***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: 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 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 A double-blind placebo-controlled crossover trial of digoxin withdrawal was undertaken in 22 patients with sinus rhythm who had a previous history of frank heart failure and were taking therapeutic doses of the drug . During the course of the study , 14 patients showed no clinical change whether taking digoxin or placebo , five patients deteriorated on placebo ( four with heart failure and one with supraventricular tachycardia ) , and three on digoxin ( two with heart failure and one with digoxin toxicity ) . These differences were not statistically significant . Compared to placebo , patients , while taking digoxin , had lower resting heart rates and significant shortening of all the systolic time intervals . The drug appears to exert a sustained positive inotropic effect during maintenance therapy , but this is not of clinical benefit to the majority of patients 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 A r and omised , double blind , placebo controlled , crossover study of digoxin withdrawal and re introduction was carried out over two periods of eight weeks each after long term treatment . Forty four patients with stable heart failure in sinus rhythm and plasma digoxin concentrations over 0.8 ng/ml were studied . Their progress was assessed by clinical criteria , by haemodynamic measurements ( systolic time intervals and echocardiography ) , and by pharmacological measurements of erythrocytic sodium pump numbers and activity . After withdrawal of digoxin clinical deterioration occurred in only 25 % of the patients . Furthermore , in only 9 % of cases was digoxin re introduction thought to be necessary . There was deterioration in only 11 % of the patients during digoxin treatment . Deterioration during digoxin withdrawal was accompanied by changes in systolic time intervals , but similar , albeit smaller changes in systolic time intervals also occurred in patients with no deterioration . Deterioration was accompanied by changes in the pharmacological effects of digoxin on the erythrocytes , consistent with a loss of effect , and these changes did not occur in those who did not deteriorate . The occurrence of deterioration could not be predicted by any clinical , haemodynamic , or pharmacological measurements made before withdrawal The view that digitalis clinical ly benefits patients with heart failure and sinus rhythm lacks support from a well-controlled study . Using a r and omized , double-blind , crossover protocol , we compared the effects of oral digoxin and placebo on the clinical courses of 25 out patients without atrial fibrillation . According to a clinicoradiographic scoring system , the severity of heart failure was reduced by digoxin in 14 patients ; in nine of these 14 , improvement was confirmed by repeated trials ( five patients ) or right-heart catheterization ( four patients ) . The other 11 patients had no detectable improvement from digoxin . Patients who responded to digoxin had more chronic and more severe heart failure , greater left ventricular dilation and ejection-fraction depression , and a third heart sound . Multivariate analysis showed that the third heart sound was the strongest correlate of the response to digoxin ( P less than 0.0001 ) . These data suggest that long-term digoxin therapy is clinical ly beneficial in patients with heart failure unaccompanied by atrial fibrillation whose failure persists despite diuretic treatment and who have a third heart sound We r and omly assigned 230 patients in sinus rhythm with moderately severe heart failure to treatment with digoxin , milrinone , both , or placebo . The effects of each were compared during a 12-week , double-blind trial . Treatment with milrinone or digoxin significantly increased treadmill exercise time as compared with placebo ( by 82 and 64 seconds respectively ; 95 percent confidence limits , 44 and 123 , and 30 and 100 ) . Both treatments reduced the frequency of decompensation from heart failure , from 47 percent with placebo to 34 percent with milrinone ( P less than 0.05 ; 95 percent confidence limits , 22 and 46 ) and 15 percent with digoxin ( P less than 0.01 ; 95 percent confidence limits , 7 and 26 ) . However , the clinical condition of 20 percent of the patients taking milrinone deteriorated within two weeks after treatment was begun , as compared with only 3 percent of those taking digoxin ( P less than 0.05 ) . The left ventricular ejection fraction at rest was not significantly changed by milrinone ( + 0.2 percent ; 95 percent confidence limits , -1.5 and 1.9 ) , but it was increased by digoxin ( + 1.7 percent ; P less than 0.01 ; 95 percent confidence limits , -0.03 and 3.4 ) and decreased by placebo ( -2.0 percent ; 95 percent confidence limits , -3.8 and -0.1 ) . Three-month survival was related inversely to the base-line ejection fraction . Analysis of mortality from all causes according to the intention to treat suggested an adverse effect of milrinone ( P = 0.064 ) . After adjustment for an excess of patients with lower ejection fractions r and omly assigned to receive milrinone , this trend was not significant ( P = 0.26 ) . Increased ventricular arrhythmias occurred more frequently in patients who received milrinone than in those who did not ( 18 vs. 4 percent ; P less than 0.03 ) . We conclude that milrinone significantly increased exercise tolerance and reduced the frequency of worsened heart failure . However , in the population of patients studied , milrinone or the combination of milrinone and digoxin offered no advantage over digoxin alone . Furthermore , our data suggest that milrinone may aggravate ventricular arrhythmias This multicenter , double-blind , placebo-controlled study compares the effects of captopril treatment with those of digoxin treatment during maintenance diuretic therapy in patients with mild to moderate heart failure . Compared with placebo , captopril therapy result ed in significantly improved exercise time ( mean increase , 82 s vs 35 s ) and improved New York Heart Association class ( 41 % vs 22 % ) , but digoxin therapy did not . Digoxin treatment increased ejection fraction ( 4.4 % increase ) compared with captopril therapy ( 1.8 % increase ) and placebo ( 0.9 % increase ) . The number of ventricular premature beats decreased 45 % in the captopril group and increased 4 % in the digoxin group in patients with more than ten ventricular premature beats per hour . Treatment failures , increased requirements for diuretic therapy , and hospitalizations were significantly more frequent in patients receiving placebo compared with those receiving either active drug . Transitory hypotension occurred more frequently with administration of captopril . Captopril treatment is significantly more effective than placebo and is an alternative to digoxin therapy in patients with mild to moderate heart failure who are receiving diuretic maintenance therapy To assess the efficacy of digitalis in patients with chronic clinical ly compensated congestive heart failure and normal sinus rhythm , we performed a double-blind crossover study with digoxin and placebo in 30 consecutive out patients fulfilling these criteria ;  serum digoxin levels , clinical symptoms and signs , and objective indexes of cardiac function were monitored . No patient 's clinical condition deteriorated during three months of placebo administration . Discontinuation of digoxin result ed in a small increase in echocardiographically determined resting left ventricular end-diastolic dimension ( 1.8 + /- 0.6 mm , p less than 0.001 ) and a similar decrease in velocity of circum 
    Output:
    
We concluded the use of digitalis for chronic heart failure probably leads to little or no decrease in mortality , but they might reduce hospitalizations and clinical deterioration .