 % for CV hospitalization ( unadjusted HR 1.00 ; 95 % CI 0.69 - 1.45 ) and 6.6 % vs. 9.9 % for all-cause mortality or HF hospitalization ( unadjusted HR 0.62 ; 95 % CI 0.34 - 1.13 ) in the digoxin group vs the no-digoxin group . CONCLUSION The use of digoxin was not associated with increased morbidity and mortality ACCF : American College of Cardiology Foundation ACCP : American College of Chest Physicians ACS : acute coronary syndrome ACT : Atrial arrhythmia Conversion Trial ADONIS : American – Australian – African trial with DronedarONe In atrial fibrillation or flutter for the maintenance of Sinus rhythm AF : atrial fibrillation AHA : American Heart Association AND ROMEDA : ANtiarrhythmic trial with DROnedarone in Moderate-to-severe congestive heart failure Evaluating morbidity DecreAse APHRS : Asia Pacific Heart Rhythm Society aPTT : activated partial thromboplastin time ARB : angiotensin-receptor blocker ARISTOTLE : Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation ATHENA : A placebo-controlled , double-blind , parallel arm Trial to assess the efficacy of dronedarone 400 mg b.i.d . for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter ATRIA : AnTicoagulation and Risk factors In Atrial fibrillation AVERROES : Apixaban VErsus acetylsalicylic acid ( ASA ) to Reduce the Rate Of Embolic Stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment AVRO : A prospect i ve , r and omized , double-blind , Active-controlled , superiority study of Vernakalant vs. amiodarone in Recent Onset atrial fibrillation b.i.d : bis in die ( twice daily ) b.p.m . : beats per minute CABANA : Catheter ABlation vs . ANtiarrhythmic drug therapy for Atrial fibrillation CABG : coronary artery bypass graft CAP : Continued Access to Protect AF CHA2DS2-VASc : Congestive heart failure or left ventricular dysfunction Hypertension , Age ≥75 ( doubled ) , Diabetes , Stroke (doubled)-Vascular disease , Age 65–74 , Sex category ( female ) CHADS2 : Congestive heart failure , Hypertension , Age ≥75 , Diabetes , Stroke ( doubled ) CI : confidence interval CRAFT : Controlled R and omized Atrial Fibrillation Trial CrCl : creatinine clearance DAFNE : Dronedarone Atrial FibrillatioN study after Electrical cardioversion DIONYSOS : R and omized Double blind trIal to evaluate efficacy and safety of drOnedarone ( 400 mg b.i.d . ) vs . amiodaroNe ( 600 mg q.d . for 28 daYS , then 200 mg qd thereafter ) for at least 6 mOnths for the maintenance of Sinus rhythm in patients with atrial fibrillation EAST : Early treatment of Atrial fibrillation for Stroke prevention Trial EHRA : European Heart Rhythm Association ECG : electrocardiogram EMA : European Medicines Agency ERATO : Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation EURIDIS : EURopean trial In atrial fibrillation or flutter patients receiving Dronedarone for the maIntenance of Sinus rhythm FAST : atrial Fibrillation catheter Ablation vs . Surgical ablation Treatment FDA : Food and Drug Administration Flec-SL : Flecainide Short-Long trial HAS-BLED : Hypertension , Abnormal renal/liver function , Stroke , Bleeding history or predisposition , Labile INR , Elderly , Drugs/alcohol concomitantly HF-PEF : heart failure with preserved ejection fraction HF-REF : heart failure with reduced ejection fraction HR : hazard ratio HRS : Heart Rhythm Society ICH : intracranial haemorrhage INR : international normalized ratio i.v . : intravenous J-RHYTHM : Japanese RHYTHM management trial for atrial fibrillation LAA : left atrial appendage LoE : level of evidence LVEF : left ventricular ejection fraction MANTRA-PAF : Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation NICE : National Institute for Health and Clinical Excellence NOAC : novel oral anticoagulant NSAID : non-steroidal anti-inflammatory drug NYHA : New York Heart Association OAC : oral anticoagulant or oral anticoagulation o.d . : omni die ( every day ) PALLAS : Permanent Atrial fibriLLAtion outcome Study using dronedarone on top of st and ard therapy PCI : percutaneous coronary intervention PREVAIL : Prospect i ve R and omized EVAluation of the LAA closure device In patients with atrial fibrillation v s. Long-term warfarin therapy PROTECT AF : WATCHMAN LAA system for embolic PROTECTion in patients with Atrial Fibrillation PT : prothrombin time RAAFT : Radio frequency Ablation Atrial Fibrillation Trial RE-LY : R and omized Evaluation of Long-term anticoagulant therapY with dabigatran etexilate ROCKET-AF : Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in atrial fibrillation RRR : relative risk reduction TE : thromboembolism TIA : transient ischaemic attack t.i.d . : ter in die ( three times daily ) TOE : transoesophageal echocardiogram TTR : time in therapeutic range VKA : vitamin K antagonist Guidelines summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition , taking into account the impact on 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 r and omized , double-blind clinical trial . METHODS In the main trial , patients with a left ventricular ejection fraction of 0.45 or less were r and omly 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 r and omly 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 BACKGROUND Heart failure is a leading cause of hospital admission and readmission in older adults . The new United States healthcare reform law has created provisions for financial penalties for hospitals with higher than expected 30-day all-cause readmission rates for hospitalized Medicare beneficiaries aged ≥65 years with heart failure . We examined the effect of digoxin on 30-day all-cause hospital admission in older patients with heart failure and reduced ejection fraction . METHODS In the main Digitalis Investigation Group trial , 6800 ambulatory patients with chronic heart failure ( ejection fraction ≤45 % ) were r and omly assigned to digoxin or placebo . Of these , 3405 were aged ≥65 years ( mean age , 72 years ; 25 % were women ; 11 % were nonwhite ) . The main outcome in the current analysis was 30-day all-cause hospital admission . RESULTS In the first 30 days after r and omization , all-cause hospitalization occurred in 5.4 % ( 92/1693 ) and 8.1 % ( 139/1712 ) of patients in the digoxin and placebo groups , respectively , ( hazard ratio { HR } when digoxin was compared with placebo , 0.66 ; 95 % confidence interval { CI } , 0.51 - 0.86 ; P=.002 ) . Digoxin also reduced both 30-day cardiovascular ( 3.5 % vs 6.5 % ; HR , 0.53 ; 95 % CI , 0.38 - 0.72 ; P<.001 ) and heart failure ( 1.7 vs 4.2 % ; HR , 0.40 ; 95 % CI , 0.26 - 0.62 ; P<.001 ) hospitalizations , with similar trends for 30-day all-cause mortality ( 0.7 % vs 1.3 % ; HR , 0.55 ; 95 % CI , 0.27 - 1.11 ; P=.096 ) . Younger patients were at lower risk of events but obtained similar benefits from digoxin . CONCLUSIONS Digoxin  reduces 30-day all-cause hospital admission in ambulatory older patients with chronic systolic heart failure . Future studies need to examine its effect on 30-day all-cause hospital readmission in hospitalized patients with acute heart failure BACKGROUND Some evidence s suggest that the use of digoxin may be harmful inatrial fibrillation ( AF ) patients . The aim of the study was to investigate in a " real world " of AF patients receiving vitamin K antagonists ( VKAs )  , the relationship between digoxin use and mortality . METHODS Prospect i ve single-center observational study including 815 consecutive non-valvular AF patients treated with VKAs .  Total mortality was the primary outcome of the study . We also performed a sub- analysis considering only cardiovascular ( CV ) deaths . Time in therapeutic range ( TTR ) was used for anticoagulation quality . RESULTS Median follow-up was 33.2months ( 2460 person-years ) ; 171 ( 21.0 % ) patients were taking digoxin .  Compared to those without , patients on digoxin were older ( p=0.007 ) , with a clinical history of HF ( p<0.001 ) and at higher risk of thromboembolic events ( p<0.001 ) . No difference in TTR between the two groups was registered ( p=0.598 ) . During the follow-up , 85 deaths occurred : 47 CV and 38 non-CV deaths ; 35 deaths occurred in digoxin users ( 20.6 % ) . A significant increased rate of total mortality was observed in  digoxin-treated  patients ( p<0.001 ) . Multivariable analysis showed that digoxin was associated with total mortality ( hazard ratio [ HR ] : 2.224 , p<0.001 ) and CV death ( HR : 4.686 , p<0.001 ) . A propensity score-matched analysis confirmed that digoxin was associated with total mortality ( HR : 2.073 , p=0.0263 ) and CV death ( HR : 4.043 , p=0.004 ) . CONCLUSIONS In AF patients on good anticoagulation control with VKAs , digoxin use was associated with a higher rate of total and CV mortality Background — About half of the 5 million heart failure patients in the United States have diastolic heart failure ( clinical heart failure with normal or near-normal ejection fraction ) . Except for c and esartan , no drugs have been tested in r and omized clinical trials in these patients . Although digoxin was tested in an appreciable number of diastolic heart failure patients in the Digitalis Investigation Group ancillary trial , detailed findings from this important study have not previously been published . Methods and Results — Ambulatory chronic heart failure patients ( n=988 ) with normal sinus rhythm and ejection fraction > 45 % ( median , 53 % ) from the United States and Canada ( 1991 to 1993 ) were r and omly assigned to digoxin ( n=492 ) or placebo ( n=496 ) . During follow-up with a mean length of 37 months , 102 patients ( 21 % ) in the digoxin group and 119 patients ( 24 % ) in the placebo group ( hazard ratio [ HR ] , 0.82 ; 95 % confidence interval [ CI ] , 0.63 to 1.07 ; P=0.136 ) experienced the primary combined outcome of heart failure hospitalization or heart failure mortality .  Digoxin had no effect on all-cause or cause-specific mortality or on all-cause or cardiovascular hospitalization . Use of digoxin was associated with a trend toward a reduction in hospitalizations result ing from worsening heart failure ( HR , 0.79 ; 95 % CI , 0.59 to 1.04 ; P=0.094 ) but also a trend toward an increase in hospitalizations for unstable angina ( HR , 1.37 ; 95 % CI , 0.99 to 1.91 ; P=0.061 ) . Conclusions — In ambulatory patients with chronic mild to moderate diastolic heart failure and normal sinus rhythm receiving angiotensin-converting enzyme inhibitor and diuretics , digoxin had no effect on natural history end points such as mortality and all-cause or cardiovascular hospitalizations INTRODUCTION AND OBJECTIVES We aim ed to assess and compare the effect of digoxin on clinical outcomes in patients with atrial fibrillation vs those under beta-blockers or none of these drugs . METHODS AFBAR is a prospect i ve registry study carried out by a team of primary care physicians ( n=777 patients ) . Primary endpoints were survival , survival free of admission due to any cause , and survival free of admission due to cardiovascular causes . The mean follow up was 2.9 years . Four groups were analyzed : patients receiving digoxin , beta-blockers , or digoxin plus beta-blockers , and patients receiving none of these drugs . RESULTS Overall , 212 patients ( 27.28 % ) received digoxin as the only heart control strategy , 184 received beta-blockers ( 23.68 % ) , 58 ( 7.46 % ) were administered both , and 323 ( 41.57 % ) received none of these drugs . Digoxin was not associated with all-cause mortality ( estimated hazard ratio=1.42 ; 95 % confidence interval , 0.77 - 2.60 ; P=.2 ) , admission due to any cause ( estimated hazard ratio=1.03 ; 95 % confidence interval , 0.710 - 1.498 ; P=.8 ) , or admission due to cardiovascular causes ( estimated hazard ratio=1.193 ; 95 % confidence interval , 0.725 - 1.965 ; P=.4 ) . No association was found between digoxin use and all-cause mortality , admission due to any cause , or admission due to cardiovascular causes in patients without heart failure . There was no interaction between digoxin use and sex in all-cause mortality or in survival free of admission due to any cause . However , an association was found between sex and admission due to cardiovascular causes . CONCLUSIONS Digoxin was not associated with increased all-cause mortality , survival free of admission due to any cause , or admission due to cardiovascular causes , regardless of underlying heart failure AIMS Digoxin is recommended for long-term rate control in paroxysmal , persistent , and permanent atrial fibrillation ( AF ) . While some analyses suggest an association of digoxin with a higher mortality in AF , the intrinsic nature of this association has not been examined in propensity-matched cohorts , which is the objective of the current study . METHODS AND RESULTS In Atrial Fibrillation Follow-up Investigation of Rhythm Management ( AFFIRM ) , 4060 patients with paroxysmal and persistent AF were r and omized to rate ( n = 2027 ) vs. rhythm ( n = 2033 ) control strategies . Of these , 1377 received digoxin as initial therapy and 1329 received no digoxin at baseline . Propensity scores for digoxin use were estimated for each of these 2706 patients and used to assemble a cohort of 878 pairs of patients receiving and not receiving digoxin , who were balanced on 59 baseline characteristics . Matched patients had a mean age of 70 years , 40 % were women , and 11 % non-white . During the 3.4 years of the mean follow-up , all-cause mortality occurred in 14 and 13 % of matched patients receiving and not receiving digoxin , respectively [ hazard ratio ( HR ) associated with digoxin use : 1.06 ; 95 % confidence interval ( CI ) : 0.83 - 1.37 ; P = 0.640 ] . Among matched patients , digoxin had no association with all-cause hospitalization ( HR : 0.96 ; 95 % CI : 0.85 - 1.09 ; P = 0.510 ) or incident non-fatal cardiac arrhythmias ( HR : 0.90 ; 95 % CI : 0.37 - 2.23 ; P = 0.827 ) . Digoxin had no multivariable-adjusted or propensity score-adjusted associations with these outcomes in the pre-match cohort . CONCLUSIONS In patients with paroxysmal and persistent AF , we found no evidence of increased mortality or hospitalization in those taking digoxin as baseline initial therapy CONTEXT The 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 . OBJECTIVE To assess variations in serum digoxin concentration ( SDC ) and their association with mortality and hospitalization in patients with heart failure . DESIGN , SETTING , AND PATIENTS Post hoc analysis of the r and omized , 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 r and omly 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 > or = 1.2 ng/mL , n = 277 ) and compared with patients r and omly assigned to receive placebo ( n = 2611 ) . MAIN OUTCOME MEASURE All-cause mortality at a mean follow-up of 37 months . RESULTS Higher 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 > or = 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 > or = 1.2 ng/mL HR 1.16 , 95 % CI , 0.96 - 1.39 ; and HR of 1.00 [ referent ] for placebo ) . CONCLUSIONS Our 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 BACKGROUND The use of digitalis is recommended for the treatment of heart failure to reduce hospitalization . Recent data suggest that digitalis treatment may adversely affect survival in women but not in men . We studied patients with left ventricular dysfunction enrolled in the Studies of Left Ventricular Dysfunction ( SOLVD ) to determine whether there was a gender-based survival difference in patients treated with digitalis .  METHODS AND RESULTS Symptomatic ( n = 2569 ) and asymptomatic ( n = 4228 ) patients with left ventricular ejection fraction < or = 0.35 were studied . Digitalis use was assessed at baseline and baseline demographic variables were catalogued and compared . A multivariate analysis , incorporating known covariates of risk for adverse cardiovascular events , was used to examine the association of digitalis with all-cause mortality , cardiovascular death , death from heart failure , and arrhythmic death , with , or without , worsening heart failure in women compared with men . Analysis for an interaction between digitalis and gender on mortality was also performed . No interaction between gender and digitalis treatment on survival was found , and there was no significant difference in the hazard ratios for men and women on digitalis either with respect to all-cause mortality , cardiovascular mortality , heart failure mortality , or arrhythmic death with worsening heart failure . When mortality for arrhythmic death without worsening heart failure was adjusted for the probability of being treated with digitalis ( propensity analysis ) , women fared better than men . CONCLUSION Data from the SOLVD trials suggest that digitalis treatment of heart failure does not result in a difference in survival between men and women . Because a r and omized trial to definitively answer the question is unlikely , and perhaps inappropriate , examination of other heart failure population s for a gender-digitalis interaction is indicated Background —Elevated serum digoxin concentration can cause toxicity , including death .  Dronedarone increases digoxin concentration by P-glycoprotein interaction . In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of St and ard Therapy Trial ( PALLAS ) , dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation . The present analysis examines whether the dronedarone – digoxin interaction might explain these adverse outcomes . Methods and Results —Subgroup analysis was performed to compare outcomes of patients on digoxin at baseline or not . In PALLAS , 1619 patients were r and omized to dronedarone and 1617 to placebo , of whom 544 ( 33.6 % ) and 526 ( 32.5 % ) were receiving digoxin , respectively .  Median ( Q1,Q3 ) digoxin serum concentration on day 7 was 1.1 ( 0.7,1.5 ) ng/mL on dronedarone and 0.7 ( 0.5,1.1 ) ng/mL on placebo ( P<0.001 ) . Among patients on digoxin , there were 15 ( 8.6%/year ) cardiovascular deaths on dronedarone and 2 ( 1.2%/year ) on placebo ( adjusted hazard ratio , 7.31 ; 95 % confidence interval , 1.66–32.20 ; P=0.009 ) . Among patients not on digoxin , there were 6 cardiovascular deaths on dronedarone ( 1.7%/year ) and 8 on placebo ( 2.2%/year ; adjusted hazard ratio , 0.67 ; 95 % confidence interval , 0.23–1.95 ; P=0.46 ; interaction P value 0.01 ) . In patients on digoxin , there were 11 arrhythmic deaths on dronedarone and none on placebo ; and in patients not on digoxin , there were 2 arrhythmic deaths on dronedarone and 4 on placebo ( P value for interaction 0.002 ) . There was no interaction between baseline digoxin use and the adverse effect of dronedarone on heart failure events . Conclusions —In PALLAS , there was a strong effect of concurrent digoxin use on the adverse effect of dronedarone on cardiovascular death , but not on occurrence of heart failure . Clinical Trial Registration —http://www . clinical trials.gov . Unique identifier : NCT01151137 Objective : In heart failure , digitalis increases exercise capacity and reduces morbidity , but has no effect on survival . This raises the suspicion that the inotropic benefits of digitalis may be counteracted by serious adverse effects . Patients with atrial fibrillation ( AF ) were studied to clarify this . Design : In the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation ( SPORTIF ) III and V studies , 7329 patients with AF at moderate-to-high risk were r and omised to preventive treatment of thromboembolism , either with warfarin or the oral direct thrombin inhibitor ximelagatran . The survival of users and non-users of digitalis was investigated . Results : At baseline , 53.4 % of the study population used digitalis , and these patients had a higher mortality than non-users ( 255/3911 ( 6.5 % ) vs 141/3418 ( 4.1 % ) , p<0.001 ; hazard ratio ( HR ) = 1.58 ( 95 % CI 1.29 to 1.94 ) ) . Digitalis users also had more baseline risk factors . After multivariate risk factor adjustment , the increased mortality persisted ( p<0.001 ; HR = 1.53 ( 95 % CI 1.22 to 1.92 vs 1.23 to 1.92 ) ) . Conclusions : The results suggest that digitalis , like other inotropic drugs , may increase mortality . This may be concealed in heart failure , but be revealed in patients with AF , who need the rate-reducing effect of digitalis , but do not benefit much from an increased inotropy . Cautious interpretation of the data is m and atory since the patients were not r and omised with respect to digitalis use Previous studies on digoxin use in patients with atrial fibrillation ( AF ) and the risk of all-cause mortality  found conflicting results . We conducted a population -based , retrospective , cohort study of patients aged ≥65 years admitted to a hospital with a primary or secondary diagnosis of AF , in Quebec province , Canada , from 1998 to 2012 . The AF cohort was grouped into patients with and without heart failure ( HF ) and into  digoxin and no-digoxin users according to the first prescription filled for digoxin within 30 days after AF hospital discharge . We derived propensity score-matched digoxin and no-digoxin treatment groups for the groups of patients with and without HF , respectively , and conducted multivariable Cox proportional hazards regression analyses to determine association between digoxin use and all-cause mortality . The AF propensity score-matched cohorts of patients with and without HF were well balanced on baseline characteristics . In the propensity score-matched HF group , digoxin use was associated with a 14 % greater risk of all-cause mortality ( adjusted hazard ratio 1.14 , 95 % confidence interval 1.10 to 1.17 ) . In the propensity score-matched no-HF group , digoxin use was associated with a 17 % greater risk of all-cause mortality ( adjusted hazard ratio 1.17 , 95 % confidence interval 1.14 to 1.19 ) . In conclusion , our retrospective analyses found that digoxin use was associated with a greater risk for all-cause mortality in patients aged ≥65 years with AF regardless of concomitant HF . Large , multicenter , r and omized controlled trials or prospect i ve cohort studies are required to clarify this issue AIMS In the Digitalis Investigation Group ( DIG ) trial , digoxin reduced mortality or hospitalization due to heart failure  ( HF ) in several pre-specified high-risk subgroups of HF patients , but data on protocol -specified 2-year outcomes were not presented . In the current study , we examined the effect of digoxin on HF death or HF hospitalization and all-cause death or all-cause hospitalization in high-risk subgroups during the protocol -specified 2 years of post-r and omization follow-up . METHODS AND RESULTS In the DIG trial , 6800 ambulatory patients with chronic HF , normal sinus rhythm , and LVEF ≤45 % ( mean age 64 years , 26 % women , 17 % non-whites ) were r and omized to receive digoxin or placebo .  The three high-risk groups were defined as NYHA class III-IV symptoms ( n = 2223 ) , LVEF < 25 % ( n = 2256 ) , and cardiothoracic ratio ( CTR ) > 55 % ( n = 2345 ) . In all three high-risk subgroups , compared with patients in the placebo group , those in the digoxin group had a significant reduction in the risk of the 2-year composite endpoint of HF mortality or HF hospitalization : NYHA III-IV [ hazard ratio ( HR ) 0.65 ; 95 % confidence interval ( CI ) 0.57 - 0.75 ; P < 0.001 ] , LVEF < 25 % ( HR 0.61 ; 95 % CI 0.53 - 0.71 ; P < 0.001 ) , and CTR > 55 % ( HR 0.65 ; 95 % CI 0.57 - 0.75 ; P < 0.001 ) .  Digoxin-associated HRs ( 95 % CI ) for 2-year all-cause mortality or all-cause hospitalization for subgroups with NYHA III-IV , LVEF < 25 % , and CTR > 55 % were 0.88 ( 0.80 - 0.97 ; P = 0.012 ) , 0.84 ( 0.76 - 0.93 ; P = 0.001 ) , and 0.85 ( 0.77 - 0.94 ; P = 0.002 ) , respectively . CONCLUSIONS Digoxin  improves outcomes in chronic HF patients with NYHA class III-IV , LVEF < 25 % , or CTR > 55 % , and should be considered in these patients BACKGROUND The Digitalis Investigation Group trial reported that treatment with digoxin did not decrease overall mortality among patients with heart failure and depressed left ventricular systolic function , although it did reduce hospitalizations slightly . Even though the epidemiologic features , causes , and prognosis of heart failure vary between men and women , sex-based differences in the effect of digoxin were not evaluated . METHODS We conducted a post hoc subgroup analysis to assess whether there were sex-based differences in the effect of digoxin therapy among the 6800 patients in the Digitalis Investigation Group study . The presence of an interaction between sex and digoxin therapy with respect to the primary end point of death from any cause was evaluated with the use of Mantel-Haenszel tests of heterogeneity and a multivariable Cox proportional-hazards model , adjusted for demographic and clinical variables . RESULTS There was an absolute difference of 5.8 percent ( 95 percent confidence interval , 0.5 to 11.1 ) between men and women in the effect of digoxin on the rate of death from any cause ( P=0.034 for the interaction ) . Specifically , women who were r and omly assigned to digoxin had a higher rate of death than women who were r and omly assigned to placebo ( 33.1 percent vs. 28.9 percent ; absolute difference , 4.2 percent , 95 percent confidence interval , -0.5 to 8.8 ) . In contrast , the rate of death was similar among men r and omly assigned to digoxin and men r and omly assigned to placebo ( 35.2 percent vs. 36.9 percent ; absolute difference , -1.6 percent ; 95 percent confidence interval , -4.2 to 1.0 ) . In the multivariable analysis , digoxin was associated with a significantly higher risk of death among women ( adjusted hazard ratio for the comparison with placebo , 1.23 ; 95 percent confidence interval , 1.02 to 1.47 ) , but it had no significant effect among men ( adjusted hazard ratio , 0.93 ; 95 percent confidence interval , 0.85 to 1.02 ; P=0.014 for the interaction ) . CONCLUSIONS The effect of digoxin therapy differs between men and women .  Digoxin therapy is associated with an increased risk of death from any cause among women , but not men , with heart failure and depressed left ventricular systolic function OBJECTIVES The purpose of this study was to determine whether digoxin is effective in patients with chronic , stable mild to moderate heart failure . BACKGROUND Digoxin has been a traditional therapy in heart failure , but method ologic limitations in earlier studies have prevented definitive conclusions regarding its efficacy . METHODS Withdrawal of digoxin ( placebo group , n = 46 ) or its continuation ( digoxin group , n = 42 ) was performed in a prospect i ve , r and omized , double-blind , placebo-controlled multicenter trial of patients with chronic , stable mild to moderate heart failure secondary to left ventricular systolic dysfunction who had normal sinus rhythm and were receiving long-term treatment with diuretic drugs and digoxin .  RESULTS Patients withdrawn from digoxin therapy showed worsened maximal exercise capacity ( median change in exercise time -96 s ) compared with that of patients who continued to receive digoxin ( change in exercise time + 4.5 s ) ( p = 0.003 ) . Patients withdrawn from digoxin therapy showed an increased incidence of treatment failures ( p = 0.039 ) ( 39 % , digoxin withdrawal group vs. 19 % , digoxin maintenance group ) and a decreased time to treatment failure ( p = 0.037 ) . In addition , patients who continued to receive digoxin had a lower body weight ( p = 0.044 ) and heart rate ( p = 0.003 ) and a higher left ventricular ejection fraction ( p = 0.016 ) . CONCLUSIONS These data provide strong evidence of the clinical efficacy of digoxin in patients with normal sinus rhythm and mild to moderate chronic heart failure secondary to systolic dysfunction who are treated with diuretics Background Recent studies of patients with heart failure and of patients receiving intensive care indicate that digoxin may increase mortality if the patient has atrial fibrillation ( AF ) . Objective To study which patients receive  digoxin treatment for AF and what the prognosis is for patients given this treatment . Method 2824 patients with AF were studied prospect ively for a mean of 4.6 years . Information about medication was obtained from the local hospital registry . Information about diagnoses , hospitalisations and deaths was obtained from national registries . Propensity score matching and Cox regression was used to account for confounding . Results Factors associated with digoxin use were permanent AF ( hazard ratio ( HR ) = 3.2 , confidence interval ( CI ) 2.7 to 3.9 ) , absence of pacemaker ( HR = 2.3 , CI 1.6 to 3.2 ) , history of heart failure ( HR = 2.0 , CI 1.7 to 2.5 ) , treatment in an internal medicine ward rather than a cardiology ward ( HR = 1.6 , CI 1.3 to 2.0 ) , female sex ( HR = 1.6 , CI 1.3 to 1.9 ) and age ≥80 years ( HR = 1.4 , CI 1.1 to 1.7 ) . More patients with than without digoxin died ( 51 % vs 31 % , p<0.001 ) . After adjustment for covariates , however , no disadvantages related to digoxin use could be found for all-cause mortality , myocardial infa rct ion , ischaemic stroke , time to readmission to hospital or days at hospital/year at risk . The only end point significantly associated with digoxin use was pacemaker implantations , which were more common in digoxin-treated patients ( HR = 2.0 , CI 1.2 to 3.4 ) . Conclusion Digoxin is mainly given to an elderly and frailer subset of patients with AF and is thus associated with an increased mortality . When differences in patient characteristics are accounted for digoxin use seems to have a neutral effect on mortality and major cardiovascular events in patients with AF
target: The present systematic review and meta- analysis of all available data sources suggest that digoxin use is associated with an increased mortality risk , particularly among patients suffering from AF
background: There are conflicting data regarding the effect of digoxin use on mortality in patients with atrial fibrillation ( AF ) or with congestive heart failure ( CHF ) .
  The aim of this meta- analysis was to provide detailed analysis of the currently available study reports .