***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 —In 3 r and omized controlled trials in heart failure ( HF ) , mineralocorticoid receptor antagonists  reduced mortality . The net benefit from r and omized controlled trials may not be generalizable , and eplerenone was , but spironolactone was not , studied in mild HF . We tested the hypothesis that spironolactone is associated with reduced mortality also in a broad unselected contemporary population with HF and reduced ejection fraction , in particular New York Heart Association ( NYHA ) I – II . Methods and Results —We prospect ively studied 18 852 patients ( age 71±12 years ; 28 % women ) with NYHA I – IV and ejection fraction < 40 % who were registered in the Swedish Heart Failure Registry between 2000 and 2012 and who were ( n=6551 ) or were not ( n=12 301 ) treated with spironolactone .  We derived propensity scores for spironolactone treatment based on 41 covariates . We assessed survival by Cox regression with adjustment for propensity scores and with matching based on propensity score . We performed sensitivity and residual confounding analyses and analyzed the NYHA I – II and III – IV subgroups separately . One-year survival was 83 % versus 84 % in treated versus untreated patients ( log rank P<0.001 ) . After adjustment for propensity scores , the hazard ratio for spironolactone was 1.05 ( 95 % confidence interval , 1.00–1.11 ; P=0.054 ) . Spironolactone interacted with NYHA ( P<0.001 ) . In the NYHA I – II subgroup , after adjustment for propensity scores , the hazard ratio  for spironolactone was 1.11 ( 95 % confidence interval , 1.02–1.21 ; P=0.019 ) . Conclusions —In an unselected contemporary population of HF with reduced ejection fraction  , spironolactone was not associated with reduced mortality . The net benefits of spironolactone may be lower outside the clinical trial setting and in milder HF Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items AIMS Hospitalizations for heart failure ( HF ) are common and are associated with significant morbidity , mortality and cost . However , precipitating factors leading to HF hospitalization and their importance with respect to subsequent outcomes are not well understood . METHODS AND RESULTS The symptoms and signs present at admission and investigator-identified factors thought to have contributed to the first adjudicated HF hospitalization in the C and esartan in Heart Failure : Assessment of Reduction in Mortality and Morbidity ( CHARM ) programme were prospect ively collected and stratified by ejection fraction ( EF ) . Potential precipitants were collected using a specifically design ed case report form and categorized according to the presence of cardiovascular ( CV ) , non-CV and unknown factors . Associations between these factors and subsequent rehospitalization and mortality rates were examined . Of 1668 patients who experienced HF hospitalization , 1152 had reduced EF ( ≤40 % , HFrEF ) and 516 had preserved EF ( HFpEF ) . Overall , 54 % had CV , 32 % had non-CV and 14 % had unknown factors thought to have precipitated HF , with similar proportions in the HFrEF and HFpEF groups . The most common precipitants were arrhythmia ( 15 % ) , other non-CV factors ( 11 % ) and respiratory infection ( 10 % ) . Subsequent CV readmission rates were highest in those whose initial HF hospitalization was precipitated by CV factors . However , mortality rates were similar among patients with any of the three categories of precipitating factors . Results were similar in HFrEF and HFpEF . CONCLUSIONS Among chronic HF patients hospitalized for decompensation , the investigator-reported precipitating factor was not associated with the subsequent mortality rate , but was associated with type of readmission : readmissions for CV reasons were more likely when the index precipitant was CV AIMS Many patients who receive a diagnosis of heart failure have neither a low left ventricular ( LV ) ejection fraction nor valve disease . Few substantial r and omized controlled trials have been conducted in this population , none has focussed on patients with evidence of diastolic dysfunction and none has shown clear benefit on symptoms , morbidity , or mortality . METHODS AND RESULTS This was a r and omized double-blind trial , comparing placebo with perindopril , 4 mg/day in patients aged > or = 70 years with a diagnosis of heart failure , treated with diuretics and an echocardiogram suggesting diastolic dysfunction and excluding substantial LV systolic dysfunction or valve disease . The primary endpoint was a composite of all-cause mortality and unplanned heart failure related hospitalization with a minimum follow-up of 1 year . A total of 850 patients were r and omized . Their mean age was 76 ( SD 5 ) years and 55 % were women . Median follow-up was 2.1 ( IQR 1.5 - 2.8 ) years . Enrollment and event rates were lower than anticipated , reducing the power of the study to show a difference in the primary endpoint to 35 % . Many patients withdrew from perindopril ( 28 % ) and placebo ( 26 % ) after 1 year and started taking open-label ACE-inhibitors . Overall , 107 patients 
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By contrast , dispensing β-blockers at discharge was associated with 35 % lower risk of all-cause deaths in HFrEF and has a weak association with borderline statistical significance on improving overall survival in HFpEF .