***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: 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 AIMS Elevated natriuretic peptides ( NPs ) are associated with an increased cardiovascular risk following acute coronary syndromes ( ACSs ) . However , the therapeutic implication s are still undefined . We hypothesized that early inhibition of renin-angiotensin-aldosterone system ( RAAS ) in patients with preserved left ventricular function but elevated NPs but following ACS would reduce haemodynamic stress as reflected by a greater reduction NP compared with placebo . METHODS AND RESULTS AVANT GARDE-TIMI 43 trial , a multinational , double-blind trial , r and omized 1101 patients stabilized after ACS without clinical evidence of heart failure or left ventricular function < or=40 % but with an increased level of NP 3 - 10 days after admission to aliskiren , valsartan , their combination , and placebo .  The primary endpoint was the change in NT-proBNP from baseline to Week 8 . NT-proBNP declined significantly in each treatment arm , including placebo , by Week 8 , though there were no differences in the reduction between treatment strategies ( 42 % in placebo , 44 % in aliskiren , 39 % in valsartan , and 36 % in combination arm ) . Although several subgroups had higher baseline levels of NP and greater reductions over the study period , there were no differences among treatment groups in any subgroup . There were no differences in clinical outcomes but there were more adverse events , including serious events and adverse events leading to early study drug discontinuation , in patients treated with active therapy . CONCLUSION In this study of a high-risk population with elevated levels of NPs but relatively preserved systolic function and no evidence of heart failure following ACS , there was no evidence for a benefit of early initiation of inhibition of RAAS with valsartan , aliskiren , or their combination compared with placebo with respect to a reduction in NP over 8 weeks of therapy . Moreover , adverse events were reported more frequently in patients assigned to active therapy Combination therapy with angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors ( ACEIs ) requires further evaluation in patients with diabetic nephropathy and hypertension . In a post hoc analysis of the Olmesartan Reducing Incidence of Endstage renal disease in diabetic Nephropathy Trial with hypertension , we examined the effects of olmesartan on renal and cardiovascular outcomes in the presence or absence of an ACEI . Among 563 patients r and omized to receive either olmesartan ( n=280 ) or placebo ( n=283 ) , 73.5 % ( n=414 ) received a concomitant ACEI . Compared with placebo , olmesartan significantly reduced proteinuria in both the ACEI-treated and non-ACEI-treated groups . The respective changes in the urinary protein creatinine ratio in the olmesartan-treated and placebo-treated groups were −32.6 % and + 21.1 % without an ACEI ( P=0.001 ) and −17.0 % and + 2.2 % with an ACEI ( P=0.028 ) . In the olmesartan group , 115 patients developed primary renal outcomes ( 41.1 % ) compared with 129 ( 45.6 % ) in the placebo group ( hazard ratio ( HR ) : 0.97 , P=0.787 ) . The respective HRs in the ACEI-treated and non-ACEI-treated groups were 1.02 ( P=0.891 ) and 0.84 ( P=0.450 ) . 40 olmesartan-treated patients ( 14.3 % ) and 53 placebo-treated patients ( 18.7 % ) developed secondary cardiovascular outcomes ( HR : 0.65 , P=0.042 ) . The respective HRs in the ACEI-treated and non-ACEI-treated groups were 0.69 ( P=0.129 ) and 0.51 ( P=0.129 ) . Olmesartan was well tolerated . Dual blockade treatment caused more hyperkalemia than monotherapy . In patients with diabetic nephropathy and hypertension  , olmesartan significantly reduced proteinuria , independent of ACEI treatment and cardiovascular outcome but failed to show additional renal benefit compared with ACEI treatment alone . The cardiovascular benefit of dual treatment requires further evaluation Background —Loss of negative feedback inhibition of renin release during chronic treatment with an angiotensin-converting enzyme ( ACE ) inhibitor leads to a compensatory rise in renin secretion and downstream components of the renin-angiotensin-aldosterone ( RAAS ) cascade . This may overcome ACE inhibition but should be blocked by a direct renin inhibitor . We studied the effects of adding the direct renin inhibitor aliskiren to an ACE inhibitor in patients with heart failure . Methods and Results — Patients with New York Heart Association class II to IV heart failure , current or past history of hypertension , and plasma brain natriuretic peptide ( BNP ) concentration > 100 pg/mL who had been treated with an ACE inhibitor ( or angiotensin receptor blocker ) and β-blocker were r and omized to 3 months of treatment with placebo  ( n=146 ) or aliskiren 150 mg/d ( n=156 ) . The primary efficacy outcome was the between-treatment difference in N-terminal pro-BNP ( NT-proBNP ) . Patients ’ mean age was 68 years , mean ejection fraction was 31 % , and mean±SD systolic blood pressure was 129±17.4 mm Hg . Sixty-two percent of the patients were in New York Heart Association functional class II , and 33 % were taking an aldosterone antagonist . Plasma NT-proBNP rose by 762±6123 pg/mL with placebo and fell by 244±2025 pg/mL with aliskiren  ( P=0.0106 ) . BNP and urinary ( but not plasma ) aldosterone were also reduced by aliskiren . Clinical ly important differences in blood pressure and biochemistry were not seen between aliskiren and placebo . Conclusions —Addition of aliskiren to an ACE inhibitor ( or angiotensin receptor blocker ) and β-blocker had favorable neurohumoral effects in heart failure and appeared to be well tolerated BACKGROUND Angiotensin II type 1 receptor blockers have favourable effects on haemodynamic measurements , neurohumoral activity , and left-ventricular remodelling when added to angiotensin-converting-enzyme ( ACE ) inhibitors in patients with chronic heart failure ( CHF ) . We aim ed to find out whether these drugs improve clinical outcome . METHODS Between March , 1999 , and November , 1999 , we enrolled 2548 patients with New York Heart Association functional class II-IV CHF and left-ventricular ejection fraction 40 % or lower , and who were being treated with ACE inhibitors .  We r and omly assigned patients c and esartan ( n=1276 , target dose 32 mg once daily ) or placebo ( n=1272 ) . At baseline , 55 % of patients were also treated with beta blockers and 17 % with spironolactone . The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF . Analysis was done by intention to treat . FINDINGS The median follow-up was 41 months . 483 ( 38 % ) patients in the c and esartan group and 538 ( 42 % ) in the placebo group experienced the primary outcome ( unadjusted hazard ratio 0.85 [ 95 % CI 0.75 - 0.96 ] , p=0.011 ; covariate adjusted p=0.010 ) . C and esartan reduced each of the components of the primary outcome significantly , as well as the total number of hospital admissions for CHF . The benefits of c and esartan were similar in all predefined subgroups , including patients receiving baseline beta blocker treatment . INTERPRETATION The addition of c and esartan to ACE inhibitor and other treatment leads to a further clinical ly important reduction in relevant cardiovascular events in patients with CHF and reduced left-ventricular ejection fraction AIMS We evaluated the effect of ( dual ) renin-angiotensin-aldosterone system ( RAAS ) blockade with valsartan and an ACE inhibitor [ 92.7 % of patients were treated with an ACE inhibitor in the Valsartan in Heart Failure Trial ( Val-HeFT ) ] in patients with NYHA class II-IV heart failure ( HF ) and reduced EF on  cardiovascular ( CV ) death and HF hospitalization  by subgroups and by presence of early worsening of renal function ( EWRF ) and according to baseline estimated glomerular filtration rate ( eGFR ) . METHODS AND RESULTS We analysed the data from 5010 patients enrolled in the Val-HeFT study . A total of 2346 ( 46.8 % ) patients had baseline renal impairment ( i.e. baseline eGFR < 60 mL/min/1.73 m(2 ) ) . Further , 425 patients ( 8.6 % ) had EWRF ( i.e. eGFR decrease > 20 % within 1 month after r and omization ) , whereas 4503 patients ( 91.4 % ) had ≤20 % decline in eGFR . Overall , the difference between valsartan and placebo on the composite endpoint of CV death and HF hospitalization was significant [ P = 0.0005 ; hazard ratio ( HR ) 0.83 , 95 % confidence interval ( CI ) 0.75 - 0.92 ) ] . In patients with baseline renal impairment , the difference between the treatment groups was also significant ( P = 0.0002 ; HR 0.76 , 95 % CI 0.66 - 0.88 ) . Patients with EWRF had higher risk of CV death and HF hospitalization vs. those without ERWF ( P < 0.0001 ; HR 1.44 , 95 % CI 1.21 - 1.71 ) , and within the EWRF group a significant difference was also observed between valsartan and placebo ( P = 0.0086 ; HR 0.63 , 95 % CI 0.45 - 0.89 ) . However , the interaction between treatment and eGFR at Month 1 was not significant ( P = 0.1160 ) . CONCLUSION Benefits were maintained in patients with renal dysfunction at baseline and those who experienced EWRF BACKGROUND In patients who have vascular disease or high-risk diabetes without heart failure , angiotensin-converting-enzyme ( ACE ) inhibitors reduce mortality and morbidity from cardiovascular causes , but the role of angiotensin-receptor blockers ( ARBs ) in such patients is unknown . We compared the ACE inhibitor ramipril , the ARB telmisartan , and the combination of the two drugs in patients with vascular disease or high-risk diabetes . METHODS After a 3-week , single-blind run-in period , patients underwent double-blind r and omization , with 8576 assigned to receive 10 mg of ramipril per day , 8542 assigned to receive 80 mg of telmisartan per day , and 8502 assigned to receive both drugs ( combination therapy ) . The primary composite outcome was death from cardiovascular causes , myocardial infa rct ion , stroke , or hospitalization for heart failure . RESULTS Mean blood pressure was lower in both the telmisartan group ( a 0.9/0.6 mm Hg greater reduction ) and the combination-therapy group ( a 2.4/1.4 mm Hg greater reduction ) than in the ramipril group . At a median follow-up of 56 months , the primary outcome had occurred in 1412 patients in the ramipril group ( 16.5 % ) , as compared with 1423 patients in the telmisartan group ( 16.7 % ; relative risk , 1.01 ; 95 % confidence interval [ CI ] , 0.94 to 1.09 ) . As compared with the ramipril group , the telmisartan group had lower rates of cough ( 1.1 % vs. 4.2 % , P<0.001 ) and angioed 
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These results were consistent in cohorts of patients with diabetes mellitus , kidney disease or heart failure .
CONCLUSIONS Dual RAS blockade increased ( vs monotherapy ) the risks of hyperkalemia , hypotension , renal failure and treatment discontinuation .
Dual RAS blockade did not offer additional benefit in reducing overall mortality , cardiovascular mortality or stroke .
These findings are consistent over time