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: Increasingly combined antihypertensive agents are being used in practice to enhance control and improve compliance . To determine whether a capsule containing a quarter of the st and ard dose of 4 antihypertensive agents has greater efficacy than the st and ard dose of each individually , we prospect ively r and omized 108 untreated white hypertensive patients ( 55 % male ) aged 50±1 years ( mean±SEM ) , with mean blood pressure 160±1/96±1 mm Hg . Patients received amlodipine ( 5 mg ; n=22 ) , atenolol ( 50 mg ; n=20 ) , bendroflumethiazide ( 2.5 mg ; n=22 ) , captopril ( 50 mg twice daily ; n=22 ) or a capsule containing each of the 4 above at one-quarter dosage ( n=22 ) in a parallel group design for 4 weeks . Blood pressure was measured using a semiautomated device ( Omron 705 ) , and the reduction in mean arterial pressure with the combined preparation was compared with that of the individual components . Statistical analysis used ANOVA and Tukey-Kramer honestly significant difference for multiple comparisons . The reduction in mean arterial pressure with the combination ( 19±2 mm Hg ) was significantly greater than that with individual agents  amlodipine ( 10±2 mm Hg ; P<0.005 ) , atenolol ( 10±2 mm Hg ; P<0.005 ) , bendroflumethiazide ( 6±1 mm Hg ; P<0.005 ) , and captopril ( 11±1 mm Hg ; P<0.01 ) . In addition , the percentage reduction in systolic ( 18±1 mm Hg ; P<0.005 ) and diastolic ( 17±2 mm Hg ; P=0.06 ) blood pressure was greater with the combination . More patients achieved a blood pressure of < 140/90 mm Hg with the combination ( 60 % ) than any individual drug ( 15 % to 45 % ; P<0.05 ) . A low-dose combination of 4 agents representing 4 classes of st and ard antihypertensive agents was more efficacious than a st and ard single dose of each agent individually It is our experience that in many setting s , crossover trials that have within-period baseline measurements are analyzed wrongly . A " conventional " analysis of covariance in this setting uses each baseline as a covariate for the following outcome variable in the same period but not for any other outcome . If used with r and om subject effects such an analysis leads to biased treatment comparisons ; this is an example of cross-level bias . Using a postulated covariance structure that reflects the symmetry of the crossover setting , we quantify such bias and , at the same time , investigate potential gains and losses in efficiency through the use of the baselines . We then describe alternative methods of analysis that avoid the cross-level bias . The development is illustrated throughout with 2 example trials , one balanced and orthogonal and one highly unbalanced and nonorthogonal . BACKGROUND It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure . METHODS We r and omly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan ( 300 mg daily ) , amlodipine ( 10 mg daily ) , or  placebo .  The target blood pressure was 135/85 mm Hg or less in all groups . We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration , the development of end-stage renal disease , or death from any cause . We also compared them with regard to the time to a secondary , cardiovascular composite end point . RESULTS The mean duration of follow-up was 2.6 years . Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group ( P=0.02 ) and 23 percent lower than that in the amlodipine group ( P=0.006 ) . The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group ( P=0.003 ) and 37 percent lower in the irbesartan group than in the amlodipine group ( P<0.001 ) . Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups ( P=0.07 for both comparisons ) . These differences were not explained by differences in the blood pressures that were achieved . The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group ( P=0.008 ) and 21 percent more slowly than in the amlodipine group ( P=0.02 ) . There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point . CONCLUSIONS The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes . This protection is independent of the reduction in blood pressure it causes Background A Polypill is proposed for the primary prevention of cardiovascular disease in people judged to be at risk on account of their age alone . Its efficacy in reducing cholesterol and blood pressure is uncertain . Methods We conducted a r and omized double-blind placebo-controlled crossover trial of a Polypill among individuals aged 50 + without a history of cardiovascular disease and compared the reductions with those predicted from published estimates of the effects of the individual drugs . Participants took the Polypill ( amlodipine 2.5 mg , losartan 25 mg , hydrochlorothiazide 12.5 mg and simvastatin 40 mg ) each evening for 12 weeks and a placebo each evening for 12 weeks in r and om sequence . The mean within-person differences in blood pressure and low density lipoprotein ( LDL ) cholesterol at the end of each 12 week period were determined . Results 84 out of 86 participants completed both treatment periods . The mean systolic blood pressure was reduced by 17.9 mmHg ( 95 % CI , 15.7–20.1 ) on the Polypill , diastolic blood pressure by 9.8 mmHg ( 8.1–11.5 ) , and LDL cholesterol by 1.4 mmol/L ( 1.2–1.6 ) , reductions of 12 % , 11 % , and 39 % respectively . The results were almost identical to those predicted ; 18.4 mmHg , 9.7 mmHg , and 1.4 mmol/L respectively . Conclusion The Polypill result ed in the predicted reductions in blood pressure and LDL cholesterol . Long term reductions of this magnitude would have a substantial effect in preventing heart attacks and strokes . Trial Registration Controlled-Trials.com IS RCT CONTEXT Hypertension is a leading cause of end-stage renal disease ( ESRD ) in the United States , with no known treatment to prevent progressive declines leading to ESRD . OBJECTIVE To compare the effects of 2 levels of blood pressure ( BP ) control and 3 antihypertensive drug classes on glomerular filtration rate ( GFR ) decline in hypertension . DESIGN R and omized 3 x 2 factorial trial with enrollment from February 1995 to September 1998 . SETTING AND PARTICIPANTS A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease ( GFR , 20 - 65 mL/min per 1.73 m(2 ) ) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years . INTERVENTIONS Participants were r and omly assigned to 1 of 2 mean arterial pressure goals , 102 to 107 mm Hg ( usual ; n = 554 ) or 92 mm Hg or less ( lower ; n = 540 ) , and to initial treatment with either a beta-blocker ( metoprolol 50 - 200 mg/d ; n = 441 ) , an angiotensin-converting enzyme inhibitor ( ramipril 2.5 - 10 mg/d ; n = 436 ) or a dihydropyridine calcium channel blocker , ( amlodipine 5 - 10 mg/d ; n = 217 ) . Open-label agents were added to achieve the assigned BP goals . MAIN OUTCOME MEASURES Rate of change in GFR ( GFR slope ) ; clinical composite outcome of reduction in GFR by 50 % or more ( or > or = 25 mL/min per 1.73 m2 ) from baseline , ESRD , or death . Three primary treatment comparisons were specified : lower vs usual BP goal ; ramipril vs metoprolol ; and amlodipine vs metoprolol . RESULTS Achieved BP averaged ( SD ) 128/78 ( 12/8 ) mm Hg in the lower BP group and 141/85 ( 12/7 ) mm Hg in the usual BP group . The mean ( SE ) GFR slope from baseline through 4 years did not differ significantly between the lower BP group ( -2.21 [ 0.17 ] mL/min per 1.73 m2 per year ) and the usual BP group ( -1.95 [ 0.17 ] mL/min per 1.73 m2 per year ; P = .24 ) , and the lower BP goal did not significantly reduce the rate of the clinical composite outcome ( risk reduction for lower BP group = 2 % ; 95 % confidence interval [ CI ] , -22 % to 21 % ; P = .85 ) . None of the drug group comparisons showed consistent significant differences in the GFR slope . However , compared with the metoprolol and amlodipine groups , the ramipril group manifested risk reductions in the clinical composite outcome of 22 % ( 95 % CI , 1%-38 % ; P = .04 ) and 38 % ( 95 % CI , 14%-56 % ; P = .004 ) , respectively . There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups . CONCLUSIONS No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal . Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline Notwithst and ing the availability of antihypertensive drugs and practice guidelines , blood pressure control remains suboptimal . The complexity of current treatment guidelines may contribute to this problem . To determine whether a simplified treatment algorithm is more effective than guideline -based management , we studied 45 family practice s in southwestern Ontario , Canada , using a cluster r and omization trial comparing the simplified treatment algorithm with the Canadian Hypertension Education Program guidelines . The simplified treatment algorithm consisted of the following : ( 1 ) initial therapy with a low-dose angiotensin-converting enzyme inhibitor/diuretic or angiotensin receptor blocker/diuretic combination ; ( 2 ) up-titration of combination therapy to the highest dose ; ( 3 ) addition of a calcium channel blocker and up-titration ; and ( 4 ) addition of a non — first-line antihypertensive agent . The proportion of patients treated to target blood pressure ( systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg for patients without diabetes mellitus or systolic blood pressure < 130 mm Hg and diastolic blood pressure < 80 mm Hg for diabetic patients ) at 6 months was analyzed at the practice level . The proportion of patients achieving target was significantly higher in the intervention group ( 64.7 % versus 52.7 % ; absolute difference : 12.0 % ; 95 % CI : 1.5 % to 22.4 % ; P=0.026 ) . Multivariate analysis of patient-level data showed that assignment to the intervention arm increased the chance of reaching the target by 20 % ( P=0.028 ) , when adjusted for other covariates . In conclusion , the Simplified Treatment Intervention to Control Hypertension Study indicates that a simplified antihypertensive algorithm using initial low-dose fixed-dose combination therapy is superior to guideline -based practice for the management of hypertension The Modification of Diet in Renal Disease ( MDRD ) Study examined the effects of dietary protein restriction and strict blood pressure control on the decline in glomerular filtration rate ( GFR ) in 840 patients with diverse renal diseases . We describe a systematic analysis to determine baseline factors that predict the decline in GFR , or which alter the efficacy of the diet or blood pressure interventions . Univariate analysis identified 18 of 41 investigated baseline factors as significant ( P < 0.05 ) predictors of GFR decline . In multivariate analysis , six factors -- greater urine protein excretion , diagnosis of polycystic kidney disease ( PKD ) , lower serum transferrin , higher mean arterial pressure , black race , and lower serum HDL cholesterol -- independently predicted a faster decline in GFR . Together with the study interventions , these six factors accounted for 34.5 % and 33.9 % of the variance between patients in GFR slopes in Studies A and B , respectively , with proteinuria and PKD playing the predominant role . The mean 
    Output:
    
agent
***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: Increasingly combined antihypertensive agents are being used in practice to enhance control and improve compliance . To determine whether a capsule containing a quarter of the st and ard dose of 4 antihypertensive agents has greater efficacy than the st and ard dose of each individually , we prospect ively r and omized 108 untreated white hypertensive patients ( 55 % male ) aged 50±1 years ( mean±SEM ) , with mean blood pressure 160±1/96±1 mm Hg . Patients received amlodipine ( 5 mg ; n=22 ) , atenolol ( 50 mg ; n=20 ) , bendroflumethiazide ( 2.5 mg ; n=22 ) , captopril ( 50 mg twice daily ; n=22 ) or a capsule containing each of the 4 above at one-quarter dosage ( n=22 ) in a parallel group design for 4 weeks . Blood pressure was measured using a semiautomated device ( Omron 705 ) , and the reduction in mean arterial pressure with the combined preparation was compared with that of the individual components . Statistical analysis used ANOVA and Tukey-Kramer honestly significant difference for multiple comparisons . The reduction in mean arterial pressure with the combination ( 19±2 mm Hg ) was significantly greater than that with individual agents  amlodipine ( 10±2 mm Hg ; P<0.005 ) , atenolol ( 10±2 mm Hg ; P<0.005 ) , bendroflumethiazide ( 6±1 mm Hg ; P<0.005 ) , and captopril ( 11±1 mm Hg ; P<0.01 ) . In addition , the percentage reduction in systolic ( 18±1 mm Hg ; P<0.005 ) and diastolic ( 17±2 mm Hg ; P=0.06 ) blood pressure was greater with the combination . More patients achieved a blood pressure of < 140/90 mm Hg with the combination ( 60 % ) than any individual drug ( 15 % to 45 % ; P<0.05 ) . A low-dose combination of 4 agents representing 4 classes of st and ard antihypertensive agents was more efficacious than a st and ard single dose of each agent individually It is our experience that in many setting s , crossover trials that have within-period baseline measurements are analyzed wrongly . A " conventional " analysis of covariance in this setting uses each baseline as a covariate for the following outcome variable in the same period but not for any other outcome . If used with r and om subject effects such an analysis leads to biased treatment comparisons ; this is an example of cross-level bias . Using a postulated covariance structure that reflects the symmetry of the crossover setting , we quantify such bias and , at the same time , investigate potential gains and losses in efficiency through the use of the baselines . We then describe alternative methods of analysis that avoid the cross-level bias . The development is illustrated throughout with 2 example trials , one balanced and orthogonal and one highly unbalanced and nonorthogonal . BACKGROUND It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure . METHODS We r and omly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan ( 300 mg daily ) , amlodipine ( 10 mg daily ) , or  placebo .  The target blood pressure was 135/85 mm Hg or less in all groups . We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration , the development of end-stage renal disease , or death from any cause . We also compared them with regard to the time to a secondary , cardiovascular composite end point . RESULTS The mean duration of follow-up was 2.6 years . Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group ( P=0.02 ) and 23 percent lower than that in the amlodipine group ( P=0.006 ) . The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group ( P=0.003 ) and 37 percent lower in the irbesartan group than in the amlodipine group ( P<0.001 ) . Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups ( P=0.07 for both comparisons ) . These differences were not explained by differences in the blood pressures that were achieved . The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group ( P=0.008 ) and 21 percent more slowly than in the amlodipine group ( P=0.02 ) . There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point . CONCLUSIONS The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes . This protection is independent of the reduction in blood pressure it causes Background A Polypill is proposed for the primary prevention of cardiovascular disease in people judged to be at risk on account of their age alone . Its efficacy in reducing cholesterol and blood pressure is uncertain . Methods We conducted a r and omized double-blind placebo-controlled crossover trial of a Polypill among individuals aged 50 + without a history of cardiovascular disease and compared the reductions with those predicted from published estimates of the effects of the individual drugs . Participants took the Polypill ( amlodipine 2.5 mg , losartan 25 mg , hydrochlorothiazide 12.5 mg and simvastatin 40 mg ) each evening for 12 weeks and a placebo each evening for 12 weeks in r and om sequence . The mean within-person differences in blood pressure and low density lipoprotein ( LDL ) cholesterol at the end of each 12 week period were determined . Results 84 out of 86 participants completed both treatment periods . The mean systolic blood pressure was reduced by 17.9 mmHg ( 95 % CI , 15.7–20.1 ) on the Polypill , diastolic blood pressure by 9.8 mmHg ( 8.1–11.5 ) , and LDL cholesterol by 1.4 mmol/L ( 1.2–1.6 ) , reductions of 12 % , 11 % , and 39 % respectively . The results were almost identical to those predicted ; 18.4 mmHg , 9.7 mmHg , and 1.4 mmol/L respectively . Conclusion The Polypill result ed in the predicted reductions in blood pressure and LDL cholesterol . Long term reductions of this magnitude would have a substantial effect in preventing heart attacks and strokes . Trial Registration Controlled-Trials.com IS RCT CONTEXT Hypertension is a leading cause of end-stage renal disease ( ESRD ) in the United States , with no known treatment to prevent progressive declines leading to ESRD . OBJECTIVE To compare the effects of 2 levels of blood pressure ( BP ) control and 3 antihypertensive drug classes on glomerular filtration rate ( GFR ) decline in hypertension . DESIGN R and omized 3 x 2 factorial trial with enrollment from February 1995 to September 1998 . SETTING AND PARTICIPANTS A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease ( GFR , 20 - 65 mL/min per 1.73 m(2 ) ) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years . INTERVENTIONS Participants were r and omly assigned to 1 of 2 mean arterial pressure goals , 102 to 107 mm Hg ( usual ; n = 554 ) or 92 mm Hg or less ( lower ; n = 540 ) , and to initial treatment with either a beta-blocker ( metoprolol 50 - 200 mg/d ; n = 441 ) , an angiotensin-converting enzyme inhibitor ( ramipril 2.5 - 10 mg/d ; n = 436 ) or a dihydropyridine calcium channel blocker , ( amlodipine 5 - 10 mg/d ; n = 217 ) . Open-label agents were added to achieve the assigned BP goals . MAIN OUTCOME MEASURES Rate of change in GFR ( GFR slope ) ; clinical composite outcome of reduction in GFR by 50 % or more ( or > or = 25 mL/min per 1.73 m2 ) from baseline , ESRD , or death . Three primary treatment comparisons were specified : lower vs usual BP goal ; ramipril vs metoprolol ; and amlodipine vs metoprolol . RESULTS Achieved BP averaged ( SD ) 128/78 ( 12/8 ) mm Hg in the lower BP group and 141/85 ( 12/7 ) mm Hg in the usual BP group . The mean ( SE ) GFR slope from baseline through 4 years did not differ significantly between the lower BP group ( -2.21 [ 0.17 ] mL/min per 1.73 m2 per year ) and the usual BP group ( -1.95 [ 0.17 ] mL/min per 1.73 m2 per year ; P = .24 ) , and the lower BP goal did not significantly reduce the rate of the clinical composite outcome ( risk reduction for lower BP group = 2 % ; 95 % confidence interval [ CI ] , -22 % to 21 % ; P = .85 ) . None of the drug group comparisons showed consistent significant differences in the GFR slope . However , compared with the metoprolol and amlodipine groups , the ramipril group manifested risk reductions in the clinical composite outcome of 22 % ( 95 % CI , 1%-38 % ; P = .04 ) and 38 % ( 95 % CI , 14%-56 % ; P = .004 ) , respectively . There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups . CONCLUSIONS No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal . Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline Notwithst and ing the availability of antihypertensive drugs and practice guidelines , blood pressure control remains suboptimal . The complexity of current treatment guidelines may contribute to this problem . To determine whether a simplified treatment algorithm is more effective than guideline -based management , we studied 45 family practice s in southwestern Ontario , Canada , using a cluster r and omization trial comparing the simplified treatment algorithm with the Canadian Hypertension Education Program guidelines . The simplified treatment algorithm consisted of the following : ( 1 ) initial therapy with a low-dose angiotensin-converting enzyme inhibitor/diuretic or angiotensin receptor blocker/diuretic combination ; ( 2 ) up-titration of combination therapy to the highest dose ; ( 3 ) addition of a calcium channel blocker and up-titration ; and ( 4 ) addition of a non — first-line antihypertensive agent . The proportion of patients treated to target blood pressure ( systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg for patients without diabetes mellitus or systolic blood pressure < 130 mm Hg and diastolic blood pressure < 80 mm Hg for diabetic patients ) at 6 months was analyzed at the practice level . The proportion of patients achieving target was significantly higher in the intervention group ( 64.7 % versus 52.7 % ; absolute difference : 12.0 % ; 95 % CI : 1.5 % to 22.4 % ; P=0.026 ) . Multivariate analysis of patient-level data showed that assignment to the intervention arm increased the chance of reaching the target by 20 % ( P=0.028 ) , when adjusted for other covariates . In conclusion , the Simplified Treatment Intervention to Control Hypertension Study indicates that a simplified antihypertensive algorithm using initial low-dose fixed-dose combination therapy is superior to guideline -based practice for the management of hypertension The Modification of Diet in Renal Disease ( MDRD ) Study examined the effects of dietary protein restriction and strict blood pressure control on the decline in glomerular filtration rate ( GFR ) in 840 patients with diverse renal diseases . We describe a systematic analysis to determine baseline factors that predict the decline in GFR , or which alter the efficacy of the diet or blood pressure interventions . Univariate analysis identified 18 of 41 investigated baseline factors as significant ( P < 0.05 ) predictors of GFR decline . In multivariate analysis , six factors -- greater urine protein excretion , diagnosis of polycystic kidney disease ( PKD ) , lower serum transferrin , higher mean arterial pressure , black race , and lower serum HDL cholesterol -- independently predicted a faster decline in GFR . Together with the study interventions , these six factors accounted for 34.5 % and 33.9 % of the variance between patients in GFR slopes in Studies A and B , respectively , with proteinuria and PKD playing the predominant role . The mean 
    Output:
    