***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background — Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist ( TOPCAT )  patients with heart failure and preserved left ventricular ejection fraction assigned to spironolactone did not achieve a significant reduction in the primary composite outcome ( time to cardiovascular death , aborted cardiac arrest , or hospitalization for management of heart failure ) compared with patients receiving placebo . In a post hoc analysis , an ≈4-fold difference was identified in this composite event rate between the 1678 patients r and omized from Russia and Georgia compared with the 1767 enrolled from the United States , Canada , Brazil , and Argentina ( the Americas ) . Methods and Results — To better underst and this regional difference in clinical outcomes , demographic characteristics of these population s and their responses to spironolactone were explored . Patients from Russia/Georgia were younger , had less atrial fibrillation and diabetes mellitus , but were more likely to have had prior myocardial infa rct ion or a hospitalization for heart failure . Russia/Georgia patients also had lower left ventricular ejection fraction and creatinine but higher diastolic blood pressure ( all P<0.001 ) . Hyperkalemia and doubling of creatinine were more likely and hypokalemia was less likely in patients receiving spironolactone in the Americas with no significant treatment effects in Russia/Georgia . All clinical event rates were markedly lower in Russia/Georgia , and there was no detectable impact of spironolactone on any outcomes . In contrast , in the Americas , the rates of the primary outcome , cardiovascular death , and hospitalization for heart failure were significantly reduced by spironolactone . Conclusions — This post hoc analysis demonstrated greater potassium and creatinine changes and possible clinical benefits with spironolactone in patients with heart failure and preserved ejection fraction from the Americas . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00094302 Background —The Minnesota Living with Heart Failure Question naire ( MLHFQ ) was used in a large , multinational , r and omized , placebo-controlled trial to measure adverse effects of heart failure with preserved ejection fraction ( HF-PEF ) on patients ' lives and the effects of irbesartan . Methods and Results — Patients with symptomatic HF-PEF were r and omly assigned to irbesartan ( up to 300 mg daily ) or placebo . The MLHFQ was administered at baseline ( n=3605 ) , month 6 ( n=3137 ) , month 14 ( n=2904 ) , and the end of study ( median , 56 months , n=2205 ) . Baseline MLHFQ scores of 43±21 indicated that HF-PEF had a substantial adverse effects . Estimated retest reliability was 0.80 . Baseline MLHFQ scores were associated with other measures of the severity of heart failure including symptoms , signs of congestion , cardiac structure , and time to hospitalizations or deaths attributed to heart failure . Slight improvement in shortness of breath or fatigue was associated with significant improvement in MLHFQ scores ( −5.9 and −5.0 , P<0.0001 ) . Compared with placebo , further improvement in MLHFQ scores was not observed with irbesartan after 6 months ( mean adjusted difference , 0.4 ; 95 % confidence interval , −0.8 to 1.7 ) , 14 months ( 0.5 ; 95 % confidence interval , −0.9 to 1.8 ) , or the end of study ( 2.0 ; 95 % confidence interval , −4.1 to 0.01 ) . Conclusions —The MLHFQ scores are a reliable , valid , and sensitive measure of the adverse impact of HF-PEF on patients ' lives . Irbesartan did not substantially improve MLHFQ scores during a long period of follow-up . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00095238 Background —Specific treatments targeting the pathophysiology of hypertensive heart disease are lacking . As aldosterone has been implicated in the genesis of myocardial fibrosis , hypertrophy , and dysfunction , we sought to determine the effects of aldosterone antagonism on myocardial function in hypertensive patients with suspected diastolic heart failure by using sensitive quantitative echocardiographic techniques in a r and omized , double-blinded , placebo-controlled study . Methods and Results —Thirty medically treated ambulatory hypertensive patients ( 19 women , age 62±6 years ) with exertional dyspnea , ejection fraction > 50 % , and diastolic dysfunction ( E/A < 1 , E deceleration time > 250m/sec ) and without ischemia were r and omized to spironolactone 25 mg/d or placebo for 6 months . Patients were overweight ( 31±5 kg/m2 ) with reduced treadmill exercise capacity ( 6.7±2.1 METS ) . Long-axis strain rate ( SR ) , peak systolic strain , and cyclic variation of integrated backscatter ( CVIB ) were averaged from 6 walls in 3 st and ard apical views . Mean 24-hour ambulatory blood pressure at baseline ( 133±17/80±7 mm Hg ) did not change in either group . Values for SR , peak systolic strain , and CVIB were similar between groups at baseline and remained unchanged with placebo . Spironolactone therapy was associated with increases in SR ( baseline : −1.57±0.46 s−1 versus 6-months : −1.91±0.36 s−1 , P<0.01 ) , peak systolic strain ( −20.3±5.0 % versus −26.9±4.3 % , P<0.001 ) , and CVIB ( 7.4±1.7dB versus 8.6±1.7 dB , P=0.08 ) . Each parameter was significantly greater in the spironolactone group compared with placebo at 6 months ( P=0.05 , P=0.02 , and P=0.02 , respectively ) , and the increases remained significant after adjusting for baseline differences . The increase in strain was independent of changes in blood pressure with intervention . The spironolactone group also exhibited reduction in posterior wall thickness ( P=0.04 ) and a trend to reduced left atrial area ( P=0.09 ) . Conclusions —Aldosterone antagonism improves myocardial function in hypertensive heart disease Background — Heart failure with preserved ejection fraction ( HFPEF ) is a common and increasing public health problem . Myocardial fibrosis is a key pathological feature of HFPEF . Peripheral collagen markers may reflect this excess fibrosis ; however , the relation of these markers to prognosis in patients with HFPEF has not as yet been determined . Methods and Results — This sub study of the Irbesartan in Heart Failure With Preserved Systolic Function ( I-PRESERVE ) trial measured plasma levels of procollagen type I amino-terminal peptide , procollagen type III amino-terminal peptide , and osteopontin in 334 patients with HFPEF . Measurements were performed at baseline and 6 months after r and omization to placebo or irbesartan 300 mg/day . The relation of baseline collagen markers to the I-PRESERVE primary end point ( all-cause death and hospitalization for prespecified cardiovascular causes ) was evaluated by single and multivariable analysis . Similar evaluations were performed for all-cause death alone as well as heart failure events ( death or hospitalization because of heart failure ) . Increased plasma levels of collagen markers at baseline were associated with increased frequency of the study primary end point for all collagen markers . For each 10-&mgr;g/L increase in procollagen type I amino-terminal peptide , the hazard ratio ( HR ) for the primary end point was 1.09 ( 95 % CI , 1.052 to 1.13 ; P<0.0001 ) ; for each 10-&mgr;g/L increase in procollagen type III amino-terminal peptide procollagen type I amino-terminal peptide , the HR was 2.47 ( 95 % CI , 0.97 to 6.33 ; P=0.059 ) ; and for each 10-nmol/L increase in osteopontin , the HR was 1.084 ( 95 % CI , 1.026 to 1.15 ; P=0.004 ) . No variable remained significant as an independent predictor when introduced into a multivariable model . Both treatment groups tended to reduce collagen markers , with the reduction significantly greater for placebo versus irbesartan for procollagen type III amino-terminal peptide only ( P=0.0185 ) . Conclusions — Increased peripheral collagen turnover markers were not independently associated with increased mortality and cardiovascular hospitalization in an HFPEF population on multivariable analysis but were associated on single-variable analysis . These findings provide some support to the hypothesis that pathological fibrosis in the heart , and possibly the peripheral vasculature , may be contributory to adverse clinical outcomes in patients with HFPEF . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00095238 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 OBJECTIVES The aims of this study were to explore the relationship of baseline levels of natriuretic peptides ( NPs ) with outcomes and to test for an interaction between baseline levels of NPs and the effects spironolactone . BACKGROUND Plasma NPs are considered to be helpful in the diagnosis of heart failure ( HF ) with preserved ejection fraction ( HFpEF ) , and elevated levels are associated with adverse outcomes . Levels of NPs higher than certain cutoffs are often used as inclusion criteria in clinical trials of HFpEF to increase the likelihood that patients have HF and to select patients at higher risk for events . Whether treatments have a differential effect on outcomes across the spectrum of NP levels is unclear . METHODS The TOPCAT ( Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial ) trial r and omized patients with HFpEF and either prior hospitalization for HF or elevated natriuretic peptide levels ( B-type NP [ BNP ] ≥100 pg/ml or N-terminal proBNP ≥360 pg/ml ) to spironolactone or placebo .  Baseline BNP ( n = 430 ) or N-terminal proBNP ( n = 257 ) levels were available in 687 patients enrolled from the Americas in the elevated-NP stratum of TOPCAT . RESULTS Higher levels of NPs were independently associated with an increased risk for TOPCAT 's primary endpoint of cardiovascular mortality , aborted cardiac arrest , or hospitalization for HF when analyzed either continuously or grouped by terciles , adjusting for region of enrollment , age , sex , atrial fibrillation , diabetes , renal function , body mass index , and heart rate . There was a significant interaction between the effect of spironolactone  and baseline NP terciles for the primary outcome ( p = 0.017 ) , with greater benefit of the drug in the lower compared with higher NP terciles . CONCLUSIONS Similar to the effects of irbesartan in the I-PRESERVE ( Irbesartan in Heart Failure With Preserved Ejection Fraction ) trial , a greater benefit of spironolactone was observed in the group with lower levels of NPs and overall risk in TOPCAT . Elevated 
    Output:
    
MRA treatment reduced heart failure hospitalisation ( 11 % of participants in the intervention arm versus 14 % in the control arm ; RR 0.82 ; 95 % CI 0.69 to 0.98 ; NNTB 41 ; 3714 participants ; 3 studies ; moderate- quality evidence ) however , little or no effect on all-cause and cardiovascular mortality and quality of life measures was observed .
The evidence suggested that ACEI treatment likely has little or no effect on cardiovascular mortality , all-cause mortality , heart failure hospitalisation , or quality of life .
There is evidence that MRA treatment reduces heart failure hospitalisation in heart failure with preserverd ejection fraction , however the effects on mortality related outcomes and quality of life remain unclear .