***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 with cholinesterase inhibitors improves cognition in patients with Alzheimer disease ( AD ) . In studies design ed with a washout period at the end of the study , after treatment with a cholinesterase inhibitor is discontinued , the cognitive benefits of therapy are no longer apparent following washout . The rivastigmine trials discussed in this article were not design ed with a posttreatment washout period at the end of the study . Therefore , to evaluate the effect of discontinuing treatment , we analyzed the retrieved dropout ( RDO ) population . OBJECTIVE To evaluate the change in cognition ( at week 26 vs baseline ) observed in patients from 3 large clinical trials of AD who prematurely discontinued treatment with placebo or rivastigmine .  DESIGN AND METHODS Eligible patients with AD ( Mini-Mental State Examination [ MMSE ] score , 10 - 26 , inclusive ) were enrolled in 1 of three 26-week , double-blind , placebo-controlled studies ( Novartis US Pivotal [ dose-range ] Trial , US fixed-dose study , and a Global Pivotal [ dose-range ] Trial ) that compared rivastigmine therapy with placebo .  Patients who discontinued study participation ( for any reason ) ( considered to be the RDO population ) were encouraged to return for their scheduled week 26 efficacy evaluations . Effects on cognition were assessed using the Alzheimer 's Disease Assessment Scale-Cognitive subscale ( ADAS-Cog ) . RESULTS The results for the Novartis US Pivotal Trials and for the 3 studies combined ( Novartis studies B352 , B351 , and B303 ) are reported . In the US pivotal trial , RDO patients in the 6- to 12-mg/d group had been not receiving the drug ( to be called " off drug " ) for 102 ( 57.7 ) days ( mean [ SD ] ) compared with 68 ( 51.7 ) days in the RDO placebo group . In these RDO analyses , a statistically significantly greater worsening on the ADAS-Cog mean change score was observed in the placebo group ( n = 17 ) compared with the rivastigmine 6- to 12-mg/d group ( n = 33 ) at week 26 ( MMSE score , -8.2 vs -3.0 ; P = .009 ) . In the pooled studies , the mean ( SD ) number of days off treatment was 95 ( 52.0 ) days for the rivastigmine 6- to 12-mg/d group and 66 ( 52.7 ) days for the placebo group . The RDO analysis also showed a statistically significantly greater decline in cognitive function as measured by the ADAS-Cog mean change score in the placebo group ( n = 38 ) compared with the rivastigmine 6- to 12-mg/d group ( n = 88 ) at week 26 ( MMSE score , -5.69 vs -2.5 ; P = .004 ) . A significantly greater proportion of patients in the placebo group exhibited at least a 4-point and 7-point worsening in ADAS-Cog scores at week 26 compared with the rivastigmine 6- to 12-mg/d group in both the Novartis US Pivotal Trials ( P = .007 , P = .009 ) and the pooled studies ( P = .002 , P = .017 ) . CONCLUSIONS After discontinuation of therapy , rivastigmine-treated patients exhibited less deterioration in cognitive function compared with placebo-treated patients . The less severe worsening of cognition after withdrawal of treatment in patients previously treated with rivastigmine suggests an effect on disease progression OBJECTIVE To develop a simple , readily administered and scored screening test for dementia utilizing the clock-drawing task . DESIGN Retrospective analysis of clock-drawing errors and prospect i ve validations . SETTING Hospital-based outpatient geriatric assessment clinic , rehabilitation service , apartment building for older adults , and long-term care facility . PARTICIPANTS Convenience sample of patients attending the geriatric assessment clinic , patients on the rehabilitation service , or residents of the above sites . MEASUREMENTS Sensitivity and specificity of a clock-scoring system  in identifying patients with dementia and the comparison of this system with the  Short Blessed Test ( SBT )  in the diagnosis of dementia and in the prospect i ve validation of the test . RESULTS Of the 10 clock-drawing errors evaluated , placement of digits in a pre-drawn circle had the greatest sensitivity and specificity in distinguishing patients with irreversible dementia from patients with other disorders who did not meet NINCDS-ADRDA criteria for probable dementia . The derived scoring system had a sensitivity of 87 % and a specificity of 82 % , compared with a sensitivity of 82 % and a specificity of 88 % for the SBT in identifying dementia . Test-retest reliability for the distinction between demented and non-demented was 82 % , with a Kappa of 0.63 for the clock completion , and 82 % , with a Kappa of 0.62 for the SBT . Inter-rater reliability for clock completion was 0.90 to 0.93 . CONCLUSION A simple , completely objective scoring system for a  clock completion test  has been developed which involves only the number of digits placed in the fourth quadrant of a pre-drawn circle . This readily administered test is as effective in screening for dementia as the longer six-item SBT Most cost-effectiveness studies using simulation modeling have demonstrated that donepezil , rivastigmine , and galantamine are cost effective for the treatment of mild-to-moderate Alzheimer disease ( AD ) . These conclusions are in large part based on the assumption that improvement in cognitive status , or prevention of cognitive and functional decline , reduces the amount of time patients spend institutionalized or receiving other full-time care . However , as discussed in this article , outcomes besides delay to institutionalization affect the costs of AD . In review s of utilization data from Medicare and managed care organizations , it was noted that hospitalization and post acute care in skilled nursing facilities accounted for the largest amount of excess direct costs , even among patients with mild or moderate AD . These utilization review s also suggest that many patients with AD and related dementias require inpatient care because they are not able to self-manage comorbid conditions . The improvements in cognitive status and daily functioning associated with acetylcholinesterase inhibitor ( AChEI ) therapy are expected to translate into improved management of comorbidities and reduced caregiver burden , thus reducing the total cost of care . To confirm these and other economic benefits of AChEIs , pharmacoeconomic outcomes should be evaluated routinely as part of r and omized , controlled trials and through well-controlled observational studies of AD patients in community and institutional setting BACKGROUND Although less likely to be reported in clinical trials than expressions of the statistical significance of differences in outcomes , whether or not a treatment has delivered a specified minimum clinical ly important difference ( MCID ) is also relevant to patients and their caregivers and doctors . Many dementia treatment r and omised controlled trials ( RCTs ) have not reported MCIDs and , where they have been done , observed differences have not reached these . METHODS As part of the development of the Statistical Analysis Plan for the DOMINO trial , investigators met to consider expert opinion- and distribution-based values for the MCID and triangulated these to provide appropriate values for three outcome measures , the  St and ardised Mini-mental State Examination ( sMMSE ) , Bristol Activities of Daily Living Scale ( BADLS ) and Neuropsychiatric Inventory ( NPI ) . Only st and ard deviations ( SD ) were presented to investigators who remained blind to treatment allocation . RESULTS Adoption of values for MCIDs based upon 0.4 of the SD of the change in score from baseline on the sMMSE , BADLS and NPI in the first 127 participants to complete DOMINO yielded MCIDs of 1.4 points for sMMSE , 3.5 for BADLS and 8.0 for NPI . CONCLUSIONS Reference to MCIDs is important for the full interpretation of the results of dementia trials and those conducting such trials should be open about the way in which they have determined and chosen their values for the MCIDs This article reports the development and psychometric properties of the Alzheimer 's Disease Cooperative Study - Clinical Global Impression of Change ( ADCS-CGIC ) . At present , a number of unvali date d CGIC scales are used in clinical trials , with various methods for making ratings . The ADCS-CGIC was design ed on the basis of a survey of  ADCS clinicians  and by adapting existing instruments . It includes an organized but unstructured format , with which a clinician can address clinical ly relevant change . The instrument 's reliability and validity were assessed in a prospect i ve trial of Alzheimer 's disease ( AD ) and healthy subjects over a 12-month period . It showed good short-term reliability at 1 and 2 months , with 90 and 94 % of AD subjects , respectively , rated as having changed not at all or only minimally . The ADCS-CGIC 's  face validity was demonstrated by untreated . AD subjects rated as having worsened over time at both 6 months ( 56 % rated as having worsened ) and 12 months ( 81 % rated as having worsened ) , whereas only 2 % of control subjects showed minimal worsening . As a measure of predictive validity , ADCS-CGIC ratings at 12 months were significantly associated with change on four severity scales . As with other measures , change ratings were sensitive to dementia severity . Moderately impaired subjects showed greater worsening than other subjects . ADCS-CGIC ratings of greater worsening were made after the informant interview , regardless of whether informants or subjects were interviewed first . The ADCS-CGIC is a valid and reliable instrument for use in clinical trials OBJECTIVE To estimate per-patient potential cost savings using rivastigmine in the treatment of Alzheimer 's disease ( AD ) in Canada . BACKGROUND In recent years , new members of a class of pharmaceuticals known as cholinesterase inhibitors have been introduced for the treatment of patients with AD . Two recent studies conducted in the United Kingdom and the United States estimated potential cost savings from the new cholinesterase inhibitor rivastigmine . The present study combined the disease-progression model used in those 2 studies with Canadian costs to estimate per-patient potential savings result ing from the treatment of AD in Canada . METHODS Efficacy data from 2 pivotal , phase III clinical trials of rivastigmine were used in a hazard model of disease progression to estimate long-term differences in cognitive functioning between patients receiving rivastigmine and patients receiving no treatment . We used the Mini-Mental State Examination ( MMSE ) score as our measure of disease progression . We also used Canadian costs of AD care , estimated as a function of MMSE score , to estimate cost savings experienced by treated patients compared with patients receiving no treatment . All costs and cost savings are presented in 1997 Canadian dollars . We used a societal perspective in this analysis . RESULTS Rivastigmine was estimated to delay the transition to more severe stages of AD by up to 188 days for patients with mild AD after 2 years of treatment . For patients with mild-to-moderate and moderate disease , this delay was estimated to be 106 and 44 days , respectively . For patients with the mild stage of AD , estimated average daily cost savings ( excluding the cost of rivastigmine ) ranged from Can $ 0.45 per patient per day at 6 months to Can $ 6.44 per patient per day after 2 years of treatment . For all patients , these estimated average daily cost savings ranged from a low of Can $ 0.71 per patient per day after 6 months of treatment to a high of Can $ 4.93 per patient per day after 2 years . CONCLUSION On average , treatment with rivastigmine yields savings in the direct cost of caring for AD patients that exceed the cost of the drug after 2 years of treatment Rivastigmine has demonstrated significant benefits in patients with mild to moderate Alzheimer 's disease ( AD ) . We aim ed to confirm whether rivastigmine was effective in patients with or without concurrent vascular risk factors ( VRF ) , as previously suggested . We chose to stratify the 725 patients involved in an international dose-ranging study according to the presence of arterial hypertension ( a marker of VRF ) at baseline . Efficacy in each subgroup was assessed using the ADAS-cog , a measure of cognitive performance , the Progressive Deterioration Scale ( PDS ) and the Clinician 's Interview-Based Impression of Change ( CIBIC ) with caregiver input . Patients receiving rivastigmine 6 - 12 mg/day showed better outcomes on the ADAS-cog than those receiving placebo , in both the hypertensive and non-hypertensive subgroups . Hypertensive patients receiving rivastigmine 6 - 12 mg/day also showed improvement over those receiving 1 - 4 mg/day ( p = 0.023 ) . Rivastigmine 6 - 12 mg/day also provided better outcomes than placebo on the PDS in the hypertensive ( p = 0.031 ) and non-hypertensive ( p = 0.035 ) subgroups . All patients receiving rivastigmine 6 - 12 mg/day had superior CIBIC-plus scores than those receiving placebo . There was a trend for lower incidences of nausea and vomiting in rivastigmine-treated patients with hypertension than in those without hypertension . No cardiac adverse events or drug-drug interactions were reported . Our data support the hypothesis that rivastigmine provides benefits to patients with or without hypertension , and contribute to the evidence that particular benefits may be observed in those with vascular risk factors 
    Output:
    
Rivastigmine ( 6 to 12 mg daily orally or 9.5 mg daily transdermally ) appears to be beneficial for people with mild to moderate Alzheimer 's disease .
In comparisons with placebo , better outcomes were observed for rate of decline of cognitive function and activities of daily living , although the effects were small and of uncertain clinical importance .
There was also a benefit from rivastigmine on the outcome of clinician 's global assessment .
There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers .
At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy .