human
***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: In a prospect i ve cohort study , associations of resting heart rate with  risk of coronary , cardiovascular disease , cancer , and all-cause mortality in age-specific cohorts of black and white men and women were examined over 22 years of follow-up . Participants were employees from 84 companies and organizations in the Chicago , Illinois , area who volunteered for a screening examination . Participants included 9,706 men aged 18 - 39 years , 7,760 men aged 40 - 59 years , 1,321 men aged 60 - 74 years , 6,928 women aged 18 - 39 years , 6,915 women aged 40 - 59 years , and 1,151 women aged 60 - 74 years at the baseline examination in 1967 - 1973 . Vital status was ascertained through 1992 . For fatal coronary disease , multivariate-adjusted relative risks associated with a 12 beats per minute higher heart rate ( one st and ard deviation ) were as follows : for men aged 18 - 39 years , relative risk ( RR ) = 1.27 ( 95 % confidence interval ( CI ) 1.08 - 1.48 ) ; for men aged 40 - 59 years , RR = 1.13 ( 95 % CI 1.05 - 1.21 ) ; for men aged 60 - 74 years , RR = 1.00 ( 95 % CI 0.89 - 1.12 ) ; for women aged 40 - 59 years , RR = 1.21 ( 95 % CI 1.07 - 1.36 ) ; and for women aged 60 - 74 years , RR = 1.16 ( 95 % CI 0.99 - 1.37 ) . Corresponding risks for all fatal cardiovascular diseases were similar to those for coronary death alone . Deaths from cancer were significantly associated with heart rate in men and women aged 40 - 59 years . All-cause mortality was associated with higher heart rate in men aged 18 - 39 years ( RR = 1.11 , 95 % CI 1.01 - 1.20 ) , men aged 40 - 59 years ( RR = 1.16 , 95 % CI 1.11 - 1.21 ) , and women aged 40 - 59 years ( RR = 1.20 , 95 % CI 1.13 - 1.27 ) . Heart rate was not associated with mortality in women aged 18 - 39 years . In summary , heart rate was a risk factor for mortality from coronary disease , all cardiovascular diseases , and all causes in younger men and in middle-aged men and women , and for cancer mortality in middle-aged men and women Summary In a multicentre , double-blind , between-patient study the hypotensive effect of oxprenolol was investigated in 329 patients with mild to moderate hypertension . A factorial experimental design with three factors was chosen : oxprenolol — none or daily doses of 20 , 40 , 60 and 80 mg ; dihydralazine and hydrochlorothiazide , respectively , none or 30 mg daily . Each treatment was given for 4 weeks after an adequate period of withdrawal from any other possible hypotensive therapy and one week of placebo wash-out . Irrespective of the association with dihydralazine and /or hydrochlorothiazide , oxprenolol had a hypotensive effect linearly related to dose for st and ing systolic ( P<0.05 ) and diastolic ( P<0.01 ) pressure , and for lying diastolic ( P<0.05 ) pressure . The addition of dihydralazine enhanced the time-course of the hypotensive effect of oxprenolol , particularly the 80 mg dose level . In general , the combination of oxprenolol with dihydralazine and hydrochlorothiazide caused larger reductions in blood pressure , particularly with oxprenolol 80 mg . In the latter group , the eventual falls in blood pressure were 30.5 and 14.4 mmHg for lying systolic and diastolic , respectively ; and 32.1 and 20.0 mmHg for the st and ing systolic and diastolic pressures . The drug was well tolerated ; major side effects ( heart failure and bronchospasm ) occurred in three patients The effect of atenolol , a new beta-1-adrenergic receptor blocking agent , was studied in a double-blind cross-over trial in 24 carefully selected hypertensive out patients . After a four-week run-in period on matching placebo each patient received atenolol 200 mg/day , atenolol 400 mg/day , a combination of atenolol 200/mg day with bendrofluazide 5 mg/day , and bendrofluazide 5 mg/day alone , according to a r and om sequence . Atenolol at either dose produced a significantly greater reduction in all blood pressure levels except st and ing systolic pressure than bendrofluazide alone . There was no statistically significant difference between the effects of the two atenolol doses on either blood pressure or pulse rate . The addition of bendrofluazide to atenolol result ed in a further significant lowering of the blood pressure . A significant effect of thiazide on weight was noted . The study shows that atenolol , a cardioselective beta-blocker of similar potency to propranolol in animals but without membrane-stabilizing or partial agonist acitivity , is an effective and well-tolerated hypotensive agent This r and omised , double-blind study was design ed to investigate the efficacy of a once-daily ( OD ) combination of the AT1 receptor blocker , eprosartan 600 mg , and the thiazide diuretic , hydrochlorothiazide ( HCTZ ) 12.5 mg , in patients with mild to moderate hypertension ( sitting diastolic blood pressure ( sitDBP ) ⩾98 mm Hg and ⩽114 mm Hg ) not adequately controlled with eprosartan 600 mg OD . A total of 494 patients entered the open-label monotherapy run-in phase , which consisted of eprosartan 600 mg OD for 3 weeks . Patients who responded to monotherapy were not eligible to enter the r and omised phase of the study and were withdrawn . The remaining 309 patients were then r and omised to either eprosartan 600 mg plus HCTZ 12.5 mg OD or to continue on eprosartan 600 mg OD . In the eprosartan plus HCTZ combination group , both sitDBP and sitting systolic blood pressure ( sitSBP ) were significantly reduced compared with the eprosartan monotherapy group . In addition , the response rate was higher in the combination group compared with the monotherapy group . There were no significant effects on reduction of sitDBP due to gender , prior use of antihypertensives or baseline severity of hypertension . The tolerability profile for the combination group was similar to that for the monotherapy group . Headache was the most frequent adverse event in both treatment groups . The majority of adverse events were mild to moderate in intensity . In this study of patients who were unresponsive to eprosartan monotherapy for 3 weeks , a combination product of eprosartan 600 mg and HCTZ 12.5 mg was shown to be an effective and well tolerated treatment Fixed-dose combination therapy has received increased interest since publication of JNC-VI report and WHO/ISH guidelines 1999 . We compared in a r and omized , double-blind study the efficacy and tolerability of valsartan 80 mg combined with hydrochlorothiazide ( HCTZ ) 12.5 mg to monotherapy with either HCTZ 12.5 mg or 25 mg in patients with essential hypertension inadequately controlled by previous HCTZ 12.5 mg monotherapy . Two hundred and seventeen patients whose blood pressure ( BP ) control remained poor ( 95 mmHg h sitting diastolic BP < 115 mmHg ) after a 4-week single-blind period with HCTZ 12.5 mg were r and omized to receive either combination therapy with valsartan 80 mg plus HCTZ 12.5 mg ( V/HCTZ ) or monotherapy with HCTZ 12.5 mg or HCTZ 25 mg for 8 weeks . Reduction of sitting trough diastolic BP between baseline and week 8 as well as tolerability was evaluated . Reduction in trough diastolic BP was most pronounced in the V/HCTZ group ( –11.3 mmHg ) and significantly greater than in the HCTZ 12.5 mg group ( –2.9 mmHg , p < 0.001 ) and the HCTZ 25 mg group ( –5.7 mmHg , p < 0.001 ) . Tolerability of study medication was comparable between all three groups . In conclusion , switching to V/HCTZ combination therapy provides an additional lowering of BP compared to dosage increase of the thiazide in patients with BP insufficiently controlled by HCTZ 12.5 mg monotherapy In this double-blind , r and omised , three-way crossover ( latin square design ) , multicentre study , the aim was to compare the efficacy and tolerability of the fixed combination of felodipine and metoprolol with the individual components as monotherapy . A total of 58 patients with supine diastolic blood pressure of 100 - 115 mmHg were treated with ( 1 ) a fixed combination of felodipine plus metoprolol 5/50 - 10/100 mg ( FM ) , ( 2 ) felodipine 5 - 10 mg ( F ) or ( 3 ) metoprolol 50 - 100 mg ( M ) , for 12 weeks each . All treatments were extended-release formulations administered once daily and blood pressure was measured 24 h after dosing . Dose titration was performed after 6 weeks if diastolic blood pressure was > 90 mmHg . After 12 weeks of active treatment , the mean supine blood pressures were 153/89 , 159/93 and 163/94 mmHg with FM , F and M , respectively . The mean differences in systolic/diastolic blood pressure were -5.6/-3.1 mmHg ( p = 0.007/p = 0.002 ) , -10.2/-4.4 mmHg ( p < 0.0001/p < 0.0001 ) and -4.6/-1.4 mmHg ( p = 0.03/p = 0.15 ) for FM vs F , FM vs M , and F vs M , respectively . Blood pressure control ( supine diastolic blood pressure < or = 90 mmHg ) after 12 weeks was achieved in a significantly greater proportion of patients during treatment with FM than with F or M ; 71 % , 45 % and 40 % were controlled with the respective treatments . With FM , 45 % of the patients were taking the higher dose after 12 weeks of treatment . The corresponding figures for F and M were 60 % and 67 % , respectively . Thirteen of the 58 patients ( 22 % ) were controlled only with FM . ( ABSTRACT TRUNCATED AT 250 WORDS In 15 patients with mild to moderate essential hypertension , the effects of diltiazem ( 120 mg twice daily ) were compared with those of atenolol ( 50 mg once daily ) , the two drugs in combination , and placebo in a r and omized double-blind cross-over study with treatment phases of 4 weeks duration . Blood pressure was reduced in the active treatment phases ( supine blood pressure : diltiazem , 172/92 mmHg ; atenolol , 172/92 mmHg ; diltiazem plus atenolol , 164/88 mmHg ; pooled estimate of s.e.m . by analysis of variance = 3/1 ) compared with placebo ( 180/101 mmHg ) . Factorial analysis confirmed fully additive antihypertensive effects of the drugs in combination . The time interval from the beginning of the P wave to the beginning of the QRS complex ( P-R interval ) was longer during combination therapy ( 0.184s ) compared with either diltiazem ( 0.175s ) or atenolol ( 0.174s ) alone , or placebo ( 0.164s ) ; s.e.m . by analysis of variance = 0.003 . No clinical ly significant conduction disturbances occurred . Plasma atrial natriuretic peptide was elevated by atenolol but not diltiazem . Thus , in subjects with uncomplicated essential hypertension , diltiazem and atenolol had equal antihypertensive efficacy when used alone , and fully additive effects in combination , on both blood pressure and cardiac conduction Summary Sixteen patients with essential hypertension completed a double blind factorial trial comparing the effects of indapamide ( 2.5 mg daily ) and pindolol ( 10 mg daily ) on blood pressure , heart rate , plasma renin activity and plasma aldosterone concentration . There were four r and omised test phases of eight weeks each during which patients received indapamide alone , pindolol alone , indapamide plus pindolol and no active treatment ( placebo ) .  Blood pressure and heart rate were measured every two weeks . Supine mean arterial pressure fell from  
    Output:
    
agent
When the blood pressure lowering effect of beta-blockers from this review was compared to that of thiazide diuretics from our previous review ( Chen 2009 ) , second-line beta-blockers reduce systolic BP to the same extent as second-line thiazide diuretics , but reduce diastolic BP to a greater degree .
The different effect on diastolic BP means that beta-blockers have little or no effect on pulse pressure whereas thiazides cause a significant dose-related decrease in pulse pressure .
This difference in the pattern of BP lowering with beta-blockers as compared to thiazides might be the explanation for the fact that beta-blockers appear to be less effective at reducing adverse cardiovascular outcomes than thiazide diuretics , particularly in older individuals
***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: In a prospect i ve cohort study , associations of resting heart rate with  risk of coronary , cardiovascular disease , cancer , and all-cause mortality in age-specific cohorts of black and white men and women were examined over 22 years of follow-up . Participants were employees from 84 companies and organizations in the Chicago , Illinois , area who volunteered for a screening examination . Participants included 9,706 men aged 18 - 39 years , 7,760 men aged 40 - 59 years , 1,321 men aged 60 - 74 years , 6,928 women aged 18 - 39 years , 6,915 women aged 40 - 59 years , and 1,151 women aged 60 - 74 years at the baseline examination in 1967 - 1973 . Vital status was ascertained through 1992 . For fatal coronary disease , multivariate-adjusted relative risks associated with a 12 beats per minute higher heart rate ( one st and ard deviation ) were as follows : for men aged 18 - 39 years , relative risk ( RR ) = 1.27 ( 95 % confidence interval ( CI ) 1.08 - 1.48 ) ; for men aged 40 - 59 years , RR = 1.13 ( 95 % CI 1.05 - 1.21 ) ; for men aged 60 - 74 years , RR = 1.00 ( 95 % CI 0.89 - 1.12 ) ; for women aged 40 - 59 years , RR = 1.21 ( 95 % CI 1.07 - 1.36 ) ; and for women aged 60 - 74 years , RR = 1.16 ( 95 % CI 0.99 - 1.37 ) . Corresponding risks for all fatal cardiovascular diseases were similar to those for coronary death alone . Deaths from cancer were significantly associated with heart rate in men and women aged 40 - 59 years . All-cause mortality was associated with higher heart rate in men aged 18 - 39 years ( RR = 1.11 , 95 % CI 1.01 - 1.20 ) , men aged 40 - 59 years ( RR = 1.16 , 95 % CI 1.11 - 1.21 ) , and women aged 40 - 59 years ( RR = 1.20 , 95 % CI 1.13 - 1.27 ) . Heart rate was not associated with mortality in women aged 18 - 39 years . In summary , heart rate was a risk factor for mortality from coronary disease , all cardiovascular diseases , and all causes in younger men and in middle-aged men and women , and for cancer mortality in middle-aged men and women Summary In a multicentre , double-blind , between-patient study the hypotensive effect of oxprenolol was investigated in 329 patients with mild to moderate hypertension . A factorial experimental design with three factors was chosen : oxprenolol — none or daily doses of 20 , 40 , 60 and 80 mg ; dihydralazine and hydrochlorothiazide , respectively , none or 30 mg daily . Each treatment was given for 4 weeks after an adequate period of withdrawal from any other possible hypotensive therapy and one week of placebo wash-out . Irrespective of the association with dihydralazine and /or hydrochlorothiazide , oxprenolol had a hypotensive effect linearly related to dose for st and ing systolic ( P<0.05 ) and diastolic ( P<0.01 ) pressure , and for lying diastolic ( P<0.05 ) pressure . The addition of dihydralazine enhanced the time-course of the hypotensive effect of oxprenolol , particularly the 80 mg dose level . In general , the combination of oxprenolol with dihydralazine and hydrochlorothiazide caused larger reductions in blood pressure , particularly with oxprenolol 80 mg . In the latter group , the eventual falls in blood pressure were 30.5 and 14.4 mmHg for lying systolic and diastolic , respectively ; and 32.1 and 20.0 mmHg for the st and ing systolic and diastolic pressures . The drug was well tolerated ; major side effects ( heart failure and bronchospasm ) occurred in three patients The effect of atenolol , a new beta-1-adrenergic receptor blocking agent , was studied in a double-blind cross-over trial in 24 carefully selected hypertensive out patients . After a four-week run-in period on matching placebo each patient received atenolol 200 mg/day , atenolol 400 mg/day , a combination of atenolol 200/mg day with bendrofluazide 5 mg/day , and bendrofluazide 5 mg/day alone , according to a r and om sequence . Atenolol at either dose produced a significantly greater reduction in all blood pressure levels except st and ing systolic pressure than bendrofluazide alone . There was no statistically significant difference between the effects of the two atenolol doses on either blood pressure or pulse rate . The addition of bendrofluazide to atenolol result ed in a further significant lowering of the blood pressure . A significant effect of thiazide on weight was noted . The study shows that atenolol , a cardioselective beta-blocker of similar potency to propranolol in animals but without membrane-stabilizing or partial agonist acitivity , is an effective and well-tolerated hypotensive agent This r and omised , double-blind study was design ed to investigate the efficacy of a once-daily ( OD ) combination of the AT1 receptor blocker , eprosartan 600 mg , and the thiazide diuretic , hydrochlorothiazide ( HCTZ ) 12.5 mg , in patients with mild to moderate hypertension ( sitting diastolic blood pressure ( sitDBP ) ⩾98 mm Hg and ⩽114 mm Hg ) not adequately controlled with eprosartan 600 mg OD . A total of 494 patients entered the open-label monotherapy run-in phase , which consisted of eprosartan 600 mg OD for 3 weeks . Patients who responded to monotherapy were not eligible to enter the r and omised phase of the study and were withdrawn . The remaining 309 patients were then r and omised to either eprosartan 600 mg plus HCTZ 12.5 mg OD or to continue on eprosartan 600 mg OD . In the eprosartan plus HCTZ combination group , both sitDBP and sitting systolic blood pressure ( sitSBP ) were significantly reduced compared with the eprosartan monotherapy group . In addition , the response rate was higher in the combination group compared with the monotherapy group . There were no significant effects on reduction of sitDBP due to gender , prior use of antihypertensives or baseline severity of hypertension . The tolerability profile for the combination group was similar to that for the monotherapy group . Headache was the most frequent adverse event in both treatment groups . The majority of adverse events were mild to moderate in intensity . In this study of patients who were unresponsive to eprosartan monotherapy for 3 weeks , a combination product of eprosartan 600 mg and HCTZ 12.5 mg was shown to be an effective and well tolerated treatment Fixed-dose combination therapy has received increased interest since publication of JNC-VI report and WHO/ISH guidelines 1999 . We compared in a r and omized , double-blind study the efficacy and tolerability of valsartan 80 mg combined with hydrochlorothiazide ( HCTZ ) 12.5 mg to monotherapy with either HCTZ 12.5 mg or 25 mg in patients with essential hypertension inadequately controlled by previous HCTZ 12.5 mg monotherapy . Two hundred and seventeen patients whose blood pressure ( BP ) control remained poor ( 95 mmHg h sitting diastolic BP < 115 mmHg ) after a 4-week single-blind period with HCTZ 12.5 mg were r and omized to receive either combination therapy with valsartan 80 mg plus HCTZ 12.5 mg ( V/HCTZ ) or monotherapy with HCTZ 12.5 mg or HCTZ 25 mg for 8 weeks . Reduction of sitting trough diastolic BP between baseline and week 8 as well as tolerability was evaluated . Reduction in trough diastolic BP was most pronounced in the V/HCTZ group ( –11.3 mmHg ) and significantly greater than in the HCTZ 12.5 mg group ( –2.9 mmHg , p < 0.001 ) and the HCTZ 25 mg group ( –5.7 mmHg , p < 0.001 ) . Tolerability of study medication was comparable between all three groups . In conclusion , switching to V/HCTZ combination therapy provides an additional lowering of BP compared to dosage increase of the thiazide in patients with BP insufficiently controlled by HCTZ 12.5 mg monotherapy In this double-blind , r and omised , three-way crossover ( latin square design ) , multicentre study , the aim was to compare the efficacy and tolerability of the fixed combination of felodipine and metoprolol with the individual components as monotherapy . A total of 58 patients with supine diastolic blood pressure of 100 - 115 mmHg were treated with ( 1 ) a fixed combination of felodipine plus metoprolol 5/50 - 10/100 mg ( FM ) , ( 2 ) felodipine 5 - 10 mg ( F ) or ( 3 ) metoprolol 50 - 100 mg ( M ) , for 12 weeks each . All treatments were extended-release formulations administered once daily and blood pressure was measured 24 h after dosing . Dose titration was performed after 6 weeks if diastolic blood pressure was > 90 mmHg . After 12 weeks of active treatment , the mean supine blood pressures were 153/89 , 159/93 and 163/94 mmHg with FM , F and M , respectively . The mean differences in systolic/diastolic blood pressure were -5.6/-3.1 mmHg ( p = 0.007/p = 0.002 ) , -10.2/-4.4 mmHg ( p < 0.0001/p < 0.0001 ) and -4.6/-1.4 mmHg ( p = 0.03/p = 0.15 ) for FM vs F , FM vs M , and F vs M , respectively . Blood pressure control ( supine diastolic blood pressure < or = 90 mmHg ) after 12 weeks was achieved in a significantly greater proportion of patients during treatment with FM than with F or M ; 71 % , 45 % and 40 % were controlled with the respective treatments . With FM , 45 % of the patients were taking the higher dose after 12 weeks of treatment . The corresponding figures for F and M were 60 % and 67 % , respectively . Thirteen of the 58 patients ( 22 % ) were controlled only with FM . ( ABSTRACT TRUNCATED AT 250 WORDS In 15 patients with mild to moderate essential hypertension , the effects of diltiazem ( 120 mg twice daily ) were compared with those of atenolol ( 50 mg once daily ) , the two drugs in combination , and placebo in a r and omized double-blind cross-over study with treatment phases of 4 weeks duration . Blood pressure was reduced in the active treatment phases ( supine blood pressure : diltiazem , 172/92 mmHg ; atenolol , 172/92 mmHg ; diltiazem plus atenolol , 164/88 mmHg ; pooled estimate of s.e.m . by analysis of variance = 3/1 ) compared with placebo ( 180/101 mmHg ) . Factorial analysis confirmed fully additive antihypertensive effects of the drugs in combination . The time interval from the beginning of the P wave to the beginning of the QRS complex ( P-R interval ) was longer during combination therapy ( 0.184s ) compared with either diltiazem ( 0.175s ) or atenolol ( 0.174s ) alone , or placebo ( 0.164s ) ; s.e.m . by analysis of variance = 0.003 . No clinical ly significant conduction disturbances occurred . Plasma atrial natriuretic peptide was elevated by atenolol but not diltiazem . Thus , in subjects with uncomplicated essential hypertension , diltiazem and atenolol had equal antihypertensive efficacy when used alone , and fully additive effects in combination , on both blood pressure and cardiac conduction Summary Sixteen patients with essential hypertension completed a double blind factorial trial comparing the effects of indapamide ( 2.5 mg daily ) and pindolol ( 10 mg daily ) on blood pressure , heart rate , plasma renin activity and plasma aldosterone concentration . There were four r and omised test phases of eight weeks each during which patients received indapamide alone , pindolol alone , indapamide plus pindolol and no active treatment ( placebo ) .  Blood pressure and heart rate were measured every two weeks . Supine mean arterial pressure fell from  
    Output:
    