title: Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Reproducibility and responsiveness of quality of life assessment and six minute walk test in elderly heart failure patients Atriobiventricular pacing improves exercise capacity in patients with heart failure and intraventricular conduction delay. The effect of digoxin on the quality of life in patients with heart failure. Effects of amlodipine on exercise tolerance, quality of life, and left ventricular function in patients with heart failure from left ventricular systolic dysfunction. Long-term evaluation of treatment for chronic heart failure: A 1 year comparative trial of flosequinan and captopril Dose-response of chronic beta-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Bucindolol Investigators. Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure? Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. Comparative effects of long-term therapy with captopril and ibopamine in chronic congestive heart failure in old patients. Beta-blockade in heart failure: a comparison of carvedilol with metoprolol. Safety and efficacy of valsartan versus enalapril in heart failure patients. Effect of beta blockade (carvedilol or metoprolol) on activation of the renin-angiotensin-aldosterone system and natriuretic peptides in chronic heart failure. Controlled Trial of Intravenous Immune Globulin in Recent-Onset Dilated Cardiomyopathy Clinical and Neurohormonal Effects of Nicardipine Hydrochloride in Patients With Severe Chronic Heart Failure Receiving Angiotensin‐Converting Enzyme Inhibitor Therapy Beta blockers in heart failure: a comparison of a vasodilating beta blocker with metoprolol. Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. Comparison of the effects of losartan and enalapril on clinical status and exercise performance in patients with moderate or severe chronic heart failure. The Effect of Quinapril on Functional Status of Elderly Patients with Diastolic Heart Failure Comparative effects of losartan and enalapril on exercise capacity and clinical status in patients with heart failure. The Losartan Pilot Exercise Study Investigators. Beneficial effects of metoprolol on myocardial sympathetic function: Evidence from a randomized, placebo-controlled study in patients with congestive heart failure. Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomised double blind placebo controlled trial Effect of encouragement on walking test performance. Effect of Erythropoietin on Exercise Capacity in Patients With Moderate to Severe Chronic Heart Failure Effect of carvedilol on survival in severe chronic heart failure. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. Comparison of permanent left ventricular and biventricular pacing in patients with heart failure and chronic atrial fibrillation: prospective haemodynamic study Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Symptomatic improvement in patients treated with intermittent infusion of inotropes: a double-blind placebo controled pilot study. MIC trial: metoprolol in patients with mild to moderate heart failure: effects on ventricular function and cardiopulmonary exercise testing. Captopril treatment of chronic heart failure in the very old. Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Effects of exercise training in patients with heart failure: the Exercise Rehabilitation Trial (EXERT). Effects of metoprolol CR in patients with ischemic and dilated cardiomyopathy : the randomized evaluation of strategies for left ventricular dysfunction pilot study. Reproducibility of the six-minute walking test in chronic heart failure patients. Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. SOLVD Investigators. Beneficial effects of statins in patients with non-ischemic 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. Safety and efficacy of carvedilol in severe heart failure. The U.S. Carvedilol Heart Failure Study Group. Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors. Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Prognostic usefulness of the six-minute walk in patients with advanced congestive heart failure secondary to ischemic or nonischemic cardiomyopathy. Cardiac resynchronization in chronic heart failure. Effects of cardiac resynchronization therapy on heart rate variability in patients with chronic systolic heart failure and intraventricular conduction delay. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy A controlled trial of digoxin in congestive heart failure. Growth hormone treatment in dilated cardiomyopathy. Comparison of the effects of cilazapril and captopril versus placebo on exercise testing in chronic heart failure patients: a double-blind, randomized, multicenter trial. The Cilazapril-Captopril Multicenter Group.
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 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-term efficacy to captopril but is associated with a higher incidence of adverse events BACKGROUND Small-scale clinical investigations have demonstrated that single doses of beta-blocking agents can improve left ventricular function in heart failure from idiopathic dilated cardiomyopathy ( IDC ) . The purpose of this multicenter clinical trial was to determine the dose-effect characteristics of beta-blockade in a heart failure population that includes ischemic dilated cardiomyopathy ( ISCD ) . METHODS AND RESULTS Bucindolol is a nonselective beta-blocking agent with mild vasodilatory properties . One hundred forty-one subjects with class II or III heart failure , left ventricular ejection fraction ( LVEF ) < or = 0.40 , and background therapy of angiotensin-converting enzyme inhibitors , digoxin , and diuretics were given an initial challenge dose of bucindolol 12.5 mg . One hundred thirty-nine subjects ( 99 with IDC , 40 with ISCDC ) tolerated challenge and were r and omized to treatment with placebo or bucindolol 12.5 mg/d ( low dose ) , 50 mg/d ( medium dose ) , or 200 mg/d ( high dose ) . At the end of 12 weeks , left ventricular function and other parameters were measured and compared with baseline values . There was a dose-related improvement in left ventricular function in bucindolol-treated subjects . In the high-dose bucindolol group , radionuclide-measured LVEF improved by 7.8 EF units ( % ) compared with 1.8 units in the placebo group ( P < .05 ) , and compared with the placebo group , a greater percentage of subjects had an increase in LVEF by > or = 5 units . In contrast , all three bucindolol doses prevented deterioration of myocardial function as defined by an LVEF decline of > or = 5 units . CONCLUSIONS In heart failure from systolic dysfunction , beta-blockade with bucindolol produces a dose-related improvement in and prevents deterioration of left ventricular function OBJECTIVES This study examined the relative merits of digoxin , carvedilol , and their combination for the management of patients with atrial fibrillation ( AF ) and heart failure ( HF ) . BACKGROUND In patients with AF and HF , both digoxin and beta-blockers reduce the ventricular rate , and both may improve symptoms , but only beta-blockers have been shown to improve prognosis . If combined therapy is not superior to beta-blockers alone , treatment of patients with HF and AF could be simplified by stopping digoxin . METHODS We enrolled 47 patients ( 29 males ; mean age 68 years ) with persistent AF and HF ( mean left ventricular ejection fraction [ LVEF ] 24 % ) in a r and omized , double-blinded , placebo-controlled study . In the first phase of the study , digoxin was compared with the combination of digoxin and carvedilol ( four months ) . In the second phase , digoxin was withdrawn in a double-blinded manner in the carvedilol-treated arm , thus allowing a comparison between digoxin and carvedilol ( six months ) . Investigations were undertaken at baseline and at the end of each phase . RESULTS Compared with digoxin alone , combination therapy lowered the ventricular rate on 24-h ambulatory electrocardiographic monitoring ( p < 0.0001 ) and during submaximal exercise ( p < 0.05 ) , whereas LVEF ( p < 0.05 ) and symptom score ( p < 0.05 ) improved . In phase 2 , there was no significant difference between digoxin alone and carvedilol alone in any variable . The mean ventricular rate rose and LVEF fell when patients switched from combination therapy to carvedilol alone . Six-minute walk distance was not significantly influenced by any therapy . CONCLUSIONS The combination of carvedilol and digoxin appears generally superior to either carvedilol or digoxin alone in the management of AF in patients with HF OBJECTIVES This study was conducted to assess the safety and effectiveness of cardiac resynchronization therapy ( CRT ) when combined with an implantable cardioverter defibrillator ( ICD ) . BACKGROUND Long-term outcome of CRT was measured in patients with symptomatic heart failure ( HF ) , intraventricular conduction delay , and malignant ventricular tachyarrhythmias ( ventricular tachycardia/ventricular fibrillation [ VT/VF ] ) requiring therapy from an ICD . METHODS Patients ( n = 490 ) were implanted with a device capable of providing both CRT and ICD therapy and r and omized to CRT ( n = 245 ) or control ( no CRT , n = 245 ) for up to six months . The primary end point was progression of HF , defined as all-cause mortality , hospitalization for HF , and VT/VF requiring device intervention . Secondary end points included peak oxygen consumption ( VO(2 ) ) , 6-min walk ( 6 MW ) , New York Heart Association ( NYHA ) class , quality of life ( QOL ) , and echocardiographic analysis . RESULTS A 15 % reduction in HF progression was observed , but this was statistically insignificant ( p = 0.35 ) . The CRT , however , significantly improved peak VO(2 ) ( 0.8 ml/kg/min vs. 0.0 ml/kg/min , p = 0.030 ) and 6 MW ( 35 m vs. 15 m , p = 0.043 ) . Changes in NYHA class ( p = 0.10 ) and QOL ( p = 0.40 ) were not statistically significant . The CRT demonstrated significant reductions in ventricular dimensions ( left ventricular internal diameter in diastole = -3.4 mm vs. -0.3 mm , p < 0.001 and left ventricular internal diameter in systole = -4.0 mm vs. -0.7 mm , p < 0.001 ) and improvement in left ventricular ejection fraction ( 5.1 % vs. 2.8 % , p = 0.020 ) . A subgroup of patients with advanced HF ( NYHA class III/IV ) consistently demonstrated improvement across all functional status end points . CONCLUSIONS The CRT improved functional status in patients indicated for an ICD who also have symptomatic HF and intraventricular conduction delay Little is known concerning the long-term drug management of  chronic heart failure ( CHF ) in old patients ( greater than or equal to 75 years ) . Accordingly , this double-blind , placebo-controlled trial compared the long-term ( over 6 months ) effect of captopril ( 37.5 - 75 mg/day ) and of ibopamine ( 150 - 300 mg/day ) on exercise testing , symptoms and subjective feeling of well-being , in 150 CHF elderly patients ( mean age 75 years ) under treatment with digitalis and /or diuretics . During an additional open follow-up of approximately 1.5 years , morbid events and deaths were also recorded . Captopril and ibopamine performed better ( p less than 0.01 ) than placebo , improving the 6-min walking distance  ( captopril from 300 to 404 m , ibopamine from 282 to 385 m ; placebo from 283 to 299 m ) . NYHA status , symptom score and patients ' global assessment . The difference between the active study drugs was not statistically significant ( p greater than 0.05 ) . Complicating events , including diuretic use , frequency of hospitalization , worsening of CHF and deaths , were grouped by patient-years . These events were significantly ( p less than 0.01 ) lower ( captopril : 28/75 patient-years ; ibopamine 33/74 patient-years ) in the active treatment groups with respect to placebo ( 58/96 patient-years ) . Captopril and ibopamine showed a different safety profile . Creatinine increase ( 2 patients ) , symptomatic hypotension ( 4 patients ) , hyperkalemia ( 2 patients ) and upper respiratory symptoms were mostly associated with captopril treatment . Gastrointestinal adverse events were observed in 11 patients under ibopamine treatment . The study provides evidence of the clinical usefulness of both captopril or ibopamine in the long-term treatment of CHF in old patients . The safety profile of each drug will suggest the preferred therapeutic application OBJECTIVES This study was performed to compare the long-term clinical efficacy of treatment with metoprolol versus carvedilol in patients with chronic heart failure . BACKGROUND Beta-adrenergic blockade is of proven value in chronic heart failure .  Metoprolol , a selective beta-blocker , is widely used , but recent trials suggest carvedilol , a nonselective beta-blocker with alpha-1-receptor antagonist activity and antioxidant activities , is also effective . It is uncertain , however , if these additional properties of carvedilol provide further clinical benefit compared with metoprolol . METHODS In this r and omized double-blind control trial , 51 patients with chronic heart failure and mean left ventricular ( LV ) ejection fraction of 26 % + /- 1.8 % were r and omly assigned treatment with metoprolol 50 mg twice daily or carvedilol 25 mg twice daily in addition to st and ard therapy after a four-week dose titration period for a total of 12 weeks . Response was assessed by a quality of life question naire , New York Heart Association class , exercise capacity ( 6-min walk test ) , radionucleotide ventriculography for LV ejection fraction , two-dimensional echocardiography measurement of LV dimensions and diastolic filling and 24-h electrocardiograph monitoring to assess heart rate variability . RESULTS Both carvedilol and metoprolol produced highly significant improvement in symptoms ( p < 0.001 ) , exercise capacity ( p < 0.05 ) and LV ejection fraction ( p < 0.001 ) , and there were no significant differences between the two drugs . Carvedilol had a significantly greater effect on sitting and st and ing blood pressure , LV end-diastolic dimension and normalized the mitral E wave deceleration time . CONCLUSIONS Both metoprolol and carvedilol were equally effective in improving symptoms , quality of life , exercise capacity and LV ejection fraction , although carvedilol lowers blood pressure more than metoprolol Although a cornerstone in the treatment of heart failure , angiotensin-converting enzyme inhibitors are under-used , partly due to side effects . If proven at least similarly efficacious to angiotensin-converting enzyme inhibitors , angiotensin-receptor blockers may replace them due to their superior tolerability . We aim ed to compare the efficacy and safety of valsartan and enalapril in heart failure patients stabilised on an angiotensin-converting enzyme inhibitor . We r and omised 141 patients ( mean 68 years , 74 % males ) with stable mild/moderate heart failure and left ventricular ejection fraction 0.45 or less , to valsartan 160 mg q.d . ( n=70 ) or enalapril 10 mg b.i.d . ( n=71 ) for 12 weeks . Changes in 6-min-walk test ( primary efficacy variable ) , patients ' wellbeing and left ventricular size and function did not differ significantly between the treatment groups . Valsartan was significantly non-inferior to enalapril in walk test distance change : least-square means treatment difference + 1.12 m ( 95 % confidence interval -21.9 to 24.1 ) , non-inferiority P<0.001 . Left ventricular size ( P<0.001 ) and function ( P=0.048 ) improved significantly only in the valsartan group . Fewer patients experienced adverse events in the valsartan group ( 50 % ) than in the enalapril group ( 63 % ) , although statistically non-significant . Valsartan is similarly efficacious and safe to enalapril in patients with stable , mild/moderate heart failure , previously stabilised on an angiotensin-converting enzyme inhibitor and directly switched to study medication Beta blockers are known to suppress renin release in hypertension and in patients taking angiotensin-converting enzyme ( ACE ) inhibitors . This study sought to explore the effect of additional beta blockade on neurohumoral modulation in patients with severe heart failure ( HF ) who received ACE inhibitors . Forty-nine patients with chronic HF who received ACE inhibitors  were given metoprolol 50 mg or carvedilol 25 mg twice daily after a 4-week dose titration period in addition to st and ard therapy in a prospect i ve trial . Sample s of  plasma renin activity ( PRA ) , aldosterone , aminoterminal B-type natriuretic peptide ( N-BNP ) , and atrial natriuretic peptide ( ANP ) were taken at baseline and at 4 , 12 , and 52 weeks after starting therapy . Treatment with either beta blocker significantly lowered PRA at 4 weeks compared with baseline ( -2.0 + /- 0.6 nmol/L/hour , p = 0.006 ) , but at 12 weeks , PRA had reduced to -1.1 + /- 0.6 nmol/L/hour ( p = 0.08 ) , but at 52 weeks , it was not significantly different from baseline ( + 1.05 + /- 0.6 nmol/L/hour , p = 0.13 ) . Aldosterone levels did not change significantly from baseline at 4 or 12 weeks , although there was a nonsignificant trend for lower levels at 52 weeks ( baseline 232 + /- 154 pmol/L , 52 weeks 192 + /- 100 pmol/L , p = 0.09 ) . There was significant reduction in N-BNP and ANP together with an improvement in symptom and left ventricular systolic function at 1-year follow-up . These results indicate that the suppressive effect of beta blockers on PRA in patients with HF taking  ACE inhibitors is temporary , and that there is no significant effect on serum aldosterone levels Background This prospect i ve placebo-controlled trial was design ed to determine whether intravenous immune globulin ( IVIG ) improves left ventricular ejection fraction ( LVEF ) in adults with recent onset of idiopathic dilated cardiomyopathy or myocarditis . Methods and Results Sixty-two patients ( 37 men , 25 women ; mean age ±SD 43.0±12.3 years ) with recent onset ( ≤6 months of symptoms ) of dilated cardiomyopathy and LVEF ≤0.40 were r and omized to 2 g/kg IVIG or placebo .  All underwent an  endomyocardial biopsy  before r and omization , which revealed cellular inflammation in 16 % . The primary outcome was change in LVEF at 6 and 12 months after r and omization . Overall , LVEF improved from 0.25±0.08 to 0.41±0.17 at 6 months ( P < 0.001 ) and 0.42±0.14 ( P < 0.001 versus baseline ) at 12 months . The increase was virtually identical in patients receiving IVIG and those given placebo ( 6 months : IVIG 0.14±0.12 , placebo 0.14±0.14 ; 12 months : IVIG 0.16±0.12 , placebo 0.15±0.16 ) . Overall , 31 ( 56 % ) of 55 patients at 1 year had an increase in LVEF ≥0.10 from study entry , and 20 ( 36 % ) of 56 normalized their ejection fraction ( ≥0.50 ) . The transplant-free survival rate was 92 % at 1 year and 88 % at 2 years . Conclusions These results suggest that for patients with recent-onset dilated cardiomyopathy  , IVIG does not augment the improvement in LVEF . However , in this overall cohort , LVEF improved significantly during follow-up , and the short-term prognosis remains favorable It has been proposed that worsening of heart failure with dihydropyridines , such as nicardipine , is related to the activation of the neuroendocrine system . To test this , we evaluated 20 patients with severe heart failure ( mean age , 55 ± 13 years ; New York Heart Association functional class III ; left ventricular ejection fraction , 18 % ± 8 % on maintenance therapy with captopril , digoxin , and diuretics ) who were r and omized to nicardipine ( 60 or 90 mg/d ) or placebo during a 4-month double-blind protocol . The following measurements were obtained at baseline , monthly , and at 4 months or last follow-up visit : rest and exercise radionuclide ventriculography , maximal treadmill time , 6-minute walking test distance , serum norepinephrine and aldosterone concentrations , and plasma renin activity . During the follow-up period , worsening of heart failure occurred in 6 patients in the nicardipine group and in 2 patients in the placebo group ( p = 0.06 ) . The maximal treadmill time for a 6-minute walking distance and exercise radionuclide ejection fraction at the last follow-up visit did not change in patients who did not deteriorate with heart failure in the placebo or nicardipine groups as compared with baseline values . In this study group of patients with severe heart failure receiving therapy with digoxin , captopril , and diuretics , nicardipine was associated with worsening heart failure without an apparent activation of the neurohormones . However , because of the small number of patients and a significant number of patients who deteriorated during the follow-up period , no definitive conclusions can be made OBJECTIVE To determine whether a third generation vasodilating beta blocker ( celiprolol ) has long term clinical advantages over metoprolol in patients with chronic heart failure . DESIGN A double blind placebo controlled r and omised trial . SETTING University teaching Hospital . PATIENTS 50 patients with stable chronic heart failure ( NYHA class II-IV ) due to idiopathic dilated , ischaemic , or hypertensive cardiomyopathy , with left ventricular ejection fraction < 0.45 . INTERVENTIONS Celiprolol 200 mg daily ( n = 21 ) , metoprolol 50 mg twice daily ( n = 19 ) , or placebo ( n = 10 ) for three months with a four week dose titration period . After the double blind period , patients entered an open label study ( with placebo group receiving beta blockers ) and were assessed after one year . MAIN OUTCOME MEASURES Clinical response , efficacy , and tolerance were assessed by the Minnesota heart failure symptom question naire six minute walk test , Doppler echocardiography ( systolic and diastolic function ) , radionuclide ventriculography , and atrial and brain natriuretic peptides measured at baseline and after three months . RESULTS In the metoprolol group at 12 weeks v baseline there was a 47 % reduction in symptom score ( p < 0.001 ) , improvement of NYHA class ( mean ( SEM ) , 2.6 ( 0.12 ) to 1.9 ( 0.13 ) , p = 0.001 ) , exercise distance ( 1246 ( 54 ) to 1402 ( 52 ) feet , p < 0.001 ) , and left ventricular ejection fraction ( 26.9(3.1)% to 31(3.0)% , p = 0.016 ) , and a fall in heart rate ( resting , 79 ( 3 ) to 62 ( 3 ) beats/min , p < 0.001 ) . In the celiprolol group there was a 38 % reduction in symptom score ( p = 0.02 ) , less improvement in exercise distance ( 1191 ( 55 ) to 1256 ( 61 ) feet , p = 0.05 ) , and no significant changes in NYHA class , left ventricular ejection fraction , or heart rate . Mortality at one year was 11 % in metoprolol and 19 % in the celiprolol group , and symptomatic improvement was maintained in the survivors . CONCLUSIONS Both drugs were well tolerated but the vasodilator properties of celiprolol do not seem to provide any obvious additional benefit in the long term treatment of heart failure OBJECTIVES We assessed the clinical efficacy of single-site left ventricular ( LV ) pacing and determined the impact of baseline conduction delay severity on the magnitude of benefit . BACKGROUND Multisite biventricular pacing can improve heart failure ( HF ) symptoms in patients with an intraventricular conduction delay by resynchronizing abnormal ventricular contractions and improving LV systolic function . METHODS Eighty-six patients with at least New York Heart Association functional class II HF , chronic LV systolic dysfunction , normal sinus rhythm , and a QRS interval over 120 ms were implanted for atrial-synchronized LV pacing . The single-blinded , r and omized , controlled , crossover study stratified patients 1:1 by the baseline QRS interval into long ( QRS > 150 ms ) and short ( QRS 120 to 150 ms ) groups , which were compared during a three-month period of active ( univentricular ) pacing and a three-month period of inactive ( ventricular inhibited ) pacing . The primary end point was peak oxygen consumption ( VO(2 ) ) followed by anaerobic threshold , distance walked in 6 min , and quality -of-life question naire score . PATIENTS Twelve patients were withdrawn before r and omization and 17 could not complete both study periods . The short QRS group did not improve in any end point with active pacing . For the long QRS group , peak VO(2 ) increased 2.46 ml/min/kg ( p < 0.001 ) , the anaerobic threshold increased 1.55 ml/min/kg ( p < 0.001 ) , the distance walked in 6 min increased 47 m ( p = 0.024 ) , and the quality -of-life score improved 8.1 points ( p = 0.004 ) . CONCLUSIONS Left ventricular pacing significantly improves exercise tolerance and quality of life in patients with chronic HF , LV systolic dysfunction , and a QRS interval over 150 ms OBJECTIVES This study assessed the feasibility of an efficacy trial comparing angiotensin-converting enzyme inhibition and angiotensin II receptor antagonism in heart failure . Patients with moderate or severe heart failure whose condition had previously been stabilized by treatment with a converting enzyme inhibitor were r and omly assigned to receive enalapril or losartan . The study was design ed to detect any signs of clinical deterioration during double-blind treatment . BACKGROUND Losartan is a specific , nonpeptide angiotensin II receptor-1 antagonist with a vasodilator hemodynamic profile similar to that of converting enzyme inhibitors . Although therapy with specific receptor blockade has certain theoretic advantages over nonspecific converting enzyme inhibition , demonstration of a comparable therapeutic effect in patients with congestive heart failure will require a major effort comparing two active agents . METHODS One hundred sixty-six patients with stable heart failure in New York Heart Association functional class III or IV and an ejection fraction < or = 35 % were included in a multicenter , double-blind , parallel , enalapril-controlled trial . After a 3-week stabilization period with optimal therapy , including digitalis , diuretic drugs and a converting enzyme inhibitor , patients were r and omly assigned to 8 weeks of therapy with losartan , 25 mg/day ( n = 52 ) ; losartan , 50 mg/day ( n = 56 ) ; or enalapril , 20 mg/day ( n = 58 ) . Patients were assessed with frequent clinical and laboratory evaluation and exercise testing . RESULTS No significant differences between groups in terms of changes in exercise capacity ( 6-min walk test ) , clinical status ( dyspnea-fatigue index ) , neurohumoral activation ( norepinephrine , N-terminal atrial natriuretic factor ) , laboratory evaluation or incidence of adverse experience were observed . CONCLUSIONS The results suggest that losartan and enalapril are of comparable efficacy and tolerability in the short-term treatment of moderate or severe congestive heart failure . A trial design ed to compare the efficacy , tolerability and effect on mortality of long-term angiotensin II receptor blockade with converting enzyme inhibition is both feasible and ethically responsible Abstract This double-blind , placebo-controlled study evaluated the effects of the ACE inhibitor , quinapril , on the functional status of elderly frail heart failure patients with preserved systolic function . Seventy-four elderly patients , mean ( SD ) age 78 ( 7 ) years , with symptomatic heart failure ( NYHA II – III ) and normal or only mildly impaired left ventricular systolic function ( ejection fraction ≥40 % ) were r and omly assigned to receive either quinapril or matched placebo ( titrated to 40 mg/day ) for 6 months . There were no significant differences at baseline in terms of age , cardiac function , aetiology , concomitant treatment , and echocardiographic values between active and placebo groups . Mean 6-minute walk distance increased at six months in the quinapril group [ 241.2 ( 132.0 ) v 267.3 ( 124.0 ) metres , p = 0.04 ] and in the placebo group [ 214.6 ( 114.5 ) v 267.6 ( 117.0 ) metres , p = 0.003 ] . The mean increases between the two groups were not significantly different . There were no significant changes in quality of life scores . The number of adverse drug events was similar in the two groups . Patients in the quinapril group were less likely to have worsening heart failure or to be admitted to hospital but these changes were not statistically significant . Conclusions . The present study confirmed the feasibility of single-centre drug trials in very elderly heart failure patients although recruitment and retention remain problematic . It did not show a beneficial effect of quinapril on exercise tolerance and quality of life in elderly heart failure patients with preserved systolic function OBJECTIVES This study was design ed to determine 1 ) whether 12-week oral administration of losartan , an angiotensin II receptor antagonist , in patients with heart failure is well tolerated ; and 2 ) whether functional capacity and clinical status of patients with heart failure in whom treatment with an angiotensin-converting enzyme ( ACE ) inhibitor is replaced with losartan for 12 weeks will remain similar to that noted in patients in whom treatment with an ACE inhibitor is continued . BACKGROUND Losartan is a specific , nonpeptide angiotensin II receptor antagonist . Although specific receptor blockade with losartan has certain theoretic advantages over nonspecific ACE inhibition , definitive demonstration of comparable effects in patients with congestive heart failure is lacking . METHODS A double-blind , multicenter , r and omized , parallel , enalapril-controlled study was conducted in 116 patients with congestive heart failure ( New York Heart Association functional classes II to IV ) and left ventricular ejection fraction < or = 45 % previously treated with stable doses of ACE inhibitors and diuretic agents , with or without concurrent digitalis and other vasodilators .  After a baseline exercise period , open-label ACE inhibitors were discontinued , and patients were r and omly assigned to 12 weeks of therapy with losartan , 25 mg/day ( n = 38 ) ; losartan , 50 mg/day ( n = 40 ) ; or enalapril , 20 mg/day ( n = 38 ) . Drug efficacy was evaluated by changes in maximal treadmill exercise time ( using a modified Naughton protocol ) , 6-min walk test , left ventricular ejection fraction and dyspnea-fatigue index . Safety was measured by the incidence of clinical and laboratory adverse experiences . RESULTS The treadmill exercise time and the 6-min walk test did not change significantly after replacement of ACE inhibitor therapy with losartan . Similarly , a significant change was not observed in either the dyspnea-fatigue index or left ventricular ejection fraction at the end of double-blind period relative to baseline . CONCLUSIONS Losartan was generally well tolerated and comparable to enalapril in terms of exercise tolerance in this short-term ( 12-week ) study of patients with heart failure . The clinical effects of long-term angiotensin II receptor blockade compared with ACE inhibition remain to be studied BACKGROUND We sought to investigate whether beta-blockers exert a presynaptic effect in the myocardium as measured by 123I-metaiodobenzylguanidine . METHODS The study comprised 59 patients with congestive heart failure , New York Heart Association class II or III , and left ventricular ejection fraction < 35 % . After an open label titration phase , patients were r and omized to their maximal tolerable dose of metoprolol or placebo .  Myocardial MIBG uptake was measured before the titration phase and after 6 months of treatment . Other parameters were maximal oxygen consumption , 6-minute walking test , plasma neurohormones , and echocardiographic parameters . RESULTS We found a 21.9 % increase in mean myocardial MIBG uptake after 6 months of treatment with metoprolol . In contrast , MIBG uptake decreased by 7.8 % in the placebo group ( P = 0.03 compared with metoprolol ) . Left ventricular end-diastolic diameter decreased from 74 + /- 11 mm to 67 + /- 10 mm ( P < .05 , within-group comparison ) and LVEF increased from 25.3 % + /- 7.4 % to 32.6 % + /- 9.6 % ( P < .05 , within-group comparison ) in the metoprolol group . Placebo-treated patients showed no significant changes . Comparison of changes in left ventricular end-diastolic diameter and LVEF between metoprolol and placebo did not reach statistical significance ( P = 0.2 ) . CONCLUSIONS This r and omized , placebo-controlled study demonstrates that metoprolol has a presynaptic effect as measured by myocardial MIBG scintigraphy in both ischemic and nonischemic cardiomyopathy Objective : To evaluate the effects of the angiotensin converting enzyme inhibitor perindopril on six minute walking distance and quality of life in very old patients with left ventricular systolic dysfunction . Design : Prospect i ve , double blind placebo controlled trial . Setting : Medicine for the elderly day hospital . Patients : 66 patients ( average age 81 ) with left ventricular systolic dysfunction identified by echocardiography . Interventions : 10 weeks of treatment with titrated doses of perindopril or placebo . Main outcome measures : Six minute walking distance 10 weeks following treatment , quality of life measurements including the Minnesota living with heart failure question naire and the 36 item short form health survey . Results : In patients with left ventricular systolic dysfunction , six minute walking distance was significantly increased in the treatment group ( 37.1 m ) compared with the placebo group ( −0.3 m , p < 0.001 ) . The medication was well tolerated and there were no significant adverse events . Conclusions : Six minute walking distance is improved considerably by treatment with perindopril in older patients with heart failure caused by left ventricular systolic dysfunction Walking tests , frequently used to document effects of treatment on exercise capacity , have never been st and ardised . We studied the effects of encouragement on walking test performance in a r and omised study that controlled for the nature of the underlying disease , time of day , and order effects . We r and omised 43 patients with chronic airflow limitation or chronic heart failure or both to receive or not receive encouragement as they performed serial two and six minute walks every fortnight for 10 weeks . Simple encouragement improved performance ( p less than 0.02 for the six minute walk ) , and the magnitude of the effect was similar to that reported for patients in studies purporting to show beneficial effects of therapeutic manoeuvres . Age and test repetition also affected performance . These results demonstrate the need for careful st and ardisation of the performance of walking tests , and suggest caution in interpreting studies in which st and ardisation is not a major feature of the study design Background — Patients with chronic heart failure ( CHF ) are frequently anemic . An increase in hemoglobin could enhance exercise performance by increasing oxygen delivery . We investigated the effect of erythropoietin ( EPO ) on exercise performance in anemic patients with CHF . Methods and Results —Twenty-six anemic patients aged 57±11 years were r and omized to receive EPO ( 15 000 to 30 000 IU per week ) or placebo for 3 months . Parameters measured at baseline and end therapy included blood parameters ( hemoglobin , hematocrit , plasma volume ) , exercise parameters ( peak oxygen consumption [ & OV0312;o2 ] , exercise duration , 6-minute walk ) , muscle aerobic metabolism ( half-time of & OV0312;o2 and near infrared recovery ) , and forearm vasodilatory function .  EPO was well tolerated by all patients . Twelve patients in the  EPO  group felt improvement versus 1 in the placebo group ( P < 0.05 ) . There were significant increases in hemoglobin ( 11.0±0.5 to 14.3±1.0 g/dL , P < 0.05 ) , peak & OV0312;o2 ( 11.0±1.8 to 12.7±2.8 mL · min−1 · kg−1 , P < 0.05 ) and exercise duration ( 590±107 to 657±119 s , P < 0.004 ) in the EPO group but no significant changes in the control group . Resting and hyperemic forearm vascular resistance and indices of the rate of muscle oxidative capacity were unchanged in both groups . Conclusion —EPO significantly enhances exercise capacity in patients with CHF . One mechanism of improvement in & OV0312;o2 is increased oxygen delivery from increased hemoglobin concentration BACKGROUND Beta-blocking agents reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure , but little is known about their effects in severe heart failure . METHODS We evaluated 2289 patients who had symptoms of heart failure at rest or on minimal exertion , who were clinical ly euvolemic , and who had an ejection fraction of less than 25 percent . In a double-blind fashion , we r and omly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol  for a mean period of 10.4 months , during which st and ard therapy for heart failure was continued . Patients who required intensive care , had marked fluid retention , or were receiving intravenous vasodilators or positive inotropic drugs were excluded . RESULTS There were 190 deaths in the placebo group and 130 deaths in the carvedilol group . This difference reflected a 35 percent decrease in the risk of death with carvedilol ( 95 percent confidence interval , 19 to 48 percent ; P=0.00013 , unadjusted ; P=0.0014 , adjusted for interim analyses ) . A total of 507 patients died or were hospitalized in the placebo group , as compared with 425 in the carvedilol group . This difference reflected a 24 percent decrease in the combined risk of death or hospitalization with carvedilol ( 95 percent confidence interval , 13 to 33 percent ; P<0.001 ) . The favorable effects on both end points were seen consistently in all the subgroups we examined , including patients with a history of recent or recurrent cardiac decompensation . Fewer patients in the carvedilol group than in the placebo group withdrew because of adverse effects or for other reasons ( P=0.02 ) . CONCLUSIONS The previously reported benefits of carvedilol with regard to morbidity and mortality in patients with mild-to-moderate heart failure were also apparent in the patients with severe heart failure who were evaluated in this trial CONTEXT Cardiac resynchronization therapy ( CRT ) through biventricular pacing is an effective treatment for heart failure ( HF ) with a wide QRS ; however , the outcomes of patients requiring CRT and implantable cardioverter defibrillator ( ICD ) therapy are unknown . OBJECTIVE To examine the efficacy and safety of combined CRT and ICD therapy in patients with New York Heart Association ( NYHA ) class III or IV congestive HF despite appropriate medical management . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , parallel-controlled trial conducted from October 1 , 1999 , to August 31 , 2001 , of 369 patients with left ventricular ejection fraction of 35 % or less , QRS duration of 130 ms , at high risk of life-threatening ventricular arrhythmias , and in NYHA class III ( n = 328 ) or IV ( n = 41 ) despite optimized medical treatment . INTERVENTIONS Of 369 r and omized patients who received devices with combined CRT and ICD capabilities , 182 were controls ( ICD activated , CRT off ) and 187 were in the CRT group ( ICD activated , CRT on ) . MAIN OUTCOME MEASURES The primary double-blind study end points were changes between baseline and 6 months in quality of life , functional class , and distance covered during a 6-minute walk . Additional outcome measures included changes in exercise capacity , plasma neurohormones , left ventricular function , and overall HF status . Survival , incidence of ventricular arrhythmias , and rates of hospitalization were also compared . RESULTS At 6 months , patients assigned to CRT had a greater improvement in median ( 95 % confidence interval ) quality of life score ( -17.5 [ -21 to -14 ] vs -11.0 [ -16 to -7 ] , P = .02 ) and functional class ( -1 [ -1 to -1 ] vs 0 [ -1 to 0 ] , P = .007 ) than controls but were no different in the change in distance walked in 6 minutes ( 55 m [ 44 - 79 ] vs 53 m [ 43 - 75 ] , P = .36 ) . Peak oxygen consumption increased by 1.1 mL/kg per minute ( 0.7 - 1.6 ) in the CRT group vs 0.1 mL/kg per minute ( -0.1 to 0.8 ) in controls ( P = .04 ) , although treadmill exercise duration increased by 56 seconds ( 30 - 79 ) in the CRT group and decreased by 11 seconds ( -55 to 12 ) in controls ( P<.001 ) . No significant differences were observed in changes in left ventricular size or function , overall HF status , survival , and rates of hospitalization . No proarrhythmia was observed and arrhythmia termination capabilities were not impaired . CONCLUSIONS Cardiac resynchronization improved quality of life , functional status , and exercise capacity in patients with moderate to severe HF , a wide QRS interval , and life-threatening arrhythmias . These improvements occurred in the context of underlying appropriate medical management without proarrhythmia or compromised ICD function OBJECTIVES We sought to compare the short- and long-term clinical effects of atrial synchronous pre-excitation of one ( univentricular ) or both ventricles ( biventricular ) , that provide cardiac resynchronization therapy ( CRT ) . BACKGROUND In patients with heart failure ( HF ) who have a ventricular conduction delay , CRT improves systolic hemodynamic function . The clinical benefit of CRT is still being investigated . METHODS Forty-one patients were r and omized to four weeks of first treatment with biventricular or univentricular stimulation  , followed by four weeks without treatment , and then four weeks of a second treatment with the opposite stimulation . The best CRT stimulation was continued for nine months . Cardiac resynchronization therapy was optimized by hemodynamic testing at implantation . The primary end points were exercise capacity measures . Data were analyzed by two-way repeated- measures analysis of variance . RESULTS The left ventricle was selected for univentricular pacing in 36 patients . The clinical effects of univentricular and biventricular CRT were not significantly different . The results of each method were pooled to assess sequential treatment effects . Oxygen uptake during bicycle exercise increased from 9.48 to 10.4 ml/kg/min at the anaerobic threshold ( p = 0.03 ) and from 12.5 to 14.3 ml/kg/min at peak exercise ( p < 0.001 ) with the first treatment , and from 10.0 to 10.7 ml/kg/min at the anaerobic threshold ( p = 0.2 ) and from 13.4 to 15.2 ml/kg/min at peak exercise ( p = 0.002 ) with the second treatment . The 6-min walk distance increased from 342 m at baseline to 386 m after the first treatment ( p < 0.001 ) and to 416 m after the second treatment ( p = 0.03 ) . All improvements persisted after 12 months of therapy . CONCLUSIONS Cardiac resynchronization therapy produces a long-term improvement in the clinical symptoms of patients with HF who have a ventricular conduction delay . The differences between optimized biventricular and univentricular therapy appear to be small for short-term treatment Objective : To compare clinical and haemodynamic variables between left ventricular and biventricular pacing in patients with severe heart failure ; and to analyse haemodynamic changes during daily life and maximum exercise during chronic left ventricular and biventricular pacing . Design : Prospect i ve single blinded r and omised study with crossover . Setting : University hospital ( tertiary referral centre ) . Patients and methods : 13 patients ( mean ( SD ) age , 62 ( 6 ) years ) with chronic atrial fibrillation , severe heart failure ( mean ejection fraction 24 (8)% ) , and QRS prolongation of ≥ 140 ms had His bundle ablation and installation of a pacemaker providing left ventricular and biventricular pacing . The pacemaker was equipped with a peak endocardial acceleration ( PEA ) sensor . The PEA pattern was used as a haemodynamic marker during exercise as it is highly correlated with left ventricular dP/dt . After a baseline period of right ventricular pacing , all patients had two months of left ventricular pacing and two months of biventricular pacing in r and om order . At the end of each phase , an echocardiogram , a haemodynamic analysis at rest and on exercise during a six minute walk test , and a cardiopulmonary exercise test were performed . Results : PEA values were higher with left ventricular pacing ( 0.58 ( 0.38 ) m/s ) and biventricular pacing ( 0.62 ( 0.24 ) m/s ) than at baseline ( 0.49 ( 0.18 ) m/s ) ( p < 0.05 ) . The six minute walk test showed similar performance in both pacing modes , but patients had more symptoms with left ventricular pacing at the end of the test ( p = 0.035 ) . On cardiopulmonary exercise testing , there was a greater increase in mean percentage variation of PEA with biventricular pacing than with left ventricular pacing ( 125 (18)% v 97 (36)% , respectively ; p = 0.048 ) and better performance figures ( 92 ( 34 ) W v 77 ( 23 ) W ; p = 0.03 ) . Conclusions : During symptom limited and daily life exercise tests , chronic biventricular pacing  provides better haemodynamic performance  than left ventricular pacing . In heart failure patients with wide QRS complexes , the interventricular dyssynchronisation induced by left ventricular pacing may impair myocardial function during exercise This study was design ed to assess the efficacy and safety of berberine for chronic congestive heart failure ( CHF ) . One hundred fifty-six patients with CHF and > 90 ventricular premature complexes ( VPCs ) and /or nonsustained ventricular tachycardia ( VT ) on 24-hour Holter monitoring were r and omly divided into 2 groups . All patients were given conventional therapy for CHF , consisting of angiotensin-converting enzyme inhibitors , digoxin , diuretics , and nitrates .  Patients in the treatment group ( n = 79 ) were also given berberine 1.2 to 2.0 g/day . The remaining 77 patients were given  placebo . Symptoms , a 6-minute walk test , left ventricular ( LV ) ejection fraction ( EF ) , frequency and complexity of VPCs , and quality of life were assessed after 8 weeks of treatment and during a mean 24-month follow-up . After treatment with berberine , there was a significantly greater increase in LVEF , exercise capacity , improvement of the dyspnea-fatigue index , and a decrease of frequency and complexity of VPCs compared with the control group . There was a significant decrease in mortality in the berberine-treated patients during long-term follow-up ( 7 patients receiving treatment died vs 13 on placebo , p < 0.02 ) . Proarrhythmia was not observed , and there were no apparent side effects . Thus , berberine improved quality of life and decreased VPCs and mortality in patients with CHF BACKGROUND Although previous studies suggested that TNF may contribute to heart failure progression , it is unclear whether antagonizing TNF is beneficial in heart failure patients . METHODS AND RESULTS Eighteen NYHA class III heart failure patients were r and omized into a double-blind dose-escalation study to examine the safety and potential efficacy of etanercept , a specific TNF antagonist ( Enbrel ) . Patients received placebo ( 6 patients ) or an escalating dose ( 1 , 4 , or 10 mg/m2 ) of etanercept ( 12 patients ) given as a single intravenous infusion . Safety parameters and patient functional status were assessed at baseline and at days 1 , 2 , 7 , and 14 . There were no significant side effects or clinical ly significant changes in laboratory indices . There was , however , a decrease in TNF bioactivity and a significant overall increase in quality -of-life scores , 6-minute walk distance , and ejection fraction in the cohort that received 4 or 10 mg/m2 of etanercept ; there was no significant change in these parameters in the placebo group . CONCLUSIONS A single intravenous infusion of etanercept was safe and well tolerated in patients with NYHA class III heart failure . These studies provide provisional evidence that suggests that etanercept is sufficient to lower levels of biologically active TNF and may lead to improvement in the functional status of patients with heart failure BACKGROUND One third of chronic heart failure patients have major intraventricular conduction and uncoordinated ventricular contraction . Non-controlled studies suggest that biventricular pacing may improve haemodynamics and well-being by reducing ventricular asynchrony . The aim of this trial was to assess the clinical efficacy and safety of this new therapy in patients with chronic atrial fibrillation . METHODS Fifty nine NYHA class III patients with left ventricular systolic dysfunction , chronic atrial fibrillation , slow ventricular rate necessitating permanent ventricular pacing , and a wide QRS complex ( paced width > or=200 ms ) , were implanted with transvenous biventricular-VVIR pacemakers . This single-blind , r and omized , controlled , crossover study compared the patients ' parameters , as monitored during two 3-month treatment periods of conventional right-univentricular vs biventricular pacing . The primary end-point was the 6-min walked distance , secondary end-points were peak oxygen uptake , quality -of-life , hospitalizations , patients ' preferred study period and mortality . RESULTS Because of a higher than expected drop-out rate ( 42 % ) , only 37 patients completed both crossover phases . In the intention-to-treat analysis , we did not observe a significant difference . However , in the patients with effective therapy the mean walked distance increased by 9.3 % with biventricular pacing ( 374+/-108 vs 342+/-103 m in univentricular;P = 0.05 ) . Peak oxygen uptake increased by 13 % ( P=0.04 ) . Hospitalizations decreased by 70 % and 85 % of the patients preferred the biventricular pacing period ( P<0.001 ) . CONCLUSION As compared with conventional VVIR pacing , effective biventricular pacing seems to improve exercise tolerance in NYHA class III heart failure patients with chronic atrial fibrillation and wide paced-QRS complexes . Further r and omized controlled studies are required to definitively vali date this therapy in such patients BACKGROUND We investigated the effects of c and esartan ( an angiotensin II antagonist ) alone , enalapril alone , and their combination on exercise tolerance , ventricular function , quality of life ( QOL ) , neurohormone levels , and tolerability in congestive heart failure ( CHF ) . METHODS AND RESULTS Seven hundred sixty-eight patients in New York Heart Association functional class ( NYHA-FC ) II to IV with ejection fraction ( EF ) < 0.40 and a 6-minute walk distance ( 6MWD ) < 500 m received either c and esartan ( 4 , 8 , or 16 mg ) ,  c and esartan ( 4 or 8 mg ) plus  20 mg  of enalapril , or  20 mg of enalapril  for 43 weeks . There were no differences among groups with regard to 6MWD , NYHA-FC , or QOL . EF increased ( P = NS ) more with c and esartan-plus-enalapril therapy ( 0.025+/-0.004 ) than with c and esartan alone ( 0.015+/-0.004 ) or enalapril alone(0.015+/-0.005 ) . End-diastolic ( EDV ) and end-systolic ( ESV ) volumes increased less with combination therapy ( EDV 8+/-4 mL ; ESV 1+/-4 mL ; P<0.01 ) than with c and esartan alone ( EDV 27+/-4 mL ; ESV 18+/-3 mL ) or enalapril alone ( EDV 23+/-7 mL ; ESV 14+/-6 mL ) . Blood pressure decreased with combination therapy ( 6+/-1/4+/-1 mm Hg ) compared with c and esartan or enalapril alone ( P<0.05 ) . Aldosterone decreased ( P<0.05 ) with combination therapy ( 23.2+/-5.3 pg/mL ) at 17 but not 43 weeks compared with c and esartan ( 0.7+/-7.8 pg/mL ) or enalapril ( -0.8+/-11 . 3 pg/mL ) . Brain natriuretic peptide decreased with combination therapy ( 5.8+/-2.7 pmol/L ; P<0.01 ) compared with c and esartan ( 4 . 4+/-3.8 pmol/L ) and enalapril alone ( 4.0+/-5.0 pmol/L ) . CONCLUSIONS C and esartan alone was as effective , safe , and tolerable as enalapril . The combination of c and esartan and enalapril was more beneficial for preventing left ventricular remodeling than either c and esartan or enalapril alone The safety and benefit of outpatient inotrope infusions in intractable heart failure remains controversial . Accordingly a prospect i ve double blind , crossover r and omization scheme was utilized in stable patients with heart failure but intractable symptoms . A total of 29 patients ( mean age 66 + /- 13 years , with a mean left ventricular systolic function of 18 + /- 9 % , New York Heart Association class 3.6 + /- 0.5 ) met all the inclusion and none of the exclusion criteria to receive  intravenous milrinone , dobutamine , or matching placebo .  Safety evaluations including routine laboratory studies , physical examinations , electrocardiographic monitoring , vital signs , assessment of quality of life scores using the Minnesota Living with Heart Failure question naire , six-minute walk tests , and echocardiographic assessment s were performed . All 29 patients completed the weaning protocol without adverse events ( mean of 27.3 + /- 11.8 treatments per patient ) . Patients initially assigned to milrinone received fewer treatment sessions ( 19 + /- 8 versus 31 + /- 12 ( dobutamine ) and 33 + /- 10 ( placebo ) ; p<0.02 . Furthermore , only 10 % of the patients treated with milrinone required crossover r and omization compared to 27 % patients assigned to dobutamine and 75 % patients assigned to placebo . A statistically significant reduction in quality of life scores ( 60 + /- 20 versus 35 + /- 18 ; p < 0.00001 ) with an increase in 6-minute walk test assessment s ( 959 + /- 431 versus 1269 + /- 469 ; p < 0.01 ) was noted . Most importantly , in patients assigned to inotropes a 23 % increase in 6-minute walk test scores was noted at the end of the study when compared to baseline scores . In contrast , a reduction of -1 % ( p < 0.001 ) was noted in patients assigned to placebo . Finally , a trend that although did not reached statistical significance was noted in patients assigned to milrinone in terms of improvement in left ventricular systolic function , reduction in the severity of mitral regurgitation and estimated right ventricular systolic pressure . These results demonstrate that outpatient infusion of inotropes appear to be safe and effective in improving heart failure symptoms , reducing need for hospitalizations and emergency room visits . Furthermore , infusion of inotropes result ed in a significant improvement on 6-minute walk test scores than placebo . It also appears that milrinone confers all these benefits sooner than dobutamine UNLABELLED Beta-blocker therapy results in a functional benefit in patients with heart failure ( CHF ) due to idiopathic dilated cardiomyopathy ( DCM ) . This study assessed if similar effects were observed in patients with ischemic heart disease ( CAD ) , NYHA II-III after 6 months of therapy with metoprolol . METHODS AND RESULTS Fifty-two patients with CHF secondary to DCM ( 26 patients ) and CAD ( 26 patients ) and a left ventricular ejection fraction (EF)<40 % were enrolled in the  placebo-controlled  study . The study medication was titrated over 6 weeks , the mean final dosage was 135 mg/day . Three patients died due to cardiogenic shock , two received placebo and one metoprolol .  Eight patients did not complete the study due to non-compliance . Metoprolol significantly reduced heart rate at rest and after submaximal and maximal exercise . Vo(2)-max and Vo(2)-AT as well as the 6-min walk test improved significantly after metoprolol treatment . There was a significant increase in EF at rest ( 27.3 - 35 . 2 % ) , submaximal ( 28.5 - 37.7 % ) and maximal exercise ( 28.7 - 40.9 % ) in the metoprolol-treated patients . No differences were found between patients with CAD and DCM . We also observed reduced left ventricular volumes . CONCLUSION The additional therapy with metoprolol improved cardiac function and the cardiopulmonary exercise capacity in patients with CHF BACKGROUND The safety and efficacy of angiotensin-converting enzyme inhibitors for very old patients with chronic heart failure have been less well documented than for younger patients . METHODS A prospect i ve , r and omized double-blind , placebo-controlled study of captopril , 25 mg twice daily , was design ed . Fifty patients ( mean age 84.2 + /- 5.2 ) participated . The degree of chronic heart failure ( according to the Boston Study Group rating ) , the distance walked in 6 minutes , and the occurrence of uncontrolled heart failure and adverse reactions were used as main outcome measures . RESULTS Significantly more patients receiving placebo developed uncontrolled heart failure than patients receiving captopril ( p = .022 ) . In an intention to treat analysis , the first and last evaluations of the degree of chronic heart failure were compared . A significantly different evolution was observed between the two treatment groups ( p < .001 ) , with a significant improvement only in the captopril-treated patients ( p < .001 ) . The distance walked in 6 minutes improved significantly only in the captopril group ( p = .004 ) . The only adverse reaction was rash in two patients receiving captopril . CONCLUSIONS The study gives further evidence that angiotensin-converting enzyme inhibitor treatment for very old patients with chronic heart failure is useful BACKGROUND Clinical trials have shown that beta-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure , but the utility and safety of these drugs in patients with advanced disease have not been evaluated . METHODS AND RESULTS We enrolled 56 patients with severe chronic heart failure into a double-blind , placebo-controlled study of the vasodilating beta-blocker carvedilol .  All patients had advanced heart failure , as evidence d by a mean left ventricular ejection fraction of 0.16 + /- 0.01 and a mean maximal oxygen consumption of 13.6 + /- 0.6 mL.kg-1.min-1 despite digitalis , diuretics , and an angiotensin-converting enzyme inhibitor ( if tolerated ) . After a 3-week , open-label , up-titration period , 49 of the 56 patients were assigned ( in a double-blind fashion using a 2:1 r and omization ) to receive either carvedilol ( 25 mg BID , n = 33 ) or matching placebo ( n = 16 ) for 14 weeks , while background therapy remained constant . Hemodynamic and functional variables were measured at the start and end of the study . Compared with the placebo group , patients in the carvedilol group showed improved cardiac performance , as reflected by an increase in left ventricular ejection fraction ( P = .005 ) and stroke volume index ( P = .010 ) and a decrease in pulmonary wedge pressure , mean right atrial pressure , and systemic vascular resistance ( P = .003 , .002 , and .017 , respectively ) . In addition , compared with placebo , patients treated with carvedilol benefited clinical ly , as shown by an improvement in symptom scores ( P = .002 ) , functional class ( P = .013 ) , and submaximal exercise tolerance ( P = .006 ) . The combined risk of death , worsening heart failure , and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group ( P = .028 ) , but carvedilol-treated patients had more dizziness and advanced heart block . CONCLUSIONS Carvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors BACKGROUND The purpose of this study was to examine the effects of exercise training on functional capacity in patients with heart failure . METHODS One hundred eighty-one patients in New York Heart Association class I to III , with ejection fraction < 40 % and 6-minute walk distance < 500 meters , were recruited into a r and omized , controlled , single-blind trial comparing 3 months of supervised training , then 9 months of home-based training with usual care . RESULTS There was a significant increase in 6-minute walk distance at 3 and 12 months but no between-group differences . Incremental peak oxygen uptake increased in the exercise group compared with the control group at 3 months ( 0.104 + /- 0.026 L/min vs 0.025 + /- 0.023 L/min ; P = .026 ) and 12 months ( 0.154 + /- 0.074 L/min vs 0.024 + /- 0.027 L/min ; P = .081 ) . Compared with the control group , significant increases were observed in the exercise group for arm and leg strength . No significant changes were observed in cardiac function or quality of life . Adherence to exercise was good during supervised training but reduced during home-based training . CONCLUSIONS Exercise training improves peak oxygen uptake and strength during supervised training . Over the final 9 months of the study , there was little further improvement , suggesting that some supervision is required for these patients . There were no adverse effects on cardiac function or clinical events BACKGROUND Metoprolol provides clinical benefits in patients with congestive heart failure ( CHF ) . In this study , we investigated the effects of controlled-release metoprolol ( metoprolol CR ) on clinical status , on left ventricular ( LV ) volumes and function , and on neurohumoral activation in a large number of patients with CHF of mixed causes . METHODS AND RESULTS Four hundred twenty-six patients with symptomatic CHF were r and omized to receive metoprolol CR or placebo for 24 weeks . Metoprolol CR did not affect 6-minute walk distance , New York Heart Association functional class , or quality of life . However , there was a significant improvement in measures of LV function with an attenuation in the increase in LV end-diastolic ( + 23+/-65 mL [ placebo ] versus + 6+/-61 mL , P=0.01 ) and LV end-systolic ( + 19+/-55 mL [ placebo ] versus -2+/-51 mL , P<0.001 ) volumes after 24 weeks of therapy . LV ejection fraction was unchanged ( -0.05 % or -0.005 ) in the placebo group but increased by 2 . 4 % in the metoprolol CR-treated patients ( P=0.001 ) . Patients receiving metoprolol CR had a greater decrease in angiotensin II ( P=0.036 ) and renin ( P=0.032 ) levels but an increase in N-terminal atrial natriuretic peptide and brain natriuretic peptide levels ( P<0 . 01 ) . There were fewer deaths in the group receiving beta-blockers ( 3 . 4 % versus 8.1 % ) , and there was a similar number of patients experiencing the composite outcomes of death or any hospitalization . CONCLUSIONS When added to ACE inhibitors , angiotensin II receptor antagonists , or both , the use of metoprolol CR improves ventricular function , reduces activation of the renin-angiotensin systems , and results in fewer deaths The six-minute walking test ( WT ) is used in trials and clinical practice as an easy tool to evaluate the functional capacity of chronic heart failure ( CHF ) patients . As WT measurements are highly variable both between and within individuals , this study aims at assessing the contribution of the different sources of variation and estimating the reproducibility of the test . A statistical model describing WT measurements as a function of fixed and r and om effects is proposed and its parameters estimated . We considered 202 stable CHF patients who performed two baseline WTs separated by a 30 minute rest ;  49 of them repeated the two tests 3 months later ( follow-up control ) . They had no changes in therapy or major clinical events . Another 31 subjects performed two baseline tests separated by 24 hours . Collected data were analysed using a mixed model methodology . There was no significant difference between measurements taken 30 minutes and 24 hours apart ( p = 0.99 ) . A trend effect of 17 ( 1.4 ) m ( mean ( SE ) ) was consistently found between duplicate tests ( p < 0.001 ) . REML estimates of variance components were : 5189 ( 674 ) for subject differences in the error-free value ; 1280 ( 304 ) for subject differences in spontaneous clinical evolution between baseline and follow-up control , and 266 ( 23 ) for the within-subject error . Hence , the st and ard error of measurement was 16.3 m , namely 4 per cent of the average WT performance ( 403 m ) in this sample . The intraclass correlation coefficient was 0.96 . We conclude that WT measurements are characterized by good intrasubject reproducibility and excellent reliability . When follow-up studies > or = 3 months are performed , unpredictable changes in individual walking performance due to spontaneous clinical evolution are to be expected . Their clinical significance , however , is not known OBJECTIVE To study the potential usefulness of the 6-minute walk test , a self-paced submaximal exercise test , as a prognostic indicator in patients with left ventricular dysfunction . DESIGN Data were collected during a prospect i ve cohort study , the Studies of Left Ventricular Dysfunction ( SOLVD ) Registry Sub study . SETTING Twenty tertiary care hospitals in the United States , Canada , and Belgium . PARTICIPANTS A stratified r and om sample of 898 patients from the SOLVD Registry who had either radiological evidence of congestive heart failure and /or an ejection fraction of 0.45 or less were enrolled in the sub study and underwent a detailed clinical evaluation including a 6-minute walk test . Patients were followed up for a mean of 242 days . OUTCOME MEASURES Mortality and hospitalization . RESULTS During follow-up , 52 walk-test participants ( 6.2 % ) died and 252 ( 30.3 % ) were hospitalized . Hospitalization for congestive heart failure occurred in 78 participants ( 9.4 % ) , and the combined endpoint of death or hospitalization for congestive heart failure occurred in 114 walk-test participants ( 13.7 % ) . Compared with the highest performance level , patients in the lowest performance level had a significantly greater chance of dying ( 10.23 % vs 2.99 % ; P = .01 ) , of being hospitalized ( 40.91 % vs 19.90 % ; P = .002 ) , and of being hospitalized for heart failure ( 22.16 % vs 1.99 % ; P < .0001 ) . In a logistic regression model , ejection fraction and distance walked were equally strong and independent predictors of mortality and heart failure hospitalization rates during follow-up . CONCLUSION The 6-minute walk test is a safe and simple clinical tool that strongly and independently predicts morbidity and mortality in patients with left ventricular dysfunction Experimentelle Arbeiten und retrospektive Analysen klinischer Studien lassen einen positiven Effekt von Statinen bei Patienten mit Herzinsuffizienz vermuten . Möglicherweise ist hieran eine direkte Wirkung von Statinen auf das Myokard beteiligt . Wir untersuchten daher in einer prospektiven , r and omisierten , doppelblinden Studie ( n = 15 ) den Effekt von Cerivastatin 0,4 mg ( Statin ) oder Placebo auf Patienten mit nichtischämischer Kardiomyopathie . Einschlusskriterien waren der angiographische Ausschluss von Koronarstenosen , stabile Herzinsuffizienz NYHA II-IV und eine etablierte Therapie mit ACE-Hemmern und Betablockern . Die Beh and lungsdauer betrug i m Mittel 20 Wochen . Die Statinbeh and lung führte bei den normo- cholesterinämischen Patienten zu einer Reduktion des LDL um 11,3 mg/dl ( p = n. s. ) . Es zeigte sich eine Verbesserung der Lebensqualität und der körperlichen Belastbarkeit in der Statin- , aber nicht in der Placebo Gruppe . Dies war assoziiert mit einem Trend zu einer verbesserten linksventrikulären Pumpfunktion und einer gesteigerten Endothel-abhängigen Vasodilatation . Die Statin Beh and lung führte i m Vergleich zu Placebo zu einer signifikanten Herabregulation der Plasmakonzentrationen von Troponin T , hochsensitivem CRP , Plasminogen Aktivator Inhibitor und Tumor Nekrose Faktor alpha , dagegen wurden ICAM-1 und IL-10 nicht signifikant reguliert . Statine zeigen positive Effekte bei Patienten mit nicht-ischämischer Kardiomyopathie und verbessern die Lebensqualität und die körperliche Belastbarkeit . Diese Pilotstudie könnte auf eine neue Beh and lungsstrategie für Patienten mit Herzinsuffizienz hinweisen . HMG CoA reductase inhibitors ( statins ) may exert a wide array of cholesterolindependent effects including antihypertrophic effects on the heart . Their role in the treatment of heart failure has not been studied . 15 patients with heart failure NYHA II-III based on non-ischemic dilated cardiomyopathy were r and omized in a double-blind study to 0.4 mg cerivastatin or placebo for an average treatment period of 20 weeks .  Quality of life and exercise capacity increased significantly in the statin treatment but not in the placebo group ( Minnesota Living with Heart Failure Question naire , 6 min walking test ) . Concomitantly , there was a trend towards increased left ventricular ejection fraction ( radionuclear ventriculography ) and improved endothelial function ( forearm blood flow ) . Statins  decreased plasma concentrations of troponine T , high sensitive C-reactive protein ( hsCRP ) , plasminogen activator inhibitor-1 ( PAI-1 ) and tumor necrosis factor alpha ( TNFα ) . Statins induce benefical effects in patients with non-ischemic cardiomyopathy leading to improvement of quality of life and exercise capacity disclosing a promising novel treatment strategy for patients with heart failure 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 Many patients remain markedly symptomatic despite optimal current therapy for heart failure . Beta-blockers have often been viewed as contraindicated in this group because of their potential adverse short-term effects on cardiac function . METHODS AND RESULTS One hundred thirty-one patients with severe congestive heart failure were enrolled into a double-blind , placebo-controlled study of the vasodilating beta-blocker carvedilol .  All patients had symptomatic , advanced heart failure while on st and ard triple therapy , as evidence d by a mean ejection fraction of 0.22 , marked reduction in distance traveled in a 6-minute corridor walk test , and severe impairment in quality of life measured by the Minnesota Living With Heart Failure Question naire . After a 2-week , open-label test of 6.25 mg twice daily carvedilol , 105 patients were r and omized ( 2:1 ) to receive either carvedilol ( up to 25 mg twice daily , n = 70 ) or matching placebo ( n = 35 ) for 6 months while background therapy with digoxin , diuretics , and an angiotensin-converting enzyme inhibitor remained constant . Ten patients ( 8 % ) did not complete the open-label period because of adverse events and 11.4 % in both the carvedilol and placebo groups dropped out in the double-blind phase . The study was terminated early by the Data Safety and Monitoring Board and follow-up evaluation was therefore aborted before the projected number of patients and follow-up time was achieved . Quality of life , which was the primary endpoint , improved similarly in the carvedilol and placebo groups , whereas the global assessment by the physicians and the patient exhibited a better response to carvedilol ( P < .05 ) . Hospitalization and mortality rate were too low to evaluate a difference , and exercise time and New York Heart Association classification did not change significantly in response to the drug . Left ventricular ejection fraction rose significantly ( + 0.09 ) in the carvedilol group compared with the placebo group ( + 0.02 , P = .004 ) . CONCLUSION The beta-blocker carvedilol can be safely employed in patients with severe heart failure . Improved left ventricular function with a trend for some improvement in symptoms combined with the experience with the drug in the larger population of less severe patients in this multicenter trial suggests that carvedilol may have a favorable long-term effect in heart failure of diverse severity BACKGROUND Many patients with congestive heart failure do not receive the benefits of angiotensin-converting enzyme ( ACE ) inhibitors because of intolerance . We sought to determine the tolerability of an angiotensin II receptor blocker , c and esartan cilexetil , among patients considered intolerant of ACE inhibitors . METHODS Patients with CHF , left ventricular ejection fraction less than 35 % , and history of discontinuing an ACE inhibitor because of intolerance underwent double-blind r and omization in a 2:1 ratio to receive c and esartan ( n = 179 ) or a placebo ( n = 91 ) . The initial dosage of c and esartan was 4 mg/d ; the dosage was increased to 16 mg/d if the drug was tolerated . A history of  intolerance of ACE inhibitor was attributed to cough ( 67 % of patients ) , hypotension ( 15 % ) , or renal dysfunction ( 11 % ) . RESULTS The study drug was continued for 12 weeks by 82.7 % of patients who received c and esartan versus 86.8 % of patients who received the placebo . This 4.1 % greater discontinuation rate with active therapy was not significant ; the 95 % confidence interval ranged from 4.8 % more discontinuation with placebo to 13 % more with c and esartan . Titration to the 16-mg target dose was possible for 69 % of patients who received c and esartan versus 84 % of those who received the placebo .  Frequencies of death and morbidity were not significantly different between the c and esartan and placebo groups ( death 3.4 % and 3.3 % , worsening heart failure 8.4 % and 13.2 % , myocardial infa rct ion 2.8 % and 5.5 % , all-cause hospitalization 12.8 % and 18.7 % , and death or hospitalization for heart failure 11.7 % and 14.3 % ) . CONCLUSIONS C and esartan was well tolerated by this population . The effect of c and esartan on major clinical end points , including death , remains to be determined BACKGROUND Drugs that improve symptoms in patients with heart failure must also be assessed for their effects on survival .  Ibopamine stimulates DA-1 and DA-2 receptors and causes peripheral and renal vasodilatation ; the drug improves symptoms of heart failure . We assessed the effect of ibopamine on survival in patients with advanced heart failure in a multicentre , r and omised placebo-controlled study . METHODS Patients with advanced severe heart failure ( New York Heart Association classes III and IV ) and evidence of severe left-ventricular disease , who were already receiving optimum treatment for heart failure , were r and omly allocated oral ibopamine 100 mg three times daily or placebo . The primary endpoint was all-cause mortality . The study was design ed to recruit 2200 patients , and the minimum duration of treatment would be 6 months . We did intention-to-treat and on-treatment analyses ; a post-hoc subgroup analysis was also done . FINDINGS After we had recruited 1906 patients the trial was stopped early , because of an excess of deaths among patients in the ibopamine group . 232 ( 25 % ) of 953 patients in the ibopamine group died , compared with 193 ( 20 % ) of 953 patients in the placebo group ( relative risk 1.26 [ 95 % CI 1.04 - 1.53 ] , p = 0.017 ) . The average length of follow-up was 347 days in the ibopamine group and 363 days in the placebo group . In multivariate analysis , only the use of antiarrhythmic drugs at baseline was a significant independent predictor of increased fatality in ibopamine-treated patients . INTERPRETATION Ibopamine seems to increase the risk of death among patients with advanced heart failure who are already receiving optimum therapy , but the reasons for this increase are not clear . Our finding that antiarrhythmic treatment was a significant predictor of increased mortality in ibopamine-treated patients may be important , but exploratory analyses must be interpreted with caution BACKGROUND Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies , but its clinical effects have not been evaluated in large , multicenter trials . METHODS AND RESULTS We enrolled 278 patients with moderate to severe heart failure ( 6-minute walk distance , 150 to 450 m ) and a left ventricular ejection fraction < or = 0.35 at 31 centers . After an open-label , run-in period , each patient was r and omly assigned ( double-blind ) to either placebo ( n = 145 ) or carvedilol ( n = 133 ; target dose , 25 to 50 mg BID ) for 6 months , while background therapy with digoxin , diuretics , and an ACE inhibitor remained constant . Compared with placebo , patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration , as evaluated by changes in the NYHA functional class ( P = .014 ) or by a global assessment of progress judged either by the patient ( P = .002 ) or by the physician ( P < .001 ) . In addition , treatment with carvedilol was associated with a significant increase in ejection fraction ( P < .001 ) and a significant decrease in the combined risk of morbidity and mortality ( P = .029 ) . In contrast , carvedilol therapy had little effect on indirect measures of patient benefit , including changes in exercise tolerance or quality -of-life scores . The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure . CONCLUSIONS These findings indicate that , in addition to its favorable effects on survival , carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin , diuretics , and an ACE inhibitor Clinicians have relied on history and results from physical examinations to guide treatment of patients with advanced congestive heart failure , but these results may not reflect disease severity or hemodynamic status . We assessed how the distance walked in 6 minutes relates to clinical outcomes and symptoms of such patients . We compared the rates of death , hospitalization , and their composite at 1 year by the distance walked in 6 minutes at baseline and at 1 month , and by the change in distance between baseline and 1 month in 440 patients enrolled in a r and omized trial . We also assessed the relations of baseline distance walked to symptom score and New York Heart Association class . The median distance increased from 218 m at baseline to 280 m at 1 month . Of 365 patients able to perform the baseline walk , 121 ( 33 % ) died and 217 ( 60 % ) were hospitalized compared with 46 ( 61 % ) and 34 ( 45 % ) of 75 patients unable to walk at baseline . Baseline distance significantly predicted mortality ( hazard ratio 0.58/100-m increase , 95 % confidence interval 0.50 to 0.68 , p < 0.001 ) , even after adjustment . Baseline distance also significantly predicted hospitalization and the composite end point , as did the 1-month distance walked . The change in distance walked from baseline to 1 month did not predict any end point . Baseline distance correlated only moderately with symptom score ( r = -0.385 , p < 0.001 ) and New York Heart Association class ( r = -0.468 , p < 0.001 ) . Distance walked during 6 minutes independently and strongly predicts mortality and hospitalization in patients with advanced congestive heart failure . This may be a simple , noninvasive , objective way to risk-stratify these patients and st and ardize their treatment BACKGROUND Previous studies have suggested that cardiac resynchronization achieved through atrial-synchronized biventricular pacing produces clinical benefits in patients with heart failure who have an intraventricular conduction delay . We conducted a double-blind trial to evaluate this therapeutic approach . METHODS Four hundred fifty-three patients with moderate-to-severe symptoms of heart failure associated with an ejection fraction of 35 percent or less and a QRS interval of 130 msec or more were r and omly assigned to a cardiac-resynchronization group ( 228 patients ) or to a control group ( 225 patients ) for six months , while conventional therapy for heart failure was maintained . The primary end points were the New York Heart Association functional class , quality of life , and the distance walked in six minutes . RESULTS As compared with the control group , patients assigned to cardiac resynchronization experienced an improvement in the distance walked in six minutes ( + 39 vs. + 10 m , P=0.005 ) , functional class ( P<0.001 ) , quality of life ( -18.0 vs. -9.0 points , P= 0.001 ) , time on the treadmill during exercise testing ( + 81 vs. + 19 sec , P=0.001 ) , and ejection fraction ( + 4.6 percent vs. -0.2 percent , P<0.001 ) . In addition , fewer patients in the group assigned to cardiac resynchronization than control patients required hospitalization ( 8 percent vs. 15 percent ) or intravenous medications ( 7 percent vs. 15 percent ) for the treatment of heart failure ( P<0.05 for both comparisons ) . Implantation of the device was unsuccessful in 8 percent of patients and was complicated by refractory hypotension , bradycardia , or asystole in four patients ( two of whom died ) and by perforation of the coronary sinus requiring pericardiocentesis in two others . CONCLUSIONS Cardiac resynchronization results in significant clinical improvement in patients who have moderate-to-severe heart failure and an intraventricular conduction delay C resynchronization therapy ( CRT ) by atriobiventricular pacing has been proposed to treat severe heart failure in patients with intraventricular conduction delay result ing in ventricular mechanical discoordination . The clinical efficacy of CRT was recently demonstrated in a single-blind , r and omized , crossover trial , namely the MUltisite STimulation In Cardiomyopathies ( MUSTIC ) study .1 The purpose of this sub study was to assess the effect of CRT on heart rate variability ( HRV ) and to analyze its correlation with clinical efficacy . • • • All patients provided written informed consent before enrollment . All had severe heart failure due to idiopathic or ischemic left ventricular systolic dysfunction , left ventricular ejection fraction 35 % , and end-diastolic diameter 60 mm . All patients were in sinus rhythm with a QRS interval 150 ms and no classic indication for pacemaker implantation.2 Patients had been in New York Heart Association ( NYHA ) class III for 1 month before inclusion while receiving individually optimized treatment , including diuretics and angiotensin-converting enzyme inhibitors at the maximum tolerated dose . Exclusion criteria have been already reported.1 The study included a 6-month r and omized crossover phase during which atriobiventricular ( active ) pacing was compared with inhibited ( inactive ) ventricular pacing at the basic rate of 40 beats/min , each for a period of 3 months in r and om order ( Figure 1 ) . Implantation was performed after a 1-month observation period to verify the stability of heart failure .  Pacemakers were programmed as inactive after implantation . Patients were r and omly assigned to experimental groups within the following 2 weeks after verification of pacemaker proper performance . Treatment order r and omization followed a block design with stratification according to center . The single-blind , crossover phase was followed by a complementary 6-month period during which the pacing system was programmed according to patients ’ preferences . All leads were implanted transvenously . The left ventricular lead was placed in a tributary of the coronary sinus according to a previously described method .3 Specially design ed electrodes were used . The preferred target site was the lateral wall . The pacemakers were triple-output devices using st and ard dual-chamber technology , with built-in adapters to synchronize pacing in both ventricles . Pacemakers were programmed as either active or inactive at r and omization . The baseline pacing rate was set at 40 beats/min and the upper rate limit at 85 % of the highest predictable heart rate according to patients ’ age and gender . Each patient underwent Doppler echocardiography to determine their optimal atrioventricular delay ( electrical delay between atrial and ventricular excitation ) during atriobiventricular pacing . No modification of medical treatment except diuretic dose adjustment was permitted between enrollment and the end of the crossover phase of the study . Twenty-four-hour ambulatory electrocardiograms with a 2-channel recorder ( ELA Medical , le PlessisRobinson , France ) were obtained in all subjects during normal activity at baseline , at r and omization , at the end of each of the 2 crossover periods , and at the end of each longitudinal follow-up period ( 9 and 12 months ) . Tapes were replayed through a Elatec analyzer ( ELA Medical ) . HRV analysis used specifically vali date d software.4 Ambulatory electrocardiographic recordings  that lasted 16 hours and whose analyzable proportion was 90 % were excluded to avoid bias linked to HRV circadian variations . After initial arrhythmia analysis and editing , the remaining normal-to-normal RR intervals in suitable recordings were measured and HRV time-domain analyses were performed according to published guidelines .5 For the purpose s of this study , 4 different time-domain HRV indexes were measured : ( 1 ) the SD of the normal-to-normal ( NN ) interval over the recording duration ( SDNN ) ; ( 2 ) the SD of the 5-minute mean NN interval over the entire recording ( SDANN [ milliseconds ] ) . Because SDANN values are obtained from successive 5-minute periods , they reflect heart rate changes caused by 5-minute cycles . They reflect long-term variations but provide no short-term variability data ; ( 3 ) the square root of the mean squared successive differences between adjacent RR intervals over the entire recording ( rMSSD [ milliseconds ] ) . This correlates more with the parasympathetic ( vagal ) activity ; ( 4 ) proportion of successive interval differences 50 ms as computed over the entire recording ( pNN50 [ percent ] ) . This also reflects parasympathetic activity . From the Departement de Cardiologie et Maladies Vasculaires , Centre Cardio-Pneumologique , Hopital Pontchaillou-CHU , Rennes , France . Dr. Daubert ’s address is : Departement de Cardiologie et Maladies Vasculaires , Centre Cardio-Pneumologique , Hopital PontchaillouCHU , 35033 Rennes Cedex , France . E-mail : jean-claude . daubert@chu-rennes.fr . Manuscript received August 23 , 2002 ; revised manuscript received and accepted January 23 , 2003 BACKGROUND AND METHODS Aldosterone is important in the pathophysiology of heart failure . In a doubleblind study , we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor , a loop diuretic , and in most cases digoxin .  A total of 822 patients were r and omly assigned to receive 25 mg of spironolactone daily , and 841 to receive placebo . The primary end point was death from all causes . RESULTS The trial was discontinued early , after a mean follow-up period of 24 months , because an interim analysis determined that spironolactone was efficacious . There were 386 deaths in the placebo group ( 46 percent ) and 284 in the spironolactone group ( 35 percent ; relative risk of death , 0.70 ; 95 percent confidence interval , 0.60 to 0.82 ; P<0.001 ) . This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes . The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group ( relative risk of hospitalization , 0.65 ; 95 percent confidence interval , 0.54 to 0.77 ; P<0.001 ) . In addition , patients who received spironolactone had a significant improvement in the symptoms of heart failure , as assessed on the basis of the New York Heart Association functional class ( P<0.001 ) . Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone , as compared with 1 percent of men in the placebo group ( P<0.001 ) . The incidence of serious hyperkalemia was minimal in both groups of patients . CONCLUSIONS Blockade of aldosterone receptors by spironolactone , in addition to st and ard therapy , substantially reduces the risk of both morbidity and death among patients with severe heart failure Several small studies have suggested beneficial effects of long-term beta-blocker treatment in idiopathic dilated cardiomyopathy . Our large multicentre study aim ed to find out whether metoprolol improves overall survival and morbidity in this disorder . 383 subjects with heart failure from idiopathic dilated cardiomyopathy ( ejection fraction < 0.40 ) were r and omly assigned placebo or metoprolol . 94 % were in New York Heart Association functional classes II and III , and 80 % were receiving background treatment . A test dose of metoprolol ( 5 mg twice daily ) was given for 2 - 7 days ; those tolerating this dose ( 96 % ) entered r and omisation . Study medication was increased slowly from 10 mg to 100 - 150 mg daily . There were 34 % ( 95 % CI -6 to 62 % , p = 0.058 ) fewer primary endpoints in the metoprolol than the placebo group ; 2 and 19 patients , respectively , deteriorated to the point of needing transplantation and 23 and 19 died . The change in ejection fraction from baseline to 12 months was significantly greater with metoprolol than with placebo ( 0.13 vs 0.06 , p < 0.0001 ) . Pulmonary capillary wedge pressure decreased more from baseline to 12 months with metoprolol than with placebo ( 5 vs 2 mm Hg , p = 0.06 ) . Exercise time at 12 months was significantly greater ( p = 0.046 ) in metoprolol-treated than in placebo-treated patients . In patients with idiopathic dilated cardiomyopathy , treatment with metoprolol prevented clinical deterioration , improved symptoms and cardiac function , and was well tolerated Because of conflicting results from studies examining the usefulness of digoxin in congestive heart failure ( CHF ) patients in sinus rhythm , a cross-over trial was conducted in which 20 patients received 7 weeks of digoxin titrated to a level of 1.54 to 2.56 nmol/liter and 7 weeks of matched placebo .  The order of treatments was determined by r and om allocation and patients , clinicians and research staff were blind to allocation . In patients with deteriorating condition , the treatment period was terminated and outcome measures were obtained . If deterioration occurred during the first period , the patient was crossed over without the code being broken . Seven patients required premature termination of study periods because of increasing symptoms of CHF .  All 7 were taking placebo at the time ( p = 0.016 ) . Small differences in dyspnea ( p = 0.044 ) , walking test score ( p = 0.055 ) , clinical assessment of CHF ( p = 0.036 ) and ejection fraction ( p = 0.004 ) favored the digoxin treatment group . Patients with more severe CHF were more likely to benefit from digoxin administration . It was concluded that oral digoxin , in doses titrated to produce a serum level of 1.54 to 2.56 nmol/liter , improved quality of life and functional exercise capacity in some patients with CHF in sinus rhythm Treatment with human recombinant growth hormone ( GH ) has yielded conflicting results in patients with congestive heart failure . We analyzed the baseline somatotrophic axis in 50 patients with dilated cardiomyopathy . Then , a double-blind , r and omized , placebo-controlled study of GH was performed . We r and omly allocated these patients to treatment with subcutaneous GH ( 2 IU daily ) or placebo for a minimum of 12 weeks . The primary end-points were the effect on left ventricular ( LV ) mass and systolic wall stress . The secondary endpoint was LV ejection fraction . Severity of heart failure as determined by cardiac index , LV end-diastolic diameter , and plasma noradrenaline concentrations correlated markedly with baseline serum insulin-like growth factor-1 ( IGF-1 ) levels . Patients in the GH group had an increase in LV mass compared with the placebo group ( p = 0.0001 ) . There was no significant difference in LV systolic wall stress , mean blood pressure , or systemic vascular resistance between the two groups . New York Heart Association ( NYHA ) functional classification and distance in 6-minute walk test remained unchanged . The change in IGF-1 concentrations between GH and placebo group was notably related ( p = 0.0001 ) to the change in LV mass ( p = 0.0001 ) . The GH-induced increase of IGF-1 predicted the changes of ejection fraction ( p < 0.05 ) . A marked increase of ejection fraction of 7 % was observed in patients whose IGF-1 increased by more than the median increase , in comparison to the patients with an increase below the median ( p = 0.03 ) . Serum levels of IGF-1 reflecting GH secretion are diminished in relation to severity of heart failure in patients with dilated cardiomyopathy . GH-induced increases of IGF-1 of more than 80 pg/mL caused notable improvement of ejection fraction . There is a marked increase in LV mass in patients with dilated cardiomyopathy given GH . Changes in LV mass are related to changes in serum IGF-1 concentrations In order to compare directly the efficacy of two different angiotensin-converting enzyme ( ACE ) inhibitors in terms of clinical status and exercise capacity , 443 patients with chronic heart failure ( New York Heart Association classes II-IV ) were r and omized into a 24-week double-blind study to receive cilazapril ( CLZ ) 1 - 2.5 mg once daily ( n = 221 ) , captopril ( CPT ) 25 - 50 mg three times daily ( n = 108 ) , or placebo ( PLA ) for 12 weeks followed by CLZ 2.5 mg ( n = 114 ) in addition to their st and ard heart failure therapy . The majority were New York Heart Association functional class II ( 56 - 62 % ) , and the most frequent etiology of chronic heart failure was coronary heart disease ( 35 - 42 % ) , followed by dilative cardiomyopathy ( approximately 28 % ) . Both ACE inhibitors prolonged the exercise tolerance test duration at all visits , and the effect at week 12 ( CLZ 62.2 + /- 7.5 s ; CPT 73.1 + /- 10.7 s ) was significantly greater than after PLA ( 28.1 + /- 12.2 s ; p = 0.011 and p = 0.005 , respectively ) . Furthermore , the distance walked during 6 min increased at all visits with ACE inhibitors ( NS vs. PLA ) . CLZ was more effective in patients with the most impaired physical ability at baseline as defined by exercise tolerance test duration < or = 6 min ( p = 0.0036 at week 12 and p = 0.0150 at week 24 ) and by walking test < or = 400 m ( p = 0.0004 at week 12 and p = 0.0009 at week 24 ) . Similar results were obtained with CPT for the walking test ( p = 0.0369 at week 12 and p = 0.0142 at week 24 ) . ( ABSTRACT TRUNCATED AT 250 WORDS
target: 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 .
background: AIMS The 6 min walk test ( 6MWT ) is commonly used in clinical trials to assess treatments for heart failure , but its ability to distinguish between effective and ineffective treatments is question able .
  The aim of this study is to investigate , using a systematic literature review , the utility of the 6MWT as a measure of the effectiveness of treatment in r and omized controlled trials of heart failure .