***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Because heart failure therapy with angiotensin-converting enzyme ( ACE ) inhibitors may not be optimal , owing to persistent levels of angiotensin II occurring through incomplete blockade and alternate pathways , the benefit of adding irbesartan , an angiotensin receptor antagonist , to conventional therapy , including ACE inhibitors , was examined . In this multicentre , r and omised , double-blind , placebo-controlled study , 109 patients with heart failure ( New York Heart Association functional class II and III ) and left ventricular ejection fraction ( LVEF ) < or = 40 % received stable doses of ACE inhibitors and diuretics before and throughout the study . Irbesartan was titrated as tolerated to 150 mg once daily in all patients . Exercise tolerance time ( ETT ) , LVEF and clinical status were assessed at baseline and after 12 weeks . Compared with placebo , irbesartan in combination with conventional therapy , including ACE inhibitors , produced favourable trends in ETT and LVEF and was well tolerated in patients with mild to moderate heart failure BACKGROUND The renin-angiotensin system plays an important part in the pathogenesis of congestive heart failure ( CHF ) . This study evaluated the effect of an angiotensin II type 1 receptor antagonist on exercise tolerance and symptoms of CHF . METHODS AND RESULTS In this multicenter , double-blind , parallel-group study , 844 patients with CHF were r and omized to 12 weeks ' treatment with placebo ( n=211 ) or c and esartan cilexetil 4 mg ( n=208 ) , 8 mg ( n=212 ) , or 16 mg ( n=213 ) after a 4-week placebo run-in period . Changes in exercise time , Dyspnea Fatigue Index score , NYHA functional class , and cardiothoracic ratio were determined . C and esartan cilexetil produced a dose-related improvement in exercise time . For the intention-to-treat population , the increase produced by c and esartan cilexetil 16 mg was significantly greater than that produced by placebo ( 47.2 versus 30.8 seconds , P=0.0463 ) . All doses of c and esartan cilexetil significantly improved the Dyspnea Fatigue Index score relative to placebo . NYHA class improved more frequently in the c and esartan cilexetil groups ; the differences relative to placebo were not significant . The decrease in cardiothoracic ratio with c and esartan 4 to 16 mg was small but statistically significant compared with placebo ( all P<0.05 ) . In all c and esartan cilexetil groups , plasma renin activity and angiotensin II levels increased from baseline and aldosterone levels decreased in the 8- and 16-mg treatment groups . C and esartan cilexetil was well tolerated at all doses . CONCLUSIONS In summary , treatment with c and esartan cilexetil demonstrated significant improvements in exercise tolerance , cardiothoracic ratio , and symptoms and signs of CHF and was well tolerated BACKGROUND Angiotensin II exerts a number of harmful effects in patients with chronic heart failure ( CHF ) and , through an increase in oxidative stress , is thought to be critical in the development of endothelial dysfunction . Angiotensin II may be elevated in CHF despite treatment with angiotensin converting enzyme ( ACE ) inhibitors , producing a rationale for adjunctive angiotensin receptor blockade . We investigated whether the addition of angiotensin antagonism to ACE inhibition would reduce oxidative stress and improve endothelial function and exercise tolerance in patients with chronic heart failure . METHODS AND RESULTS Twenty-eight heart failure patients , who were on stable ACE inhibitor therapy , were r and omised to receive adjunctive therapy with c and esartan or placebo .  Plasma lipid-derived free radicals , TBARS and neutrophil O2-generation , markers of oxidative stress , were measured in venous blood . Arterial endothelial function was assessed as the response of the brachial artery to flow-related shear stress . Exercise capacity was determined by cardiopulmonary exercise testing . Compared with placebo , c and esartan had no effect on changes in lipid derived free radicals ( -0.1+/-1.2 vs. -0.1+/-1.0 units , respectively , P = NS ) , TBARS ( -2.2+/-1.1 vs. -2.6+/-2.2 micromol/l , respectively , P = NS ) or neutrophil O2-generating capacity ( -7.3+/-5.1 vs. -8.4+/-7.9 mV/5x10(5 ) neutrophils , respectively , P = NS ) . There was no effect on changes in brachial artery flow-mediated dilatation ( 0.5+/-1.0 vs. 0.8+/-1.3 % , respectively , P = NS ) nor peak VO2 ( 1.6+/-0.7 ml/kg per min vs. 1.8+/-0.6 ml/kg per min ; P = NS ) . CONCLUSION The addition of the c and esartan to ACE inhibitor therapy had no effect on oxidative stress and did not improve endothelial function or exercise capacity in patients with CHF BACKGROUND Treatment with angiotensin-converting-enzyme ( ACE ) inhibitors reduces mortality among survivors of acute myocardial infa rct ion , but whether to use ACE inhibitors in all patients or only in selected patients is uncertain . METHODS We screened 6676 consecutive patients with 7001 myocardial infa rct ions confirmed by enzyme studies . A total of 2606 patients had echocardiographic evidence of left ventricular systolic dysfunction ( ejection fraction , < or = 35 percent ) . On days 3 to 7 after infa rct ion , 1749 patients were r and omly assigned to receive oral tr and olapril ( 876 patients ) or placebo ( 873 patients ) . The duration of follow-up was 24 to 50 months . RESULTS During the study period , 304 patients ( 34.7 percent ) in the tr and olapril group died , as compared with 369 ( 42.3 percent ) in the placebo group ( P = 0.001 ) . The relative risk of death in the tr and olapril group , as compared with the placebo group , was 0.78 ( 95 percent confidence interval , 0.67 to 0.91 ) . Tr and olapril also reduced the risk of death from cardiovascular causes ( relative risk , 0.75 ; 95 percent confidence interval , 0.63 to 0.89 ; P = 0.001 ) and sudden death ( relative risk , 0.76 ; 95 percent confidence interval , 0.59 to 0.98 ; P = 0.03 ) . Progression to severe heart failure was less frequent in the tr and olapril group ( relative risk , 0.71 ; 95 percent confidence interval , 0.56 to 0.89 ; P = 0.003 ) . In contrast , the risk of recurrent myocardial infa rct ion ( fatal or nonfatal ) was not significantly reduced ( relative risk , 0.86 ; 95 percent confidence interval , 0.66 to 1.13 ; P = 0.29 ) . CONCLUSIONS Long-term treatment with tr and olapril in patients with reduced left ventricular function soon after myocardial infa rct ion significantly reduced the risk of overall mortality , mortality from cardiovascular causes , sudden death , and the development of severe heart failure . That mortality was reduced in a r and omized study enrolling 25 percent of consecutive patients screened should encourage the selective use of ACE inhibition after myocardial infa rct ion BACKGROUND Angiotensin-converting-enzyme ( ACE ) inhibitors improve outcome of patients with chronic heart failure ( CHF ) . A substantial proportion of patients , however , experience no benefit from ACE inhibitors because of previous intolerance . We aim ed to find out whether c and esartan , an angiotensin-receptor blocker , could improve outcome in such patients not taking an ACE inhibitor . METHODS Between March , 1999 , and March , 2001 , we enrolled 2028 patients with symptomatic heart failure and left-ventricular ejection fraction 40 % or less who were not receiving ACE inhibitors because of previous intolerance . Patients were r and omly assigned c and esartan ( target dose 32 mg once daily ) or matching placebo . The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF . Analysis was by intention to treat . FINDINGS The most common manifestation of ACE-inhibitor intolerance was cough ( 72 % ) , followed by symptomatic hypotension ( 13 % ) and renal dysfunction ( 12 % ) . During a median follow-up of 33.7 months , 334 ( 33 % ) of 1013 patients in the c and esartan group and 406 ( 40 % ) of 1015 in the placebo group had cardiovascular death or hospital admission for CHF ( unadjusted hazard ratio 0.77 [ 95 % CI 0.67 - 0.89 ] , p=0.0004 ; covariate adjusted 0.70 [ 0.60 - 0.81 ] , p<0.0001 ) . Each component of the primary outcome was reduced , as was the total number of hospital admissions for CHF . Study -drug discontinuation rates were similar in the c and esartan ( 30 % ) and placebo ( 29 % ) groups . INTERPRETATION C and esartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors BACKGROUND In chronic heart failure ( CHF ) , the derangement of autonomic nervous system activity has a deep impact on the progression of the disease . It has been demonstrated that modulation of the renin-angiotensin aldosterone system ( RAAS ) increases autonomic control of heart rate and reduces adrenergic activity . We sought to evaluate , in CHF , the different effects of an ACE inhibitor ( lisinopril ) and of an AT1 receptor antagonist ( valsartan ) on heart rate variability , baroreflex sensitivity and norepinephrine plasma levels . METHODS Ninety patients ( 61 + /- 10 years , 2.3 + /- 0.5 , New York Heart Association class ) with CHF and left ventricular ejection fraction < 40 % were r and omly assigned in a double-blind fashion to receive lisinopril ( uptitrated to 20 mg/d ) or valsartan ( uptitrated to 160 mg/d ) therapy for 16 weeks . Heart rate variability ( evaluated by measuring st and ard deviation of normal R-R intervals on 24-hour ECG recordings ) , spontaneous baroreflex sensitivity and aldosterone and norepinephrine plasma levels were assessed before and after drug therapy . RESULTS There were no significant differences between valsartan and lisinopril in their effects on left ventricular function , arterial pressure , aldosterone plasma levels and autonomic control of heart rate . Both lisinopril and valsartan significantly reduced plasma norepinephrine levels , but the reduction induced by valsartan was significantly greater than that observed for lisinopril ( 27 % vs 6 % , P < .05 ) . CONCLUSIONS This study shows a comparable effect of ACE inhibition ( lisinopril ) and of AT1 receptor antagonism ( valsartan ) on cardiac vagal control of heart rate , whereas valsartan has shown a more effective modulation of sympathetic activity measured by plasma norepinephrine levels 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 enalap 
    Output:
    
In patients with symptomatic HF and systolic dysfunction or with preserved ejection fraction , ARBs compared to placebo or ACEIs do not reduce total mortality or morbidity .
ARBs are better tolerated than ACEIs but do not appear to be as safe and well tolerated as placebo in terms of withdrawals due to adverse effects .
Adding an ARB in combination with an ACEI does not reduce total mortality or total hospital admission but increases withdrawals due to adverse effects compared with ACEI alone