***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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    Input: CONTEXT Incidence of end-stage renal disease due to hypertension has increased in recent decades , but the optimal strategy for treatment of hypertension to prevent renal failure is unknown , especially among African Americans . OBJECTIVE To compare the effects of an angiotensin-converting enzyme ( ACE ) inhibitor ( ramipril ) , a dihydropyridine calcium channel blocker ( amlodipine ) , and a beta-blocker ( metoprolol ) on hypertensive renal disease progression . DESIGN , SETTING , AND PARTICIPANTS Interim analysis of a r and omized , double-blind , 3 x 2 factorial trial conducted in 1094 African Americans aged 18 to 70 years with hypertensive renal disease ( glomerular filtration rate [ GFR ] of 20 - 65 mL/min per 1.73 m(2 ) ) enrolled between February 1995 and September 1998 . This report compares the ramipril and amlodipine groups following discontinuation of the amlodipine intervention in September 2000 . INTERVENTIONS Participants were r and omly assigned to receive amlodipine , 5 to 10 mg/d ( n = 217 ) , ramipril , 2.5 to 10 mg/d ( n = 436 ) , or metoprolol , 50 to 200 mg/d ( n = 441 ) , with other agents added to achieve 1 of 2 blood pressure goals . MAIN OUTCOME MEASURES The primary outcome measure was the rate of change in GFR ; the main secondary outcome was a composite index of the clinical end points of reduction in GFR of more than 50 % or 25 mL/min per 1.73 m(2 ) , end-stage renal disease , or death . RESULTS Among participants with a urinary protein to creatinine ratio of > 0.22 ( corresponding approximately to proteinuria of more than 300 mg/d ) , the ramipril group had a 36 % ( 2.02 [ SE , 0.74 ] mL/min per 1.73 m(2)/y ) slower mean decline in GFR over 3 years ( P = .006 ) and a 48 % reduced risk of the clinical end points vs the amlodipine group ( 95 % confidence interval [ CI ] , 20%-66 % ) . In the entire cohort , there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups ( P = .38 ) . However , compared with the amlodipine group , after adjustment for baseline covariates the ramipril group had a 38 % reduced risk of clinical end points ( 95 % CI , 13%-56 % ) , a 36 % slower mean decline in GFR after 3 months ( P = .002 ) , and less proteinuria ( P<.001 ) . CONCLUSION Ramipril , compared with amlodipine , retards renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria The study was design ed to assess the antihypertensive effect of combined angiotensin-converting enzyme ( ACE ) inhibition and angiotensin II type 1 receptor ( AT1 ) antagonism in patients with essential hypertension . Twenty patients with uncontrolled ambulatory diastolic blood pressure ( BP ) after 6 weeks of ACE inhibitor monotherapy ( benazepril , 20 mg , o.d . ) were r and omized to receive double-blind valsartan , 80 mg , o.d . ( AT1 antagonist ) or matching placebo for 5 weeks while continuing to receive background benazepril . Then patients crossed over to the alternative regimen for a second 5-week period . The 24-h ambulatory BP was monitored on the final day of the benazepril monotherapy period and on the final day of each double-blind treatment period . Valsartan added to benazepril produced a significant antihypertensive effect with a benefit over placebo of 6.5 + /- 12.6/4.5 + /- 8.0 mm Hg ( systolic/diastolic ) for average awake ambulatory BP ( p < 0.05 ) , 7.1 + /- 9.4/5.6 + /- 6.5 mm Hg for asleep BP ( p < 0.01 ) , and 6.8 + /- 9.7/4.9 + /- 6.8 mm Hg for average 24-h ambulatory BP ( p < 0.01 ) . Pulse rate was unaffected . Plasma active renin was higher on the benazepril-valsartan combination compared with benazepril-placebo ( p < 0.05 ) . There was no change in routine biochemical variables when valsartan was added to benazepril . Six patients reported mild dizziness or fatigue ( three also with placebo ) . These data suggest that in hypertensive patients uncontrolled with an ACE inhibitor , the addition of an AT1 antagonist provides a powerful and safe antihypertensive drug combination BACKGROUND Treatment of hypertension with diuretics , beta-blockers , or both leads to improved outcomes . It has been postulated that agents that inhibit the renin-angiotensin system confer benefit beyond the reduction of blood pressure alone . We compared the outcomes in older subjects with hypertension who were treated with angiotensin-converting-enzyme ( ACE ) inhibitors with the outcomes in those treated with diuretic agents . METHODS We conducted a prospect i ve , r and omized , open-label study with blinded assessment of end points in 6083 subjects with hypertension who were 65 to 84 years of age and received health care at 1594 family practice s. Subjects were followed for a median of 4.1 years , and the total numbers of cardiovascular events in the two treatment groups were compared with the use of multivariate proportional-hazards models . RESULTS At base line , the treatment groups were well matched in terms of age , sex , and blood pressure . By the end of the study , blood pressure had decreased to a similar extent in both groups ( a decrease of 26/12 mm Hg ) . There were 695 cardiovascular events or deaths from any cause in the ACE-inhibitor group ( 56.1 per 1000 patient-years ) and 736 cardiovascular events or deaths from any cause in the diuretic group ( 59.8 per 1000 patient-years ; the hazard ratio for a cardiovascular event or death with ACE-inhibitor treatment was 0.89 [ 95 percent confidence interval , 0.79 to 1.00 ] ; P=0.05 ) . Among male subjects , the hazard ratio was 0.83 ( 95 percent confidence interval , 0.71 to 0.97 ; P=0.02 ) ; among female subjects , the hazard ratio was 1.00 ( 95 percent confidence interval , 0.83 to 1.21 ; P=0.98 ) ; the P value for the interaction between sex and treatment-group assignment was 0.15 . The rates of nonfatal cardiovascular events and myocardial infa rct ions decreased with ACE-inhibitor treatment , whereas a similar number of strokes occurred in each group ( although there were more fatal strokes in the ACE-inhibitor group ) . CONCLUSIONS Initiation of antihypertensive treatment involving ACE inhibitors in older subjects , particularly men , appears to lead to better outcomes than treatment with diuretic agents , despite similar reductions of blood pressure BACKGROUND Patients with type 2 diabetes are at increased risk of macro- and microvascular disease , and the presence of albuminuria and /or reduced kidney function further enhances macrovascular risk . Angiotensin-converting-enzyme inhibitors reduce both macro- and microvascular events , yet the residual renal and cardiovascular risk still remains high . Aliskiren a novel oral direct renin inhibitor that unlike ACEi and ARBs , lowers plasma renin activity , angiotensin I and angiotensin II levels , may thereby provide greater benefit compared to ACEi or ARB alone . METHODS The primary objective of the ALTITUDE trial is to determine whether aliskiren 300 mg once daily , reduces cardiovascular and renal morbidity and mortality compared with placebo when added to conventional treatment ( including ACEi or ARB ) . ALTITUDE is an international , r and omized , double-blind , placebo-controlled , parallel-group study , which will include three categories of high-risk patients with type 2 diabetes ( aged > or = 35 years ) : those with either urinary albumin/creatinine ratio ( UACR ) > or = 200 mg/g ; microalbuminuria ( UACR ) > or = 20 < 200 mg/g and eGFR > or = 30 < 60 mL/min/1.73 m2 ; and thirdly , those with a history of cardiovascular disease and eGFR > or = 30 < 60 mL/min/1.73 m2 with or without microalbuminuria . ALTITUDE is an event driven trial that aims to r and omize 8600 patients with a planned follow-up time of 48 months . The primary outcome measure is time to first event for the composite endpoint of cardiovascular death , resuscitated death , myocardial infa rct ion , stroke , unplanned hospitalization for heart failure , onset of end-stage renal disease or doubling of baseline serum creatinine concentration . Secondary endpoints include a composite CV endpoint and a composite renal endpoint . CONCLUSION ALTITUDE will determine whether dual RAAS blockade with the direct renin inhibitor aliskiren in combination with an ACEi or ARB will reduce major morbidity and mortality in a broad range of high-risk patients with type 2 diabetes BACKGROUND Angiotensin II exerts a number of harmful effects in patients with chronic heart failure ( CHF ) and , through an increase in oxidative stress , is thought to be critical in the development of endothelial dysfunction . Angiotensin II may be elevated in CHF despite treatment with angiotensin converting enzyme ( ACE ) inhibitors , producing a rationale for adjunctive angiotensin receptor blockade . We investigated whether the addition of angiotensin antagonism to ACE inhibition would reduce oxidative stress and improve endothelial function and exercise tolerance in patients with chronic heart failure . METHODS AND RESULTS Twenty-eight heart failure patients , who were on stable ACE inhibitor therapy , were r and omised to receive adjunctive therapy with c and esartan or placebo .  Plasma lipid-derived free radicals , TBARS and neutrophil O2-generation , markers of oxidative stress , were measured in venous blood . Arterial endothelial function was assessed as the response of the brachial artery to flow-related shear stress . Exercise capacity was determined by cardiopulmonary exercise testing . Compared with placebo , c and esartan had no effect on changes in lipid derived free radicals ( -0.1+/-1.2 vs. -0.1+/-1.0 units , respectively , P = NS ) , TBARS ( -2.2+/-1.1 vs. -2.6+/-2.2 micromol/l , respectively , P = NS ) or neutrophil O2-generating capacity ( -7.3+/-5.1 vs. -8.4+/-7.9 mV/5x10(5 ) neutrophils , respectively , P = NS ) . There was no effect on changes in brachial artery flow-mediated dilatation ( 0.5+/-1.0 vs. 0.8+/-1.3 % , respectively , P = NS ) nor peak VO2 ( 1.6+/-0.7 ml/kg per min vs. 1.8+/-0.6 ml/kg per min ; P = NS ) . CONCLUSION The addition of the c and esartan to ACE inhibitor therapy had no effect on oxidative stress and did not improve endothelial function or exercise capacity in patients with CHF BACKGROUND We evaluated the renoprotective effects of dual blockade of renin-angiotensin system ( RAS ) by using a low-dose combination of ACE inhibiter and angiotensin II receptor blocker in type 2 diabetic patients with advanced kidney disease . The amount of proteinuria and the urinary levels of bioassayable TGF-beta1 were used as surrogate markers of renal injury and sclerosis . METHODS We performed a prospect i ve double-blinded r and omized crossover trial consisting of three 16-week treatment periods with ramipril alone ( 10 mg/day ) , c and esartan alone ( 16 mg/day ) , and ramipril ( 5 mg/day ) plus c and esartan ( 8 mg/day ) combination therapy .  Twenty-one type 2 diabetic patients with overt nephropathy with a 24 h urinary protein excretion rate ( UPER ) of > 1.0 g/24 h and creatinine clearance ( Ccr ) of 30 to 59 ml/min/1.73 m2 completed the entire study . RESULTS Subjects consisted of 10 female and 11 male patients with a mean age of 49 + /- 8 years and duration of diabetes ranging from 4 to 13 years . At baseline , 24-h blood pressures ( BPs ) were 133 + /- 6/81 + /- 7 mmHg , Ccr 40.6 + /- 4.1 ml/min/1.73 m2 , 24-h UPER 4.1 + 
    Output:
    
In the ONTARGET trial in patients with hypertension at high cardiovascular risk , ACE inhibitor/ARB combination therapy provided no significant clinical outcome benefits over monotherapy , and was associated with a worse safety and tolerability profile .
In patients with hypertension , ACE inhibitor/ARB combinations provided limited additional reductions in blood pressure ( BP ) over monotherapy .
Outcomes benefits were unclear : VALIANT and ONTARGET demonstrated no enhanced outcome benefit of combination therapy over monotherapy ; Val-HeFT and CHARM-Added showed reduced morbidity/mortality in patients with heart failure , but at the expense of poorer tolerability .
Combination therapy with the DRI aliskiren and an ACE inhibitor or ARB provided significant additional BP reductions over monotherapy in patients with mild-to-moderate hypertension , and reduced surrogate markers of organ damage in patients with heart failure or diabetic nephropathy , with generally similar safety and tolerability to the component monotherapies .
CONCLUSIONS ACE inhibitor/ARB combinations showed equivocal effects on clinical outcomes .
DRI/ACE inhibitor and DRI/ARB combinations reduced markers of organ damage , but longer-term trials are required to establish whether more complete renin -- angiotensin -- aldosterone system control with aliskiren-based therapy translates into improved outcome benefits