***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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    ***EXAMPLES*** 
    Input: Objective : To search for major gaps in medication-taking behavior predisposing patients to cardiovascular morbidity and mortality . Design : Convenience sample ; cohort prospect ively followed for ≤5 months . Setting : General internal medicine and cardiology clinics in a university medical center . Patients : From among 893 patients , the authors identified 132 eligible individuals and entered 33 subjects ( 25 % ) with chronic cardiovascular conditions , 1–3 chronic oral medications for these conditions , overall regimen of ≤6 drugs , regular visits at 1–3-month intervals , literacy in English , willingness to use electronic monitors , and physician permission to participate . Outcome measures : Medication compliance rates and patterns by patient self-report , physician estimates , pill count , and electronic monitoring of pill vial opening . Results : Despite moderately complex regimens ( 5.4±0.5 pills daily ; range 1–11 ) , most subjects took most medications according to the prescription : median intervals between pill vial openings were 1.00 , 0.50 , and 0.43 days for once , twice , and three times daily dosing , respectively . Medication-taking gaps of ≥2 times the prescribed interdosing interval occurred for 48 % of the patients . Patients ’ dosing patterns often produced “ uncovered ” intervals ( mean duration 3.7 days , range 0–25 ) with doubtful pharmacologic effectiveness . These lapses were underestimated by patients and poorly perceived by their treating physicians , despite familiarity with their care . Baseline sociodemographic , psychosocial , medical system , or clinical characteristics did not predict the patterns or degrees of medication noncompliance . Conclusions : Major treatment gaps occur frequently , even in carefully selected ambulatory population s , and generally escape detection . The compliance patterns and gaps may contribute to reported excesses of cardiovascular morbidity and mortality BACKGROUND Suboptimal compliance in taking guideline -based pharmacotherapy in patients with chronic heart failure ( HF ) potentially increases the burden of hospitalizations and diminishes quality of life . By simplifying the medical regimen , once-daily dosing can potentially improve compliance . The Compliance And Quality of Life Study Comparing Once-Daily Controlled-Release Carvedilol CR and Twice-Daily Immediate-Release Carvedilol IR in Patients with Heart Failure ( CASPER ) Trial was design ed to measure differential compliance , satisfaction , and quality of life in chronic HF patients taking carvedilol immediate release ( IR ) twice daily versus the bioequivalent carvedilol controlled-release ( CR ) once daily . METHODS AND RESULTS CASPER was a prospect i ve multicenter , 3-arm , parallel-group , r and omized clinical trial for a 5-month period . The primary objective of the study was to evaluate and compare compliance with  carvedilol IR twice daily ( BID ) and carvedilol phosphate CR  once daily ( QD ) in patients with chronic HF who were taking carvedilol IR .  Secondary objectives included comparisons of quality of life ( Kansas City Cardiomyopathy Question naire ) , satisfaction with medication , and brain natriuretic peptide levels between subjects taking the two formulations . A total of 405 patients with chronic HF and left ventricular dysfunction were r and omized to : ( A ) carvedilol IR twice daily , given double blind ; ( B ) carvedilol CR taken in the morning and placebo in the afternoon , given double blind ; or ( C ) carvedilol CR once daily , open label . Compliance was measured using the medication event monitoring system that captures time of bottle opening . The primary end point was a comparison of taking compliance ( doses taken divided by total number of prescribed doses over the actual duration of the study ) between the double-blind carvedilol IR BID versus the open-label carvedilol CR QD groups . Sample size estimates were based on assumptions of 75 % compliance with BID dosing and 90 % compliance with QD dosing . Mean compliance with carvedilol IR BID was 89.3 % compared with 88.2 % for carvedilol CR QD , and differential mean compliance was 1.1 % ( 95 % CI -4.4 % , 6.6 % ; ie , not significant ) . There were no statistically significant differences in compliance between any of the 3 groups , nor differences in quality of life , treatment satisfaction , or physiologic measures among the 3 study arms . There were also no significant differences in adverse events or side effects among patients switching from carvedilol IR to carvedilol CR in arms B or C over the 5-month study duration compared with patients remaining on carvedilol IR . CONCLUSIONS Compliance among chronic HF patients in the CASPER trial was high at baseline and unaffected by QD versus BID dosing . Over the 5-month follow-up period , there were no differences in adverse events among patients switching from carvedilol IR to CR OBJECTIVE To compare compliance in type 2 diabetic patients treated with glimepiride once daily or glibenclamide twice to three times daily . METHODS Poorly controlled type 2 diabetic patients aged 35 - 65 years were r and omized to glimepiride 1 mg once daily or to glibenclamide 1.25 mg twice daily . During initial titration , doses ranged from 1 to 6 mg once daily ( glimepiride ) and from 1.25 mg twice daily to 5 mg 3 times daily ( glibenclamide ) to achieve fasting blood glucose < 126 mg/dL. The final titration phase doses were continued during the maintenance phase . Both treatments were packed in electronic pill-boxes fitted with a microprocessor to record date s and times of each opening . Compliance was assessed in terms of mean daily compliance ( MDC ) and the ratio of days with adequate compliance ( DAC ) . Glycemic control was assessed in terms of the adjusted mean final HbA1c , and the incidence of hypoglycemia . Patient satisfaction was evaluated using the Diabetes Treatment Satisfaction Question naire . RESULTS Compliance over the whole study was generally good , but the MDC was significantly better with glimepiride ( 87+/-16 % ) than with glibenclamide ( 80+/-17%;P < 0.0001 ) . The ratios of DAC for glimepiride and glibenclamide were 87+/-16 % and 67+/-24 % respectively ( P < 0.0001 ) . The adjusted final HbA1c , and the incidence of hypoglycemia were similar in the two groups . Treatment satisfaction on the DTSQc was greater with glimepiride than with glibenclamide ( P = 0.0034 ) . CONCLUSIONS Patient compliance and treatment satisfaction with once-daily glimepiride were significantly better than with glibenclamide 2 to 3 times daily Data from electronic dosing monitors and published pharmacokinetic parameters were used to derive medication adherence measures for immediate‐release metoprolol and examine their association with health care utilization of out patients aged 50 years or older with heart failure This study compares patient compliance with once- and twice-daily formulations of 5-isosorbide mononitrate . A total of 31 patients ( 20 men and 11 women ) with stable angina pectoris were r and omized to receive either 60 mg 5-isosorbide mononitrate in a controlled release formulation once daily , or 20 mg 5-isosorbide mononitrate twice daily . The results indicated that compliance assessed using the electronic Medication Event Monitoring System ( MEMS ® ) was better with the once-daily than with the twice-daily formulation ; patients on the once-daily regimen performed better with respect to the total number of bottle openings , the number of openings per day , the timing of openings and the intervals between openings . The apparently superior compliance with the once-daily regimen appeared to be reflected in better efficacy ; patients on the once-daily regimen experienced fewer angina attacks ( a mean of 1.7 per 7 days , compared with 3.3 per 7 days for patients on the twice-daily regimen ) and used fewer nitroglycerin tablets than those on the twice-daily regimen Long-term adherence or compliance with anti-hypertensive drug therapy is poor . It has been estimated that within the first year of treatment 16 - 50 % of hypertensives discontinue their anti-hypertensive medications . Even among those who remain on therapy long term , missed medication doses are common . Epidemiological studies have shown that drug-treated hypertensives have higher blood pressures than age- , gender- and body mass index-matched normotensives . In addition , drug-treated hypertensive men and women who achieve blood pressure normalization are less likely to die over a 9.5-year period than those whose blood pressure remains elevated while taking anti-hypertensive drugs . Thus , one reason for less than optimal reduction of blood pressure-related cardiovascular-renal risk in drug-treated hypertensives is inadequate blood pressure lowering . Quantifiable excess risk has been documented even in the short term ( < 1 year ) after interruption or discontinuation of anti-hypertensive medications as total healthcare costs are higher , mostly because of higher hospitalization rates . Data from the Treatment of Mild Hypertension Study ( TOMHS ) are relevant to long-term adherence to various anti-hypertensive drug monotherapies . At 48 months , 82.5 % and 77.8 % of participants remained on  amlodipine and acebutolol  , respectively ( both P < 0.01 compared with placebo ) . However , only 67.5 % , 66.1 % and 68.1 % , respectively , of chlorthalidone , doxazosin and enalapril participants remained on these drugs as monotherapy at 48 months . Differential adherence to long-term anti-hypertensive drug therapy could translate into a greater risk of blood pressure-related complications and higher overall healthcare expenditures . Strategies to minimize the deleterious impact of therapeutic non-adherence with anti-hypertensive medications as well as the clinical and cost implication s of the TOMHS data will be discussed Background A r and omized , controlled trial was conducted in an outpatient setting to examine the effect of beta-blocker dosing frequency on patient compliance , clinical outcome , and health-related quality of life in patients with stable angina pectoris . Methods One hundred and twelve beta-blockers-naive out patients with stable angina pectoris were r and omized to receive betaxolol , 20 mg once daily or metoprolol tartrate , 50 mg twice daily for 8 weeks . The principal outcome measure was overall compliance measured electronically , whereas secondary outcome measures were drug effectiveness and health-related quality of life . Results The overall compliance was 86.5 ± 21.3 % in the betaxolol group versus 76.1 ± 26.3 % in the metoprolol group ( p < 0.01 ) , and the correct number of doses was taken on 84.4 ± 21.6 % and 64.0 ± 31.7 % of treatment days , respectively ( p < 0.0001 ) . The percentage of missed doses was 14.5 ± 21.5 % in the once-daily group and 24.8 ± 26.4 % in the twice-daily group ( p < 0.01 ) . The percentage of doses taken in the correct time window ( 58.6 % vs 42.0 % , p = 0.01 ) , correct interdose intervals ( 77.4 % v 53.1 % , p < 0.0001 ) , and therapeutic coverage ( 85.6 % vs 73.7 % , p < 0.001 ) were significantly higher in the once-daily group . Both studied drugs had similar antianginal effectiveness . Health-related quality of life improved in both groups , but this increase was more pronounced in the betaxolol arm in some dimensions . Conclusions The study demonstrates that patient compliance with once-daily betaxolol is significantly better than with twice daily metoprolol . Similarly , this treatment provides better quality of life . These results demonstrate possible therapeutic advantages of once-daily over twice-daily beta-blockers in the treatment of stable angina pectoris Background Evidence regarding the effectiveness of oral vitamin B12 in patients with serum vitamin B12 levels between 125 - 200 pM/l is lacking . We compared the effectiveness of one-month oral vitamin B12 supplementation in patients with a subtle vitamin B12 deficiency to that of a placebo . Methods This multicentre ( 13 general practice s , two nursing homes , and one primary care center in western Switzerl and ) , parallel , r and omised , controlled , closed-label , observer-blind trial included 50 patients with serum vitamin B12 levels between 125 - 200 pM/l who were r and omized to receive either oral vitamin B12 ( 1000 μg daily , N = 26 ) or placebo ( N = 24 ) for four weeks . The institution 's pharmacist used simple r and omisation to generate a table and allocate treatments . The primary outcome was the change in serum methylmalonic acid ( MMA ) levels after one month of treatment . Secondary outcomes were changes in total homocysteine and serum vitamin B12 levels . Blood sample s were central ised for analysis and adherence to treatment was verified by an electronic device ( MEMS ; Aardex Europe , Switzerl and ) . Trial registration : IS RCT N 22063938 . Results Baseline characteristics and adherence to treatment were similar in both groups . After one month , one patient in the placebo group was lost to follow-up . Data were evaluated by intention-to-treat analysis . One month of vitamin B12 treatment ( N = 26 ) lowered serum MMA levels by 0. 
    Output:
    
Patients with chronic diseases appear to be more adherent with once-daily compared with more frequently scheduled medication regimens .
The use of more stringent definitions of adherence magnified these findings