human
***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    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 Patients with heart failure have reduced peripheral blood flow at rest , during exercise , and in response to endothelium-dependent vasodilators . Nitric oxide formed from L-arginine metabolism in endothelial cells contributes to regulation of blood flow under these conditions . A r and omized , double-blind crossover study design was used to determine whether supplemental oral L-arginine can augment peripheral blood flow and improve functional status in patients with moderate to severe heart failure . METHODS AND RESULTS Fifteen subjects were given 6 weeks of oral L-arginine hydrochloride ( 5.6 to 12.6 g/d ) and 6 weeks of matched placebo capsules in r and om sequence . Compared with placebo , supplemental oral L-arginine significantly increased forearm blood flow during forearm exercise , on average from 5.1 + /- 2.8 to 6.6 + /- 3.4 mL. min-1 . dL-1 ( P < .05 ) . Furthermore , functional status was significantly better on L-arginine compared with placebo , as indicated by increased distances during a 6-minute walk test ( 390 + /- 91 versus 422 + /- 86 m , P < .05 ) and lower scores on the Living With Heart Failure question naire ( 55 + /- 28 versus 42 + /- 26 , P < .05 ) . Oral L-arginine also improved arterial compliance from 1.99 + /- 0.38 to 2.36 + /- 0.30 mL/mm Hg ( P < .001 ) and reduced circulating levels of endothelin from 1.9 + /- 1.1 to 1.5 + /- 1.1 pmol/L ( P < .05 ) . CONCLUSIONS Supplemental oral L-arginine had beneficial effects in patients with heart failure . Further studies are needed to confirm the therapeutic potential of supplemental oral L-arginine and to identify mechanisms of action in patients with heart failure Objective To examine the reproducibility and responsiveness to change of a six minute walk test and a quality of life measure in elderly patients with heart failure . Design Longitudinal within patient study . Subjects 60 patients with heart failure ( mean age 82 years ) attending a geriatric outpatient clinic , 45 of whom underwent a repeat assessment three to eight weeks later . Main outcome measures Subjects underwent a st and ardised six minute walk test and completed the chronic heart failure question naire ( CHQ ) , a heart failure specific quality of life question naire .  Intraclass correlation coefficients ( ICC ) were calculated using a r and om effects one way analysis of variance as a measure of reproducibility . Guyatt ’s responsiveness coefficient and effect sizes were calculated as measures of responsiveness to change . Results 24 patients reported no major change in cardiac status , while seven had deteriorated and 14 had improved between the two clinic visits . Reproducibility was satisfactory ( ICC > 0.75 ) for the six minute walk test , for the total CHQ score , and for the dyspnoea , fatigue , and emotion domains of the CHQ . Effect sizes for all measures were large ( > 0.8 ) , and responsiveness coefficients were very satisfactory ( > 0.7 ) . Effect sizes for detecting deterioration were greater than those for detecting improvement . Conclusions Quality of life assessment and a six minute walk test are reproducible and responsive measures of cardiac status in frail , very elderly patients with heart failure OBJECTIVES We sought to assess the efficacy of biventricular pacing with respect to both peak and submaximal measures of exercise in patients with New York Heart Association class III heart failure ( HF ) and intraventricular conduction delay in a r and omized , blinded study . BACKGROUND Submaximal and maximal changes in exercise capacity need evaluating in this patient population with this novel therapy . METHODS Grade d exercise and 6-min walk tests were performed in patients r and omized to three months each of active ( atrio-biventricular ) and inactive pacing .  Minute ventilation ( VE ) , oxygen uptake ( VO(2 ) ) , ventilated carbon dioxide ( VCO(2 ) ) and heart rate were measured in patients achieving a respiratory quotient > 1 ( n = 30 ) . Oxygen pulse , anaerobic threshold ( AT ) and ventilatory efficiency ( VE/VCO(2 ) ) were calculated . RESULTS Active biventricular pacing increased peak VO(2 ) ( 15.8 + /- 4.3 vs. 14.4 + /- 4.6 ml/kg/min , p = 0.02 ) , exercise time ( 501 + /- 223 s vs. 437 + /- 233 s , p < 0.001 ) and oxygen pulse ( 9.3 + /- 2.8 vs. 8.1 + /- 3.1 ml/beat , p < 0.01 ) compared with inactive pacing . The submaximal measures of exercise capacity significantly increased with active pacing : AT ( 11.2 + /- 4.1 ml/kg/min vs. 9.5 + /- 2.3 ml/kg/min , p = 0.02 ) and 6-min walk ( 414 + /- 94 m vs. 359 + /- 94 m , p = 0.001 ) . Minute ventilation/ventilated carbon dioxide improved ( 32 + /- 9 vs. 36 + /- 11 , p = 0.03 ) with normalization of the VE/VCO(2 ) slope in 59 % of patients ( chi-square test , p = 0.002 ) with active pacing . CONCLUSIONS Biventricular pacing may improve maximal and submaximal exercise capacity in patients with advanced HF and intraventricular conduction delay BACKGROUND The Digitalis Investigation Group ( DIG ) trial was a r and omized double-blind placebo-controlled study that examined the effect of digoxin on mortality in 7,788 patients with heart failure and sinus rhythm . A prespecified sub study evaluated the effect of digoxin therapy on health-related quality of life ( HQOL ) in a subset of these patients . METHODS Patients in the DIG trial had clinical heart failure and were r and omized to either digoxin or placebo in addition to their baseline diuretic and angiotensin-converting enzyme therapy ( n = 7,788 ) . The patients in this sub study had HQOL measured using a self-administered question naire employing scales that measured general health , physical functioning , depression , anger , anxiety , life satisfaction , and disease specific measures . A subjective assessment by the investigator and a 6-minute walk test evaluated functional status . HQOL was measured at baseline and at the 4- and 12-month follow-up visits . RESULTS The baseline characteristics of the patients in the quality of life sub study ( n = 589 ) were comparable to the remaining patients in the study ( n = 7,199 ) by age and other clinical measures , including history of prior myocardial infa rct ion or etiology of heart failure ; heart failure was of shorter duration and the ejection fraction was slightly better than in the main trial . Within the sub study , patients receiving digoxin ( n = 298 ) or  placebo ( n = 291 ) were also similar in baseline characteristics . There was no statistically significant difference in any HQOL measure between the digoxin and the placebo groups at baseline . At the 4-month visit , only perceived health was improved in the digoxin group . At 12 months , there was no statistically significant difference in perceived health , physical functioning , Minnesota Living with Heart Failure , depression , anxiety , anger , Ladder of Life , or the 6-minute walk between the digoxin and placebo groups . CONCLUSION In this subset of the DIG population , digoxin therapy had no effect on the HQOL in patients with heart failure in sinus rhythm BACKGROUND A preliminary study suggested that the long-acting late-generation calcium-channel blocker amlodipine has favorable effects on exercise tolerance and is safe to use in heart failure , in contrast to earlier generation agents . The goal of 2 multicenter studies was to assess the effect of adjunctive therapy with amlodipine in addition to st and ard therapy on exercise capacity , quality of life , left ventricular function , and safety parameters in patients with heart failure and left ventricular systolic dysfunction . METHODS Two large multicenter trials examining the effects of amlodipine on these parameters over a 12-week period of therapy were undertaken in patients with mild to moderate heart failure and left ventricular systolic dysfunction . A total of 437 patients with stable heart failure were studied in a r and omized , double-blind , placebo-controlled prospect i ve design . RESULTS Amlodipine at a dose of 10 mg/day in addition to st and ard therapy in such patients was associated with no significant difference in change in exercise tolerance on a Naughton protocol compared with placebo in each trial . Among all patients taking amlodipine , exercise time increased 53 + /- 9 ( SE ) seconds ; exercise time for those taking placebo increased 66 + /- 9 seconds ( P = not significant ) . There were no significant differences in changes of quality of life parameters between amlodipine- and placebo-treated patients , and there were no significant differences in symptom scores or New York Heart Association classification between groups . Left ventricular function ( measured as ejection fraction ) improved 3 . 4 % + /- 0.5 % in amlodipine-treated patients and 1.5 % + /- 0.5 % in placebo-treated patients ( P = .007 ) . There was no statistically significant excess of important adverse events ( episodes of worsening heart failure in 10 % amlodipine-treated vs 6.3 % of placebo-treated patients ) or differences in need for changes in background medication between groups . CONCLUSIONS The addition of 10 mg of amlodipine per day to st and ard therapy in patients with heart failure is associated with no significant improvement in exercise time compared with placebo therapy over a 12-week period , and there was no increased incidence of adverse events . These data suggest that the addition of amlodipine to st and ard therapy in heart failure will not result in additional efficacy per se beyond st and ard therapy Summary Two hundred and nine patients with moderate to severe chronic heart failure , all of whom remained symptomatic despite at least 80 mg of frusemide daily , were r and omized to 12 months treatment with flosequinan or captopril .  The patients were stratified into two groups , a treadmill group and a corridor walk test group , depending upon their exercise capability . Sixty-five out of 102 patients r and omized to flosequinan and 43 out of 107 r and omized to captopril ( p<0.001 ) did not complete the study . There was no difference between the groups in mortality : 19 patients died while taking flosequinan and 15 while taking captopril . Both drugs had similar effects on treadmill exercise tolerance ; the mean increase at week 52 was 117 seconds in the flosequinan group and 156 seconds ( p=0.57 ) for the captopril group . For those patients stratified to the corridor walk test only , there was also very little difference in the improvement at 52 weeks ; the mean increase for patients r and omized to flosequinan was 61 meters and captopril was 75 meters ( p=0.65 ) . However , when the walk tests from all patients are examined , captopril produced a significant improvement compared with flosequinan at week 52 ( p=0.015 ) . Flosequinan has similar long- 
    Output:
    
agent
Pharmacological trials including patients with more severe heart failure were more likely to show a significant improvement with therapy than trials of milder heart failure .
Using mean values in these trials , the age of patients appeared a more important determinant of 6MWT distance than New York Heart Association classification .
The 6MWT has not yet been proven to be a robust test for the identification of effective pharmacological interventions although it appears useful for the assessment of cardiac resynchronization therapy .
The results of the 6MWT were concordant with changes in symptoms , suggesting that it may be used as supportive evidence for symptom benefit .
***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    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 Patients with heart failure have reduced peripheral blood flow at rest , during exercise , and in response to endothelium-dependent vasodilators . Nitric oxide formed from L-arginine metabolism in endothelial cells contributes to regulation of blood flow under these conditions . A r and omized , double-blind crossover study design was used to determine whether supplemental oral L-arginine can augment peripheral blood flow and improve functional status in patients with moderate to severe heart failure . METHODS AND RESULTS Fifteen subjects were given 6 weeks of oral L-arginine hydrochloride ( 5.6 to 12.6 g/d ) and 6 weeks of matched placebo capsules in r and om sequence . Compared with placebo , supplemental oral L-arginine significantly increased forearm blood flow during forearm exercise , on average from 5.1 + /- 2.8 to 6.6 + /- 3.4 mL. min-1 . dL-1 ( P < .05 ) . Furthermore , functional status was significantly better on L-arginine compared with placebo , as indicated by increased distances during a 6-minute walk test ( 390 + /- 91 versus 422 + /- 86 m , P < .05 ) and lower scores on the Living With Heart Failure question naire ( 55 + /- 28 versus 42 + /- 26 , P < .05 ) . Oral L-arginine also improved arterial compliance from 1.99 + /- 0.38 to 2.36 + /- 0.30 mL/mm Hg ( P < .001 ) and reduced circulating levels of endothelin from 1.9 + /- 1.1 to 1.5 + /- 1.1 pmol/L ( P < .05 ) . CONCLUSIONS Supplemental oral L-arginine had beneficial effects in patients with heart failure . Further studies are needed to confirm the therapeutic potential of supplemental oral L-arginine and to identify mechanisms of action in patients with heart failure Objective To examine the reproducibility and responsiveness to change of a six minute walk test and a quality of life measure in elderly patients with heart failure . Design Longitudinal within patient study . Subjects 60 patients with heart failure ( mean age 82 years ) attending a geriatric outpatient clinic , 45 of whom underwent a repeat assessment three to eight weeks later . Main outcome measures Subjects underwent a st and ardised six minute walk test and completed the chronic heart failure question naire ( CHQ ) , a heart failure specific quality of life question naire .  Intraclass correlation coefficients ( ICC ) were calculated using a r and om effects one way analysis of variance as a measure of reproducibility . Guyatt ’s responsiveness coefficient and effect sizes were calculated as measures of responsiveness to change . Results 24 patients reported no major change in cardiac status , while seven had deteriorated and 14 had improved between the two clinic visits . Reproducibility was satisfactory ( ICC > 0.75 ) for the six minute walk test , for the total CHQ score , and for the dyspnoea , fatigue , and emotion domains of the CHQ . Effect sizes for all measures were large ( > 0.8 ) , and responsiveness coefficients were very satisfactory ( > 0.7 ) . Effect sizes for detecting deterioration were greater than those for detecting improvement . Conclusions Quality of life assessment and a six minute walk test are reproducible and responsive measures of cardiac status in frail , very elderly patients with heart failure OBJECTIVES We sought to assess the efficacy of biventricular pacing with respect to both peak and submaximal measures of exercise in patients with New York Heart Association class III heart failure ( HF ) and intraventricular conduction delay in a r and omized , blinded study . BACKGROUND Submaximal and maximal changes in exercise capacity need evaluating in this patient population with this novel therapy . METHODS Grade d exercise and 6-min walk tests were performed in patients r and omized to three months each of active ( atrio-biventricular ) and inactive pacing .  Minute ventilation ( VE ) , oxygen uptake ( VO(2 ) ) , ventilated carbon dioxide ( VCO(2 ) ) and heart rate were measured in patients achieving a respiratory quotient > 1 ( n = 30 ) . Oxygen pulse , anaerobic threshold ( AT ) and ventilatory efficiency ( VE/VCO(2 ) ) were calculated . RESULTS Active biventricular pacing increased peak VO(2 ) ( 15.8 + /- 4.3 vs. 14.4 + /- 4.6 ml/kg/min , p = 0.02 ) , exercise time ( 501 + /- 223 s vs. 437 + /- 233 s , p < 0.001 ) and oxygen pulse ( 9.3 + /- 2.8 vs. 8.1 + /- 3.1 ml/beat , p < 0.01 ) compared with inactive pacing . The submaximal measures of exercise capacity significantly increased with active pacing : AT ( 11.2 + /- 4.1 ml/kg/min vs. 9.5 + /- 2.3 ml/kg/min , p = 0.02 ) and 6-min walk ( 414 + /- 94 m vs. 359 + /- 94 m , p = 0.001 ) . Minute ventilation/ventilated carbon dioxide improved ( 32 + /- 9 vs. 36 + /- 11 , p = 0.03 ) with normalization of the VE/VCO(2 ) slope in 59 % of patients ( chi-square test , p = 0.002 ) with active pacing . CONCLUSIONS Biventricular pacing may improve maximal and submaximal exercise capacity in patients with advanced HF and intraventricular conduction delay BACKGROUND The Digitalis Investigation Group ( DIG ) trial was a r and omized double-blind placebo-controlled study that examined the effect of digoxin on mortality in 7,788 patients with heart failure and sinus rhythm . A prespecified sub study evaluated the effect of digoxin therapy on health-related quality of life ( HQOL ) in a subset of these patients . METHODS Patients in the DIG trial had clinical heart failure and were r and omized to either digoxin or placebo in addition to their baseline diuretic and angiotensin-converting enzyme therapy ( n = 7,788 ) . The patients in this sub study had HQOL measured using a self-administered question naire employing scales that measured general health , physical functioning , depression , anger , anxiety , life satisfaction , and disease specific measures . A subjective assessment by the investigator and a 6-minute walk test evaluated functional status . HQOL was measured at baseline and at the 4- and 12-month follow-up visits . RESULTS The baseline characteristics of the patients in the quality of life sub study ( n = 589 ) were comparable to the remaining patients in the study ( n = 7,199 ) by age and other clinical measures , including history of prior myocardial infa rct ion or etiology of heart failure ; heart failure was of shorter duration and the ejection fraction was slightly better than in the main trial . Within the sub study , patients receiving digoxin ( n = 298 ) or  placebo ( n = 291 ) were also similar in baseline characteristics . There was no statistically significant difference in any HQOL measure between the digoxin and the placebo groups at baseline . At the 4-month visit , only perceived health was improved in the digoxin group . At 12 months , there was no statistically significant difference in perceived health , physical functioning , Minnesota Living with Heart Failure , depression , anxiety , anger , Ladder of Life , or the 6-minute walk between the digoxin and placebo groups . CONCLUSION In this subset of the DIG population , digoxin therapy had no effect on the HQOL in patients with heart failure in sinus rhythm BACKGROUND A preliminary study suggested that the long-acting late-generation calcium-channel blocker amlodipine has favorable effects on exercise tolerance and is safe to use in heart failure , in contrast to earlier generation agents . The goal of 2 multicenter studies was to assess the effect of adjunctive therapy with amlodipine in addition to st and ard therapy on exercise capacity , quality of life , left ventricular function , and safety parameters in patients with heart failure and left ventricular systolic dysfunction . METHODS Two large multicenter trials examining the effects of amlodipine on these parameters over a 12-week period of therapy were undertaken in patients with mild to moderate heart failure and left ventricular systolic dysfunction . A total of 437 patients with stable heart failure were studied in a r and omized , double-blind , placebo-controlled prospect i ve design . RESULTS Amlodipine at a dose of 10 mg/day in addition to st and ard therapy in such patients was associated with no significant difference in change in exercise tolerance on a Naughton protocol compared with placebo in each trial . Among all patients taking amlodipine , exercise time increased 53 + /- 9 ( SE ) seconds ; exercise time for those taking placebo increased 66 + /- 9 seconds ( P = not significant ) . There were no significant differences in changes of quality of life parameters between amlodipine- and placebo-treated patients , and there were no significant differences in symptom scores or New York Heart Association classification between groups . Left ventricular function ( measured as ejection fraction ) improved 3 . 4 % + /- 0.5 % in amlodipine-treated patients and 1.5 % + /- 0.5 % in placebo-treated patients ( P = .007 ) . There was no statistically significant excess of important adverse events ( episodes of worsening heart failure in 10 % amlodipine-treated vs 6.3 % of placebo-treated patients ) or differences in need for changes in background medication between groups . CONCLUSIONS The addition of 10 mg of amlodipine per day to st and ard therapy in patients with heart failure is associated with no significant improvement in exercise time compared with placebo therapy over a 12-week period , and there was no increased incidence of adverse events . These data suggest that the addition of amlodipine to st and ard therapy in heart failure will not result in additional efficacy per se beyond st and ard therapy Summary Two hundred and nine patients with moderate to severe chronic heart failure , all of whom remained symptomatic despite at least 80 mg of frusemide daily , were r and omized to 12 months treatment with flosequinan or captopril .  The patients were stratified into two groups , a treadmill group and a corridor walk test group , depending upon their exercise capability . Sixty-five out of 102 patients r and omized to flosequinan and 43 out of 107 r and omized to captopril ( p<0.001 ) did not complete the study . There was no difference between the groups in mortality : 19 patients died while taking flosequinan and 15 while taking captopril . Both drugs had similar effects on treadmill exercise tolerance ; the mean increase at week 52 was 117 seconds in the flosequinan group and 156 seconds ( p=0.57 ) for the captopril group . For those patients stratified to the corridor walk test only , there was also very little difference in the improvement at 52 weeks ; the mean increase for patients r and omized to flosequinan was 61 meters and captopril was 75 meters ( p=0.65 ) . However , when the walk tests from all patients are examined , captopril produced a significant improvement compared with flosequinan at week 52 ( p=0.015 ) . Flosequinan has similar long- 
    Output:
    