title: Aggressive Blood Pressure Control Increases Coronary Heart Disease Risk Among Diabetic Patients Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomized trial. Effect of the statistical significance of results on the time to completion and publication of randomized efficacy trials. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. Effects of Manidipine and Delapril in Hypertensive Patients With Type 2 Diabetes Mellitus: The Delapril and Manidipine for Nephroprotection in Diabetes (DEMAND) Randomized Clinical Trial A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people Reductions in the risks of recurrent stroke in patients with and without diabetes: The PROGRESS Trial Effects of Fosinopril and Pravastatin on Cardiovascular Events in Subjects With Microalbuminuria Results of the pilot study for the Hypertension in the Very Elderly Trial Cardiovascular outcomes in the first trial of antihypertensive therapy guided by self-measured home blood pressure Target Blood Pressure for Treatment of Isolated Systolic Hypertension in the Elderly: Valsartan in Elderly Isolated Systolic Hypertension Study Irbesartan in patients with atrial fibrillation. Telmisartan, ramipril, or both in patients at high risk for vascular events. The PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure – a prospective, randomized, controlled prevention trial of the German Hypertension League The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. Effect of ramipril on the incidence of diabetes. Preventing microalbuminuria in type 2 diabetes. Effectiveness of Chlorthalidone Plus Amiloride for the Prevention of Hypertension: The PREVER‐Prevention Randomized Clinical Trial Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial On-treatment diastolic blood pressure and prognosis in systolic hypertension. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39 Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study) Treatment of hypertension in patients 80 years of age or older. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial Risk of bias versus quality assessment of randomised controlled trials: cross sectional study Cardiorenal end points in a trial of aliskiren for type 2 diabetes. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. Is a systolic blood pressure target <140 mmHg indicated in all hypertensives? Subgroup analyses of findings from the randomized FEVER trial. Effects of combination lipid therapy in type 2 diabetes mellitus. Effect of valsartan on the incidence of diabetes and cardiovascular events. Overall and coronary heart disease mortality rates in relation to major risk factors in 325,348 men screened for the MRFIT. Multiple Risk Factor Intervention Trial. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial Telmisartan to prevent recurrent stroke and cardiovascular events. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Effects of intensive antihypertensive treatment on Chinese hypertensive patients older than 70 years. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial GRADE guidelines: 3. Rating the quality of evidence. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Effect of intensive blood pressure control with valsartan on urinary albumin excretion in normotensive patients with type 2 diabetes. Blood pressure, stroke, and coronary heart disease: Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. Principal Results of the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients (JATOS) Treatment of mild hypertension: a five year controlled drug trial. The Oslo study. From efficacy in trials to effectiveness in clinical practice: The Swedish Stroke Prevention Study Lowering blood pressure reduces renal events in type 2 diabetes. Prognostic value of blood pressure in patients with high vascular risk in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study Use of Enalapril To Attenuate Decline in Renal Function in Normotensive, Normoalbuminuric Patients with Type 2 Diabetes Mellitus The Medical Review Article Revisited: Has the Science Improved? Effects of verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B randomized trial The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The role of antihypertensive therapy in reducing vascular complications of type 2 diabetes. Findings from the DIabetic REtinopathy Candesartan Trials-Protect 2 study Effects of intensive blood-pressure control in type 2 diabetes mellitus. Blood pressure and risk of coronary heart disease: the Framingham study. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. The Study on COgnition and Prognosis in the Elderly (SCOPE) – Major CV events and stroke in subgroups of patients Low-dose ramipril reduces microalbuminuria in type 1 diabetic patients without hypertension: results of a randomized controlled trial. Mortality and Morbidity Results from the European Working Party on High Blood Pressure in the Elderly Trial Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. Losartan and end‐organ protection—lessons from the renaal study Systematic Reviews: Synthesis of Best Evidence for Clinical Decisions Effects of amlodipine fosinopril combination on microalbuminuria in hypertensive type 2 diabetic patients. Efficacy, safety and tolerability of metoprolol CR/XL in patients with diabetes and chronic heart failure: experiences from MERIT-HF. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). Combined angiotensin inhibition for the treatment of diabetic nephropathy. Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease. Diastolic Blood Pressure, Subclinical Myocardial Damage, and Cardiac Events: Implications for Blood Pressure Control. Effects of intensive blood pressure control in the management of patients with type 2 diabetes mellitus in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
abstract: OBJECTIVE Blood pressure control can reduce the risk of coronary heart disease ( CHD ) among diabetic patients ; however , it is not known whether the lowest risk of CHD is among diabetic patients with the lowest blood pressure level . RESEARCH DESIGN AND METHODS We performed a prospect i ve cohort  study ( 2000–2009 ) on diabetic patients including 17,536 African Americans and 12,618 whites . Cox proportional hazards regression models were used to estimate the association of blood pressure with CHD risk . RESULTS During a mean follow-up of 6.0 years , 7,260 CHD incident cases were identified . The multivariable-adjusted hazard ratios of CHD associated with different levels of systolic/diastolic blood pressure at baseline ( < 110/65 , 110–119/65–69 , 120–129/70–80 , and 130–139/80–90 mmHg [ reference group ] ; 140–159/90–100 ; and ≥160/100 mmHg ) were 1.73 , 1.16 , 1.04 , 1.00 , 1.06 , and 1.11 ( P trend < 0.001 ) , respectively , for African American diabetic patients , and 1.60 , 1.27 , 1.08 , 1.00 , 0.95 , and 0.99 ( P trend<0.001 ) for white diabetic patients , respectively . A U-shaped association of isolated systolic and diastolic blood pressure at baseline as well as blood pressure during follow-up with CHD risk was observed among both African American and white diabetic patients ( all Ptrend < 0.001 ) . The U-shaped association was present in the younger age-group ( 30–49 years ) , and this U-shaped association changed to an inverse association in the older age-group ( ≥60 years ) . CONCLUSIONS Our study suggests that there is a U-shaped or inverse association between blood pressure and the risk of CHD , and aggressive blood pressure control ( blood pressure < 120/70 mmHg ) is associated with an increased risk of CHD among both African American and white patients with diabetes BACKGROUND AND OBJECTIVES The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown ; neither is it clear whether in patients with a previous cardiovascular event , the optimal values are lower than in the low-to-moderate risk hypertensive patients , or a more cautious blood pressure ( BP ) reduction should be obtained . Because of the uncertainty whether ' the lower the better ' or the ' J-curve ' hypothesis is correct , the European Society of Hypertension and the Chinese Hypertension League have promoted a r and omized trial comparing antihypertensive treatment strategies aim ing at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack . As the optimal level of low-density lipoprotein cholesterol ( LDL-C ) level is also unknown in these patients , LDL-C-lowering has been included in the design . PROTOCOL DESIGN The European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment trial is a prospect i ve multinational , r and omized trial with a 3 × 2 factorial design comparing : three different SBP targets ( 1 , < 145 - 135 ; 2 , < 135 - 125 ; 3 , < 125 mmHg ) ; two different LDL-C targets ( target A , 2.8 - 1.8 ; target B , < 1.8 mmol/l ) . The trial is to be conducted on 7500 patients aged at least 65 years ( 2500 in Europe , 5000 in China ) with hypertension and a stroke or transient ischaemic attack 1 - 6 months before r and omization .  Antihypertensive and statin treatments will be initiated or modified using suitable registered agents chosen by the investigators , in order to maintain patients within the r and omized SBP and LDL-C windows . All patients will be followed up every 3 months for BP and every 6 months for LDL-C. Ambulatory BP will be measured yearly . OUTCOMES Primary outcome is time to stroke ( fatal and non-fatal ) . Important secondary outcomes are : time to first major cardiovascular event ; cognitive decline ( Montreal Cognitive Assessment ) and dementia . All major outcomes will be adjudicated by committees blind to r and omized allocation . A Data and Safety Monitoring Board has open access to data and can recommend trial interruption for safety . SAMPLE SIZE CALCULATION It has been calculated that 925 patients would reach the primary outcome after a mean 4-year follow-up , and this should provide at least 80 % power to detect a 25 % stroke difference between SBP targets and a 20 % difference between LDL-C targets CONTEXT Medical evidence may be biased over time if completion and publication of r and omized efficacy trials are delayed when results are not statistically significant . OBJECTIVE To evaluate whether the time to completion and the time to publication of r and omized phase 2 and phase 3 trials are affected by the statistical significance of results and to describe the natural history of such trials . DESIGN Prospect i ve cohort of r and omized efficacy trials conducted by 2 trialist groups from 1986 to 1996 . SETTING Multicenter trial groups in human immunodeficiency virus infection sponsored by the National Institutes of Health . PATIENTS A total of 109 efficacy trials ( total enrollment , 43708 patients ) . MAIN OUTCOME MEASURES Time from start of enrollment to completion of follow-up and time from completion of follow-up to peer- review ed publication assessed with survival analysis . RESULTS The median time from start of enrollment to publication was 5.5 years and was substantially longer for negative trials than for results favoring an experimental arm ( 6.5 vs 4.3 years , respectively ; P<.001 ; hazard ratio for time to publication for positive vs negative trials , 3.7 ; 95 % confidence interval [ CI ] , 1.8 - 7.7 ) . This difference was mostly attributable to differences in the time from completion to publication ( median , 3.0 vs 1.7 years for negative vs positive trials ; P<.001 ) . On average , trials with significant results favoring any arm completed follow-up slightly earlier than trials with nonsignificant results ( median , 2.3 vs 2.5 years ; P=.045 ) , but long-protracted trials often had low event rates and failed to reach statistical significance , while trials that were terminated early had significant results . Positive trials were su bmi tted for publication significantly more rapidly after completion than were negative trials ( median , 1.0 vs 1.6 years ; P=.001 ) and were published more rapidly after su bmi ssion ( median , 0.8 vs 1.1 years ; P=.04 ) . CONCLUSION Among r and omized efficacy trials , there is a time lag in the publication of negative findings that occurs mostly after the completion of the trial follow-up BACKGROUND Diabetes mellitus is a strong risk factor for cardiovascular and renal disease . We investigated whether the angiotensin-converting-enzyme ( ACE ) inhibitor ramipril can lower these risks in patients with diabetes . METHODS 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study , aged 55 years or older , who had a previous cardiovascular event or at least one other cardiovascular risk factor , no clinical proteinuria , heart failure , or low ejection fraction , and who were not taking ACE inhibitors , were r and omly assigned ramipril ( 10 mg/day ) or placebo , and vitamin E or placebo , according to a two-by-two factorial design . The combined primary outcome was myocardial infa rct ion , stroke , or cardiovascular death . Overt nephropathy was a main outcome in a sub study . FINDINGS The study was stopped 6 months early ( after 4.5 years ) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo . Ramipril lowered the risk of the combined primary outcome by 25 % ( 95 % CI 12 - 36 , p=0.0004 ) , myocardial infa rct ion by 22 % ( 6 - 36 ) , stroke by 33 % ( 10 - 50 ) , cardiovascular death by 37 % ( 21 - 51 ) , total mortality by 24 % ( 8 - 37 ) , revascularisation by 17 % ( 2 - 30 ) , and overt nephropathy by 24 % ( 3 - 40 , p=0.027 ) . After adjustment for the changes in systolic ( 2.4 mm Hg ) and diastolic ( 1.0 mm Hg ) blood pressures , ramipril still lowered the risk of the combined primary outcome by 25 % ( 12 - 36 , p=0.0004 ) . INTERPRETATION Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes . The cardiovascular benefit was greater than that attributable to the decrease in blood pressure . This treatment represents a vasculoprotective and renoprotective effect for people with diabetes Although the benefits of antihypertensive treatment in " young " elderly ( under 70 years ) hypertensive patients are well established , the value of treatment in older patients ( 70 - 84 years ) is less clear . The Swedish Trial in Old Patients with Hypertension ( STOP-Hypertension ) was a prospect i ve , r and omised , double-blind , intervention study set up to compare the effects of active antihypertensive therapy ( three beta-blockers and one diuretic ) and placebo on the frequency of fatal and non-fatal stroke and myocardial infa rct ion and other cardiovascular death in hypertensive Swedish men and women aged 70 - 84 years . We recruited 1627 patients at 116 health centres throughout Sweden , who were willing to participate , and who met the entry criteria of three separate recordings during a 1-month placebo run-in period of systolic blood pressure between 180 and 230 mm Hg with a diastolic pressure of at least 90 mm Hg , or a diastolic pressure between 105 and 120 mm Hg irrespective of the systolic pressure . The total duration of the study was 65 months and the average time in the study was 25 months . 812 patients were r and omly allocated active treatment and 815 placebo . The mean difference in supine blood pressure between the active treatment and placebo groups at the last follow-up before an endpoint , death , or study termination was 19.5/8.1 mm Hg . Compared with placebo , active treatment significantly reduced the number of primary endpoints ( 94 vs 58 ; p = 0.0031 ) and stroke morbidity and mortality ( 53 vs 29 ; p = 0.0081 ) . Although we did not set out to study an effect on total mortality , we also noted a significantly reduced number of deaths in the active treatment group ( 63 vs 36 ; p = 0.0079 ) . The benefits of treatment were discernible up to age 84 years . We conclude that antihypertensive treatment in hypertensive men and women aged 70 - 84 confers highly significant and clinical ly relevant reductions in cardiovascular morbidity and mortality as well as in total mortality CONTEXT The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease ( CAD ) and normal blood pressure remains uncertain . OBJECTIVE To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized , multicenter , 24-month trial ( enrollment April 1999-April 2002 ) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD ( > 20 % stenosis by coronary angiography ) and diastolic blood pressure < 100 mm Hg . A sub study of 274 patients measured atherosclerosis progression by intravascular ultrasound ( IVUS ) . INTERVENTIONS Patients were r and omized to receive amlodipine , 10 mg ; enalapril , 20 mg ; or placebo . IVUS was performed at baseline and study completion . MAIN OUTCOME MEASURES The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo . Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo . Events included cardiovascular death , nonfatal myocardial infa rct ion , resuscitated cardiac arrest , coronary revascularization , hospitalization for angina pectoris , hospitalization for congestive heart failure , fatal or nonfatal stroke or transient ischemic attack , and new diagnosis of peripheral vascular disease . The IVUS end point was change in percent atheroma volume . RESULTS Baseline blood pressure averaged 129/78 mm Hg for all patients ; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups , respectively ( P<.001 for both vs placebo ) . Cardiovascular events occurred in 151 ( 23.1 % ) placebo-treated patients , in 110 ( 16.6 % ) amlodipine-treated patients ( hazard ratio [ HR ] , 0.69 ; 95 % CI , 0.54 - 0.88 [ P = .003 ] ) , and in 136 ( 20.2 % ) enalapril-treated patients ( HR , 0.85 ; 95 % CI , 0.67 - 1.07 [ P = .16 ] . Primary end point comparison for enalapril vs amlodipine was not significant ( HR , 0.81 ; 95 % CI , 0.63 - 1.04 [ P = .10 ] ) . The IVUS sub study showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo ( P = .12 ) , with significantly less progression in the subgroup with systolic blood pressures greater than the mean ( P = .02 ) . Compared with baseline , IVUS showed progression in the placebo group ( P<.001 ) , a trend toward progression in the enalapril group ( P = .08 ) , and no progression in the amlodipine group ( P = .31 ) . For the amlodipine group , correlation between blood pressure reduction and progression was r = 0.19 , P = .07 . CONCLUSIONS Administration of amlodipine to patients with CAD and normal blood pressure result ed in reduced adverse cardiovascular events . Directionally similar , but smaller and nonsignificant , treatment effects were observed with enalapril . For amlodipine , IVUS showed evidence of slowing of atherosclerosis progression To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications , we compared glomerular filtration rate ( GFR ; primary outcome ) , cardiovascular events , retinopathy , and neuropathy in 380 hypertensive type 2 diabetics with albuminuria < 200 mg/min included in a multicenter , double-blind , placebo-controlled trial ( DEM AND [ Delapril and Manidipine for Nephroprotection in Diabetes ] ) and r and omized to 3-year treatment with manidipine/delapril combination ( 10/30 mg/d ; n=126 ) , delapril ( 30 mg/d ; n=127 ) , or placebo ( n=127 ) . GFR was central ly measured by iohexol plasma clearance . Median monthly GFR decline ( interquartile range [ IQR ] ) was 0.32 mL/min per 1.73 m2 ( IQR : 0.16–0.50 mL/min per 1.73 m2 ) on combined therapy , 0.36 mL/min per 1.73 m2 ( IQR : 0.18–0.53 mL/min per 1.73 m2 ) on delapril , and 0.30 mL/min per 1.73 m2 ( IQR : 0.12–0.50 mL/min per 1.73 m2 ) on placebo ( P=0.87 and P=0.53 versus combined therapy or delapril , respectively ) . Similar findings were observed when baseline GFR values were not considered for slope analyses . Albuminuria was stable in the 3 treatment groups . The hazard ratio ( 95 % CI ) for major cardiovascular events between combined therapy and placebo was 0.17 ( 0.04–0.78 ; P=0.023 ) . Among 192 subjects without retinopathy at inclusion , the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 ( 0.07–0.99 ; P=0.048 ) . Among 200 subjects with central ized neurological evaluation , the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 ( 0.24–0.87 ; P=0.017 ) and 0.52 ( 0.27–0.99 ; P=0.048 ) , respectively . Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo ( P=0.03 ) but did not change on combined or delapril therapy . Treatment was well tolerated . In hypertensive type 2 diabetic patients , combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease , retinopathy , and neuropathy and stabilized insulin sensitivity BACKGROUND Treatment with angiotensin-converting-enzyme ( ACE ) inhibitors reduces mortality among survivors of acute myocardial infa rct ion , but whether to use ACE inhibitors in all patients or only in selected patients is uncertain . METHODS We screened 6676 consecutive patients with 7001 myocardial infa rct ions confirmed by enzyme studies . A total of 2606 patients had echocardiographic evidence of left ventricular systolic dysfunction ( ejection fraction , < or = 35 percent ) . On days 3 to 7 after infa rct ion , 1749 patients were r and omly assigned to receive oral tr and olapril ( 876 patients ) or placebo ( 873 patients ) . The duration of follow-up was 24 to 50 months . RESULTS During the study period , 304 patients ( 34.7 percent ) in the tr and olapril group died , as compared with 369 ( 42.3 percent ) in the placebo group ( P = 0.001 ) . The relative risk of death in the tr and olapril group , as compared with the placebo group , was 0.78 ( 95 percent confidence interval , 0.67 to 0.91 ) . Tr and olapril also reduced the risk of death from cardiovascular causes ( relative risk , 0.75 ; 95 percent confidence interval , 0.63 to 0.89 ; P = 0.001 ) and sudden death ( relative risk , 0.76 ; 95 percent confidence interval , 0.59 to 0.98 ; P = 0.03 ) . Progression to severe heart failure was less frequent in the tr and olapril group ( relative risk , 0.71 ; 95 percent confidence interval , 0.56 to 0.89 ; P = 0.003 ) . In contrast , the risk of recurrent myocardial infa rct ion ( fatal or nonfatal ) was not significantly reduced ( relative risk , 0.86 ; 95 percent confidence interval , 0.66 to 1.13 ; P = 0.29 ) . CONCLUSIONS Long-term treatment with tr and olapril in patients with reduced left ventricular function soon after myocardial infa rct ion significantly reduced the risk of overall mortality , mortality from cardiovascular causes , sudden death , and the development of severe heart failure . That mortality was reduced in a r and omized study enrolling 25 percent of consecutive patients screened should encourage the selective use of ACE inhibition after myocardial infa rct ion Summary Background The associations of blood pressure with the different manifestations of incident cardiovascular disease in a contemporary population have not been compared . In this study , we aim ed to analyse the associations of blood pressure with 12 different presentations of cardiovascular disease . Methods We used  linked electronic health records from 1997 to 2010 in the CALIBER ( CArdiovascular research using LInked Bespoke studies and Electronic health Records ) programme to assemble a cohort of 1·25 million patients , 30 years of age or older and initially free from cardiovascular disease , a fifth of whom received blood pressure-lowering treatments . We studied the heterogeneity in the age-specific associations of clinical ly measured blood pressure with 12 acute and chronic cardiovascular diseases , and estimated the lifetime risks ( up to 95 years of age ) and cardiovascular disease-free life-years lost adjusted for other risk factors at index ages 30 , 60 , and 80 years . This study is registered at Clinical Trials.gov , number NCT01164371 . Findings During 5·2 years median follow-up , we recorded 83 098 initial cardiovascular disease presentations . In each age group , the lowest risk for cardiovascular disease was in people with systolic blood pressure of 90–114 mm Hg and diastolic blood pressure of 60–74 mm Hg , with no evidence of a J-shaped increased risk at lower blood pressures . The effect of high blood pressure varied by cardiovascular disease endpoint , from strongly positive to no effect . Associations with high systolic blood pressure were strongest for intracerebral haemorrhage ( hazard ratio 1·44 [ 95 % CI 1·32–1·58 ] ) , subarachnoid haemorrhage ( 1·43 [ 1·25–1·63 ] ) , and stable angina ( 1·41 [ 1·36–1·46 ] ) , and weakest for abdominal aortic aneurysm ( 1·08 [ 1·00–1·17 ] ) . Compared with diastolic blood pressure , raised systolic blood pressure had a greater effect on angina , myocardial infa rct ion , and peripheral arterial disease , whereas raised diastolic blood pressure had a greater effect on abdominal aortic aneurysm than did raised systolic pressure . Pulse pressure associations were inverse for abdominal aortic aneurysm ( HR per 10 mm Hg 0·91 [ 95 % CI 0·86–0·98 ] ) and strongest for peripheral arterial disease ( 1·23 [ 1·20–1·27 ] ) . People with  hypertension ( blood pressure ≥140/90 mm Hg or those receiving blood pressure-lowering drugs ) had a lifetime risk of overall cardiovascular disease at 30 years of age of 63·3 % ( 95 % CI 62·9–63·8 ) compared with 46·1 % ( 45·5–46·8 ) for those with normal blood pressure , and developed cardiovascular disease 5·0 years earlier ( 95 % CI 4·8–5·2 ) . Stable and unstable angina accounted for most ( 43 % ) of the cardiovascular disease-free years of life lost associated with hypertension from index age 30 years , whereas heart failure and stable angina accounted for the largest proportion ( 19 % each ) of years of life lost from index age 80 years . Interpretation The widely held assumptions that blood pressure has strong associations with the occurrence of all cardiovascular diseases across a wide age range , and that diastolic and systolic associations are concordant , are not supported by the findings of this high-resolution study . Despite modern treatments , the lifetime burden of hypertension is substantial . These findings emphasise the need for new  blood pressure-lowering strategies , and will help to inform the design of r and omised trials to assess them . Funding Medical Research Council , National Institute for Health Research , and Wellcome Trust Background : Analyses of the risks of stroke were conducted for subjects with and without diabetes , participating in a r and omized , double‐blind , placebo‐controlled  trial of a perindopril‐based blood pressure lowering regimen in 6105 people with prior stroke or transient ischaemic attack ( TIA ) , followed for a median of 3.9 years . Findings : Seven hundred and sixty‐one patients had diabetes at baseline . Diabetes increased the risk of recurrent stroke by 35 % ( 95 % CI 10–65 % ) principally through an effect on ischaemic stroke ( 1.53 , 95 % CI 1.23–1.90 ) . Active treatment reduced blood pressure by 9.5/4.6 mmHg in patients with diabetes and by 8.9/3.9 mmHg in patients without diabetes . The proportional risk reductions achieved for stroke in patients with diabetes , 38 % ( 95 % CI 8–58 % ) , and patients without diabetes , 28 % ( 95 % CI 16–39 % ) , were not significantly different ( p homogeneity = 0.5 ) . The absolute reduction in the risk of recurrent stroke in the patients with diabetes was equivalent to one stroke avoided among every 16 ( 95 % CI 9–111 ) patients treated for 5 years . Conclusions : Diabetes is an important risk factor for stroke in patients with established cerebrovascular disease . Treatment with the ACE inhibitor perindopril with discretionary use of the diuretic indapamide produced reductions in the risk of recurrent stroke in patients with diabetes that were at least as great as those achieved in patients without diabetes Background —Microalbuminuria is associated with increased risk of cardiovascular events . We assessed whether therapeutic intervention aim ed at lowering urinary albumin excretion would reduce cardiovascular events in microalbuminuric subjects ( 15 to 300 mg/24 hours ) . Methods and Results —From the Prevention of Renal and Vascular Endstage Disease ( PREVEND ) cohort ( n=8592 ) , 1439 subjects fulfilled the inclusion criteria of the PREVEND Intervention Trial ( PREVEND IT ) . Of these subjects , 864 were r and omized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo . The mean follow-up was 46 months , and the primary end point was cardiovascular mortality and hospitalization for cardiovascular morbidity . Mean age was 51±12 years ; 65 % of subjects were male , and 3.4 % had a previous cardiovascular event . Mean cholesterol level was 5.8±1.0 mmol/L , mean systolic/diastolic blood pressure was 130±18/76±10 mm Hg , and median urinary albumin excretion was 22.8 ( 15.8 to 41.3 ) mg/24 hours . The primary end point occurred in 45 subjects ( 5.2 % ) . Fosinopril  reduced urinary albumin excretion by 26 % ( P<0.001 ) . Subjects treated with fosinopril showed a 40 % lower incidence of the primary end point ( hazard ratio 0.60 [ 95 % CI 0.33 to 1.10 ] , P=0.098 , log-rank ) . Pravastatin did not reduce urinary albumin excretion , and subjects treated with pravastatin showed a 13 % lower incidence of the primary end point than subjects in the placebo group ( 0.87 [ 0.49 to 1.57 ] , P=0.649 , log-rank ) . Conclusions —In microalbuminuric subjects , treatment with fosinopril had a significant effect on urinary albumin excretion . In addition , fosinopril treatment was associated with a trend in reducing cardiovascular events  . Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events Background The risks and benefits of treating hypertension in individuals older than 80 years are uncertain . A meta- analysis has suggested that a reduction in stroke events of 36 % may have to be balanced against a 14 % increase in total mortality . Objectives To report the results of the pilot study of the Hypertension in the Very Elderly Trial ( HYVET ) , which is in progress to address these issues . Methods The HYVET-Pilot was a multicentre international open pilot trial . In 10 European countries , 1283 patients older than 80 years and with a sustained blood pressure of 160–219/90–109 mmHg were allocated r and omly to one of three treatments : a diuretic-based regimen ( usually bendroflumethiazide ; n = 426 ) , an angiotensin-converting enzyme inhibitor regimen ( usually lisinopril ; n = 431 ) or no treatment ( n = 426 ) . The procedure permitted doses of the drug to be titrated and diltiazem slow-release to be added to active treatment . Target blood pressure was < 150/80 mmHg and mean follow-up was 13 months . Results In the combined actively treated groups , the reduction in stroke events relative hazard rate ( RHR ) was 0.47 [ 95 % confidence interval ( CI ) 0.24 to 0.93 ] and the reduction in stroke mortality RHR was 0.57 ( 95 % CI 0.25 to 1.32 ) . However , the estimate of total mortality supported the possibility of excess deaths with active treatment ( RHR 1.23 , 95 % CI 0.75 to 2.01 ) . Conclusions The preliminary results support the need for the continuing main HYVET trial . It is possible that treatment of 1000 patients for 1 year may reduce stroke events by 19 ( nine non-fatal ) , but may be associated with 20 extra non-stroke deaths Hypertension guidelines recommend blood pressure self-measurement at home ( HBP ) , but no previous trial has assessed cardiovascular outcomes in hypertensive patients treated according to HBP . The multicenter Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure ( HOMED-BP ; 2001–2010 ) trial involved 3518 patients ( 50 % women ; mean age 59.6 years ) with an untreated systolic/diastolic HBP of 135–179/85–119 mm Hg . In a 2 × 3 design , patients were r and omized to usual control ( 125–134/80–84 mm Hg ( UC ) ) vs. tight control ( < 125/<80 mm Hg ( TC ) ) of HBP and to initiation of drug treatment with angiotensin converting enzyme inhibitors , angiotensin receptor blockers or calcium channel blockers . During follow-up , a computer algorithm automatically generated treatment recommendations based on HBP . At the last follow-up ( median 5.3 years ) , TC patients used more antihypertensive drugs than UC patients ( 1.82 vs. 1.74 defined daily doses , P=0.045 ) and had a greater HBP reduction ( 21.3/13.1 mm Hg vs. 22.7/13.9 mm Hg , P=0.018/0.020 ) , but they less frequently achieved the lower HBP targets ( 37.4 vs. 63.5 % , P<0.0001 ) . The primary end point , cardiovascular death plus stroke and myocardial infa rct ion , occurred in 25 UC and 26 TC patients ( hazard ratio , 1.02 ; 95 % confidence interval , 0.59–1.77 ; P=0.94 ) . Rates were similar ( P⩾0.13 ) in the three drug groups . In all patients combined , the risk of the primary end point independently increased by 41 % ( 6–89 % ; P=0.019 ) and 47 % ( 15–87 % ; P=0.0020 ) for a 1-s.d . increase in baseline ( 12.5 mm Hg ) and follow-up ( 13.2 mm Hg ) systolic HBP . The 5-year risk was minimal ( ⩽1 % ) if on-treatment systolic HBP was 131.6 mm Hg or less . HOMED-BP proved the feasibility of adjusting antihypertensive drug treatment based on HBP and suggests that a systolic HBP level of 130 mm Hg should be an achievable and safe target In this prospect i ve , r and omized , open-label , blinded end point study , we aim ed to establish whether strict blood pressure control ( < 140 mm Hg ) is superior to moderate blood pressure control ( ≥140 mm Hg to < 150 mm Hg ) in reducing cardiovascular mortality and morbidity in elderly patients with isolated systolic hypertension . We divided 3260 patients aged 70 to 84 years with isolated systolic hypertension ( sitting blood pressure 160 to 199 mm Hg ) into 2 groups , according to strict or moderate blood pressure treatment . A composite of cardiovascular events was evaluated for ≥2 years . The  strict control ( 1545 patients ) and moderate control ( 1534 patients ) groups were well matched ( mean age : 76.1 years ; mean blood pressure : 169.5/81.5 mm Hg ) . Median follow-up was 3.07 years . At 3 years , blood pressure reached 136.6/74.8 mm Hg and 142.0/76.5 mm Hg , respectively . The blood pressure difference between the 2 groups was 5.4/1.7 mm Hg . The overall rate of the primary composite end point was 10.6 per 1000 patient-years in the strict control group and 12.0 per 1000 patient-years in the moderate control group ( hazard ratio : 0.89 ; [ 95 % CI : 0.60 to 1.34 ] ; P=0.38 ) . In summary , blood pressure targets of < 140 mm Hg are safely achievable in relatively healthy patients ≥70 years of age with isolated systolic hypertension , although our trial was underpowered to definitively determine whether strict control was superior to less stringent blood pressure targets BACKGROUND The risk of cardiovascular events among patients with atrial fibrillation is high . We evaluated whether irbesartan , an angiotensin-receptor blocker , would reduce this risk . METHODS We r and omly assigned patients with a history of risk factors for stroke and a systolic blood pressure of at least 110 mm Hg to receive either irbesartan at a target dose of 300 mg once daily or double-blind placebo . These patients were already enrolled in one of two trials ( of clopidogrel plus aspirin versus aspirin alone or versus oral anticoagulants ) . The first co primary outcome was stroke , myocardial infa rct ion , or death from vascular causes ; the second was this composite outcome plus hospitalization for heart failure . RESULTS A total of 9016 patients were enrolled and followed for a mean of 4.1 years . The mean reduction in systolic blood pressure was 2.9 mm Hg greater in the irbesartan group than in the placebo group , and the mean reduction in diastolic blood pressure was 1.9 mm Hg greater . The first co primary outcome occurred at a rate of 5.4 % per 100 person-years in both groups ( hazard ratio with irbesartan , 0.99 ; 95 % confidence interval [ CI ] , 0.91 to 1.08 ; P=0.85 ) . The second co primary outcome occurred at a rate of 7.3 % per 100 person-years among patients receiving irbesartan and 7.7 % per 100 person-years among patients receiving placebo ( hazard ratio , 0.94 ; 95 % CI , 0.87 to 1.02 ; P=0.12 ) . The rates of first hospitalization for heart failure ( a prespecified secondary outcome ) were 2.7 % per 100 person-years among patients receiving irbesartan and 3.2 % per 100 person-years among patients receiving placebo ( hazard ratio , 0.86 ; 95 % CI , 0.76 to 0.98 ) . Among patients who were in sinus rhythm at baseline , there was no benefit of irbesartan in preventing hospitalization for atrial fibrillation or atrial fibrillation recorded on 12-lead electrocardiography , nor was there a benefit in a subgroup that underwent transtelephonic monitoring . More patients in the irbesartan group than in the placebo group had symptomatic hypotension ( 127 vs. 64 ) and renal dysfunction ( 43 vs. 24 ) . CONCLUSIONS Irbesartan did not reduce cardiovascular events in patients with atrial fibrillation . ( Funded by Bristol-Myers Squibb and Sanofi-Aventis ; Clinical Trials.gov number , NCT00249795 . ) BACKGROUND In patients who have vascular disease or high-risk diabetes without heart failure , angiotensin-converting-enzyme ( ACE ) inhibitors reduce mortality and morbidity from cardiovascular causes , but the role of angiotensin-receptor blockers ( ARBs ) in such patients is unknown . We compared the ACE inhibitor ramipril , the ARB telmisartan , and the combination of the two drugs in patients with vascular disease or high-risk diabetes . METHODS After a 3-week , single-blind run-in period , patients underwent double-blind r and omization , with 8576 assigned to receive 10 mg of ramipril per day , 8542 assigned to receive 80 mg of telmisartan per day , and 8502 assigned to receive both drugs ( combination therapy ) . The primary composite outcome was death from cardiovascular causes , myocardial infa rct ion , stroke , or hospitalization for heart failure . RESULTS Mean blood pressure was lower in both the telmisartan group ( a 0.9/0.6 mm Hg greater reduction ) and the combination-therapy group ( a 2.4/1.4 mm Hg greater reduction ) than in the ramipril group . At a median follow-up of 56 months , the primary outcome had occurred in 1412 patients in the ramipril group ( 16.5 % ) , as compared with 1423 patients in the telmisartan group ( 16.7 % ; relative risk , 1.01 ; 95 % confidence interval [ CI ] , 0.94 to 1.09 ) . As compared with the ramipril group , the telmisartan group had lower rates of cough ( 1.1 % vs. 4.2 % , P<0.001 ) and angioedema ( 0.1 % vs. 0.3 % , P=0.01 ) and a higher rate of hypotensive symptoms ( 2.6 % vs. 1.7 % , P<0.001 ) ; the rate of syncope was the same in the two groups ( 0.2 % ) . In the combination-therapy group , the primary outcome occurred in 1386 patients ( 16.3 % ; relative risk , 0.99 ; 95 % CI , 0.92 to 1.07 ) ; as compared with the ramipril group , there was an increased risk of hypotensive symptoms ( 4.8 % vs. 1.7 % , P<0.001 ) , syncope ( 0.3 % vs. 0.2 % , P=0.03 ) , and renal dysfunction ( 13.5 % vs. 10.2 % , P<0.001 ) . CONCLUSIONS Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema . The combination of the two drugs was associated with more adverse events without an increase in benefit . ( Clinical Trials.gov number , NCT00153101 [ Clinical Trials.gov ] . ) Background The prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure study addresses the issue of whether progression to manifest hypertension in patients with high-normal blood pressure can be prevented with treatment . Methods A total of 1008 participants with high-normal office blood pressure were r and omized to ramipril treatment group ( n = 505 ) and a control group ( n = 503 ) . The patients were followed up for 3 years . Primary endpoint was to prevent or delay the progression to manifest hypertension . Secondary endpoints were reduction in the incidence of cerebrovascular and cardiovascular events , as well as the development of hypertension as defined by ambulatory blood pressure monitoring . Findings One hundred and fifty-five patients ( 30.7 % ) in the ramipril group , and 216 ( 42.9 % ) in the control group reached the primary endpoint ( relative risk reduction 34.4 % , P = 0.0001 ) . Ramipril also proved to be more effective in reducing the incidence of manifest office hypertension in patients with baseline ambulatory blood pressure monitoring high-normal blood pressure . The incidence of cerebrovascular and cardiovascular events showed no statistically significant differences between the two groups . Cough was more frequent in the ramipril group ( 4.8 vs. 0.4 % ) . Interpretation There is now good clinical evidence that patients with high-normal blood pressure ( prehypertension ) are more likely to progress to manifest hypertension than patients with optimal or normal blood pressure . Additional ambulatory blood pressure monitoring seems to be essential to achieve correct diagnosis . Treatment of patients with high-normal office blood pressure with the angiotensin-converting enzyme inhibitor was well tolerated , and significantly reduced the risk of progression to manifest hypertension Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more 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 Previous studies have suggested that blockade of the renin-angiotensin system may prevent diabetes in people with cardiovascular disease or hypertension . METHODS In a double-blind , r and omized clinical trial with a 2-by-2 factorial design , we r and omly assigned 5269 participants without cardiovascular disease but with impaired fasting glucose levels ( after an 8-hour fast ) or impaired glucose tolerance to receive ramipril ( up to 15 mg per day ) or placebo ( and rosiglitazone or placebo ) and followed them for a median of 3 years . We studied the effects of ramipril on the development of diabetes or death , whichever came first ( the primary outcome ) , and on secondary outcomes , including regression to normoglycemia . RESULTS The incidence of the primary outcome did not differ significantly between the ramipril group ( 18.1 % ) and the placebo group ( 19.5 % ; hazard ratio for the ramipril group , 0.91 ; 95 % confidence interval [ CI ] , 0.81 to 1.03 ; P=0.15 ) . Participants receiving ramipril were more likely to have regression to normoglycemia than those receiving placebo ( hazard ratio , 1.16 ; 95 % CI , 1.07 to 1.27 ; P=0.001 ) . At the end of the study , the median fasting plasma glucose level was not significantly lower in the ramipril group ( 102.7 mg per deciliter [ 5.70 mmol per liter ] ) than in the placebo group ( 103.4 mg per deciliter [ 5.74 mmol per liter ] , P=0.07 ) , though plasma glucose levels 2 hours after an oral glucose load were significantly lower in the ramipril group ( 135.1 mg per deciliter [ 7.50 mmol per liter ] vs. 140.5 mg per deciliter [ 7.80 mmol per liter ] , P=0.01 ) . CONCLUSIONS Among persons with impaired fasting glucose levels or impaired glucose tolerance , the use of ramipril for 3 years does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycemia . ( Clinical Trials.gov number , NCT00095654 [ Clinical Trials.gov ] . ) BACKGROUND The multicenter double-blind , r and omized Bergamo Nephrologic Diabetes Complications Trial ( BENEDICT ) was design ed to assess whether angiotensin-converting-enzyme inhibitors and non-dihydropyridine calcium-channel blockers , alone or in combination , prevent microalbuminuria in subjects with hypertension , type 2 diabetes mellitus , and normal urinary albumin excretion . METHODS We studied 1204 subjects , who were r and omly assigned to receive at least three years of treatment with tr and olapril  ( at a dose of 2 mg per day ) plus verapamil ( sustained-release formulation , 180 mg per day ) , tr and olapril alone ( 2 mg per day ) , verapamil alone ( sustained-release formulation , 240 mg per day ) , or placebo .  The target blood pressure was 120/80 mm Hg . The primary end point was the development of persistent microalbuminuria ( overnight albumin excretion , > or = 20 microg per minute at two consecutive visits ) . RESULTS The primary outcome was reached in 5.7 percent of the subjects receiving tr and olapril plus verapamil , 6.0 percent of the subjects receiving tr and olapril , 11.9 percent of the subjects receiving verapamil , and 10.0 percent of control subjects receiving placebo . The estimated acceleration factor ( which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression ) adjusted for predefined baseline characteristics was 0.39 for the comparison between verapamil plus tr and olapril and placebo ( P=0.01 ) , 0.47 for the comparison between tr and olapril and placebo ( P=0.01 ) , and 0.83 for the comparison between verapamil and placebo ( P=0.54 ) . Tr and olapril plus verapamil and tr and olapril alone delayed the onset of microalbuminuria by factors of 2.6 and 2.1 , respectively . Serious adverse events were similar in all treatment groups . CONCLUSIONS In subjects with type 2 diabetes and hypertension but with normoalbuminuria , the use of tr and olapril plus verapamil and tr and olapril alone decreased the incidence of microalbuminuria to a similar extent . The effect of verapamil alone was similar to that of placebo Background Prehypertension is associated with higher  cardiovascular risk ,  target organ damage , and incidence of hypertension . The Prevention of Hypertension in Patients with PreHypertension ( PREVER‐Prevention ) trial aim ed to evaluate the efficacy and safety of a low‐dose diuretic for the prevention of hypertension and end‐organ damage . Methods and Results This r and omized , parallel , double‐blind , placebo‐controlled trial was conducted in 21 Brazilian academic medical centers . Participants with prehypertension who were aged 30 to 70 years and who did not reach optimal blood pressure after 3 months of lifestyle intervention  were r and omized to a chlorthalidone/amiloride combination pill or placebo and were evaluated every 3 months during 18 months of treatment . The primary outcome was incidence of hypertension . Development or worsening of microalbuminuria , new‐onset diabetes mellitus , and reduction of left ventricular mass were secondary outcomes . Participant characteristics were evenly distributed by trial arms . The incidence of hypertension was significantly lower in 372 study participants allocated to diuretics compared with 358 allocated to placebo ( hazard ratio 0.56 , 95 % CI 0.38–0.82 ) , result ing in a cumulative incidence of 11.7 % in the diuretic arm versus 19.5 % in the placebo arm ( P=0.004 ) . Adverse events ; levels of blood glucose , glycosylated hemoglobin , creatinine , and microalbuminuria ; and incidence of diabetes mellitus were no different between the 2 arms . Left ventricular mass assessed through Sokolow‐Lyon voltage and voltage‐ duration product decreased to a greater extent in participants allocated to diuretic therapy compared with placebo ( P=0.02 ) . Conclusions A combination of low‐dose chlorthalidone and amiloride effectively reduces the risk of incident hypertension and beneficially affects left ventricular mass in patients with prehypertension . Clinical Trial Registration URL : http://www . Clinical Trials.gov , www.ensaiosclinicos.gov . Unique identifiers : NCT00970931 , RBR‐74rr6s BACKGROUND Calcium antagonists are widely prescribed for angina pectoris but their effect on clinical outcome is controversial . We aim ed to investigate the effect of the calcium antagonist nifedipine on long-term outcome in patients with stable angina pectoris . METHODS We r and omly assigned 3825 patients with treated stable symptomatic coronary disease to double-blind addition of nifedipine GITS  ( gastrointestinal therapeutic system ) 60 mg once daily and 3840 to placebo . The primary endpoint was the combination of death , acute myocardial infa rct ion , refractory angina , new overt heart failure , debilitating stroke , and peripheral revascularisation . Mean follow-up was 4.9 years ( SD 1.1 ) . Analysis was by intention to treat . FINDINGS 310 patients allocated nifedipine  died ( 1.64 per 100 patient-years ) compared with 291 people allocated placebo  ( 1.53 per 100 patient-years ; hazard ratio 1.07 [ 95 % CI 0.91 - 1.25 ] , p=0.41 ) . Primary endpoint rates were 4.60 per 100 patient-years for nifedipine and 4.75 per 100 patient-years for placebo ( 0.97 [ 0.88 - 1.07 ] , p=0.54 ) . With nifedipine , rate of death and any cardiovascular event or procedure was 9.32 per 100 patient-years versus 10.50 per 100 patient-years for placebo ( 0.89 [ 0.83 - 0.95 ] , p=0.0012 ) . The difference was mainly attributable to a reduction in the need for coronary angiography and interventions in patients assigned nifedipine , despite an increase in peripheral revascularisation . Nifedipine had no effect on the rate of myocardial infa rct ion . INTERPRETATION Addition of nifedipine GITS to conventional treatment of angina pectoris has no effect on major cardiovascular event-free survival .  Nifedipine GITS is safe and reduces the need for coronary angiography and interventions BACKGROUND It has been suggested that low diastolic blood pressure ( BP ) while receiving antihypertensive treatment ( hereinafter called on-treatment BP ) is harmful in older patients with systolic hypertension . We examined the association between on-treatment diastolic BP , mortality , and cardiovascular events in the prospect i ve placebo-controlled Systolic Hypertension in Europe Trial . METHODS Elderly patients with systolic hypertension were r and omized into the double-blind first phase of the trial , after which all patients received active study drugs ( phase 2 ) . We assessed the relationship between outcome and on-treatment diastolic BP by use of multivariate Cox regression analysis during receipt of placebo ( phase 1 ) and during active treatment ( phases 1 and 2 ) . RESULTS Rates of noncardiovascular mortality , cardiovascular mortality , and cardiovascular events were 11.1 , 12.0 , and 29.4 , respectively , per 1000 patient-years with active treatment ( n = 2358 ) and 11.9 , 12.6 , and 39.0 , respectively , with placebo ( n = 2225 ) . Noncardiovascular mortality , but not cardiovascular mortality , increased with low diastolic BP with active treatment ( P < .005 ) and with placebo ( P < .05 ) ; for example , hazard ratios for lower diastolic BP , that is , 65 to 60 mm Hg , were , respectively , 1.15 ( 95 % confidence interval , 1.00 - 1.31 ) and 1.28 ( 95 % confidence interval , 1.03 - 1.59 ) . Low diastolic BP with active treatment was associated with increased risk of cardiovascular events , but only in patients with coronary heart disease at baseline ( P < .02 ; hazard ratio for BP 65 - 60 mm Hg , 1.17 ; 95 % confidence interval , 0.98 - 1.38 ) . CONCLUSIONS These findings support the hypothesis that antihypertensive treatment can be intensified to prevent cardiovascular events when systolic BP is not under control in older patients with systolic hypertension , at least until diastolic BP reaches 55 mm Hg . However , a prudent approach is warranted in patients with concomitant coronary heart disease , in whom diastolic BP should probably not be lowered to less than 70 mm Hg Abstract Objective : To determine whether tight control of blood pressure with either a β blocker or an angiotensin converting enzyme inhibitor has a specific advantage or disadvantage in preventing the macrovascular and microvascular complications of type 2 diabetes . Design : R and omised controlled trial comparing an angiotensin converting enzyme inhibitor ( captopril ) with a β blocker ( atenolol ) in patients with type 2 diabetes aim ing at a blood pressure of < 150/<85 mm Hg . Setting : 20 hospital based clinics in Engl and , Scotl and , and Northern Irel and . Subjects : 1148 hypertensive patients with type 2 diabetes ( mean age 56 years , mean blood pressure 160/94 mm Hg ) . Of the 758 patients allocated to tight control of blood pressure , 400 were allocated to captopril and 358 to atenolol . 390 patients were allocated to less tight control of blood pressure . Main outcome measures : Predefined clinical end points , fatal and non-fatal , related to diabetes , death related to diabetes , and all cause mortality . Surrogate measures of microvascular and macrovascular disease included urinary albumin excretion and retinopathy assessed by retinal photography . Results : Captopril and atenolol were equally effective in reducing blood pressure to a mean of 144/83 mm Hg and 143/81 mm Hg respectively , with a similar proportion of patients ( 27 % and 31 % ) requiring three or more antihypertensive treatments . More patients in the captopril group than the atenolol group took the allocated treatment : at their last clinic visit , 78 % of those allocated captopril and 65 % of those allocated atenolol were taking the drug ( P<0.0001 ) . Captopril and atenolol were equally effective in reducing the risk of macrovascular end points . Similar proportions of patients in the two groups showed deterioration in retinopathy by two grade s after nine years ( 31 % in the captopril group and 37 % in the atenolol group ) and developed clinical grade albuminuria ≥300 mg/l ( 5 % and 9 % ) . The proportion of patients with hypoglycaemic attacks was not different between groups , but mean weight gain in the atenolol group was greater ( 3.4 kg v 1.6 kg ) . Conclusion : Blood pressure lowering with captopril or atenolol was similarly effective in reducing the incidence of diabetic complications . This study provided no evidence that either drug has any specific beneficial or deleterious effect , suggesting that blood pressure reduction in itself may be more important than the treatment used OBJECTIVE The Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial is a prospect i ve r and omized blinded clinical trial that compares the effects of intensive versus moderate blood pressure control on the incidence and progression of type 2 diabetic complications . The current article discusses the results of 5.3 years of follow-up of 470 patients with hypertension and evaluates the effects of intensive and moderate blood pressure therapy using nisoldipine versus enalapril as the initial antihypertensive medication for nephropathy , retinopathy , and neuropathy . RESEARCH DESIGN AND METHODS The 470 hypertensive subjects , defined as having a baseline diastolic blood pressure of > or = 90 mmHg , were r and omized to intensive blood pressure control ( diastolic blood pressure goal of 75 mmHg ) versus moderate blood pressure control ( diastolic blood pressure goal of 80 - 89 mmHg ) . RESULTS The mean blood pressure achieved was 132/78 mmHg in the intensive group and 138/86 mmHg in the moderate control group . During the 5-year follow-up period , no difference was observed between intensive versus moderate blood pressure control and those r and omized to nisoldipine versus enalapril with regard to the change in creatinine clearance . After the first year of antihypertensive treatment , creatinine clearance stabilized in both the intensive and moderate blood pressure control groups in those patients with baseline normo- or microalbuminuria . In contrast , patients starting with overt albuminuria demonstrated a steady decline in creatinine clearance of 5 - 6 ml.min-1.1.73 m-2 per year throughout the follow-up period whether they were on intensive or moderate therapy . There was also no difference between the interventions with regard to individuals progressing from normoalbuminuria to microalbuminuria ( 25 % intensive therapy vs. 18 % moderate therapy , P = 0.20 ) or microalbuminuria to overt albuminuria ( 16 % intensive therapy vs. 23 % moderate therapy , P = 0.28 ) . Intensive therapy demonstrated a lower overall incidence of deaths , 5.5 vs. 10.7 % , P = 0.037 . Over a 5-year follow-up period , there was no difference between the intensive and moderate groups with regard to the progression of diabetic retinopathy and neuropathy . In addition , the use of nisoldipine versus enalapril had no differential effect on diabetic retinopathy and neuropathy . CONCLUSIONS Blood pressure control of 138/86 or 132/78 mmHg with either nisoldipine or enalapril as the initial antihypertensive medication appeared to stabilize renal function in hypertensive type 2 diabetic patients without overt albuminuria over a 5-year period . The more intensive blood pressure control decreased all-cause mortality Abstract Objective To investigate whether a low dose of the angiotensin converting enzyme ( ACE ) inhibitor ramipril lowers cardiovascular and renal events in patients with type 2 diabetes who have microalbuminuria or proteinuria . Design R and omised , double blind , parallel group trial comparing ramipril ( 1.25 mg/day ) with placebo ( on top of usual treatment ) for cardiovascular and renal outcomes for at least three years . Setting Multicentre , primary care study conducted mostly by general practitioners in 16 European and north African countries . Participants 4912 patients with type 2 diabetes aged > 50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria ( urinary albumin excretion 20 mg/l in two consecutive sample s ) , and serum creatinine ≤ 150 μmol/l . Main outcome measures The primary outcome measure was the combined incidence of cardiovascular death , non-fatal myocardial infa rct ion , stroke , heart failure leading to hospital admission , and end stage renal failure . Results Participants were followed for 3 to 6 ( median 4 ) years . There were 362 primary events among the 2443 participants taking ramipril ( 37.8 per 1000 patient years ) and 377 events among the 2469 participants taking placebo ( 38.8 per 1000 patient years ; hazard ratio 1.03 ( 95 % confidence interval 0.89 to 1.20 , P = 0.65 ) ) . None of the components of the primary outcome was reduced . Ramipril  lowered systolic and diastolic blood pressures ( by 2.43 and 1.06 mm Hg respectively after two years ) and favoured regression from microalbuminuria ( 20 - 200 mg/l ) or proteinuria ( > 200mg/l ) to normal level ( < 20 mg/l ) or microalbuminuria ( P < 0.07 ) in 1868 participants who completed the study . Conclusions Low dose ( 1.25 mg ) ramipril once daily has no effect on cardiovascular and renal outcomes of patients with type 2 diabetes and albuminuria , despite a slight decrease in blood pressure and urinary albumin . The cardiovascular benefits of a daily higher dose ( 10 mg ) ramipril observed elsewhere are not found with an eightfold lower daily dose BACKGROUND Whether the treatment of patients with hypertension who are 80 years of age or older is beneficial is unclear . It has been suggested that antihypertensive therapy may reduce the risk of stroke , despite possibly increasing the risk of death . METHODS We r and omly assigned 3845 patients from Europe , China , Australasia , and Tunisia who were 80 years of age or older and had a sustained systolic blood pressure of 160 mm Hg or more to receive either the diuretic indapamide ( sustained release , 1.5 mg ) or matching placebo .  The angiotensin-converting-enzyme inhibitor perindopril ( 2 or 4 mg ) , or matching placebo , was added if necessary to achieve the target blood pressure of 150/80 mm Hg . The primary end point was fatal or nonfatal stroke . RESULTS The active-treatment group ( 1933 patients ) and the placebo group ( 1912 patients ) were well matched ( mean age , 83.6 years ; mean blood pressure while sitting , 173.0/90.8 mm Hg ) ; 11.8 % had a history of cardiovascular disease . Median follow-up was 1.8 years . At 2 years , the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group . In an intention-to-treat analysis , active treatment was associated with a 30 % reduction in the rate of fatal or nonfatal stroke ( 95 % confidence interval [ CI ] , -1 to 51 ; P=0.06 ) , a 39 % reduction in the rate of death from stroke ( 95 % CI , 1 to 62 ; P=0.05 ) , a 21 % reduction in the rate of death from any cause ( 95 % CI , 4 to 35 ; P=0.02 ) , a 23 % reduction in the rate of death from cardiovascular causes ( 95 % CI , -1 to 40 ; P=0.06 ) , and a 64 % reduction in the rate of heart failure ( 95 % CI , 42 to 78 ; P<0.001 ) . Fewer serious adverse events were reported in the active-treatment group ( 358 , vs. 448 in the placebo group ; P=0.001 ) . CONCLUSIONS The results provide evidence that antihypertensive treatment with indapamide ( sustained release ) , with or without perindopril , in persons 80 years of age or older is beneficial . ( Clinical Trials.gov number , NCT00122811 [ Clinical Trials.gov ] . ) 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 BACKGROUND Microalbuminuria in diabetes is strongly predictive of nephropathy , end-stage renal disease , and premature cardiovascular morbidity and mortality . Effective preventive therapies are therefore a clinical priority . OBJECTIVE To determine whether the angiotensin-receptor blocker c and esartan compared with placebo affects microalbuminuria incidence or rate of change in albuminuria in type 1 and type 2 diabetes . DESIGN 3 r and omized trials of the DIRECT ( Diabetic Retinopathy C and esartan Trials ) Program . SETTING 309 secondary care centers . PATIENTS 3326 and 1905 patients with type 1 and type 2 diabetes , respectively . Most were normotensive , and all had normoalbuminuria ( median urinary albumin excretion rate , 5.0 microg/min ) . INTERVENTION C and esartan , 16 mg/d increasing to 32 mg/d , versus placebo . Assignment was done central ly using an interactive voice-response system . Patients , caregivers , and research ers were blinded to treatment assignment . During a median follow-up of 4.7 years , 793 patients discontinued therapy and 63 were lost to follow-up . MEASUREMENTS Urinary albumin excretion rate , assessed annually by 2 overnight collection s ; if it was 20 microg/min or greater , then 2 further collection s were done . The primary end point was new microalbuminuria ( 3 or 4 collection s of urinary albumin excretion rate > or=20 microg/min ) . The secondary end point was rate of change in albuminuria . RESULTS Individual and pooled results of the 3 trials showed that c and esartan had little effect on risk for microalbuminuria ( pooled hazard ratio , 0.95 [ 95 % CI , 0.78 to 1.16 ] ; P = 0.60 ) . Pooled results showed that the annual rate of change in albuminuria was 5.53 % lower ( CI , 0.73 % to 10.14 % ; P = 0.024 ) with c and esartan than with placebo . LIMITATIONS Investigators recruited mainly normotensive patients or patients with well-controlled hypertension who were at low overall vascular risk , which result ed in a low rate of microalbuminuria . Studies were powered for retinal and not renal end points . CONCLUSION C and esartan , 32 mg/d , for 4.7 years did not prevent microalbuminuria in mainly normotensive patients with type 1 or type 2 diabetes BACKGROUND Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown . We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke . METHODS In this r and omised open-label trial , eligible patients lived in North America , Latin America , and Spain and had recent , MRI-defined symptomatic lacunar infa rct ions . Patients were recruited between March , 2003 , and April , 2011 , and r and omly assigned , according to a two-by-two multifactorial design , to a systolic-blood-pressure target of 130 - 149 mm Hg or less than 130 mm Hg . The primary endpoint was reduction in all stroke ( including ischaemic strokes and intracranial haemorrhages ) . Analysis was done by intention to treat . This study is registered with Clinical Trials.gov , number NCT 00059306 . FINDINGS 3020 enrolled patients , 1519 in the higher-target group and 1501 in the lower-target group , were followed up for a mean of 3·7 ( SD 2·0 ) years . Mean age was 63 ( SD 11 ) years . After 1 year , mean systolic blood pressure was 138 mm Hg ( 95 % CI 137 - 139 ) in the higher-target group and 127 mm Hg ( 95 % CI 126 - 128 ) in the lower-target group . Non-significant rate reductions were seen for all stroke ( hazard ratio 0·81 , 95 % CI 0·64 - 1·03 , p=0·08 ) , disabling or fatal stroke ( 0·81 , 0·53 - 1·23 , p=0·32 ) , and the composite outcome of myocardial infa rct ion or vascular death ( 0·84 , 0·68 - 1·04 , p=0·32 ) with the lower target . The rate of intracerebral haemorrhage was reduced significantly ( 0·37 , 0·15 - 0·95 , p=0·03 ) . Treatment-related serious adverse events were infrequent . INTERPRETATION Although the reduction in stroke was not significant , our results support that in patients with recent lacunar stroke , the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial . FUNDING National Institutes of Health-National Institute of Neurological Disorders and Stroke ( NIH-NINDS ) Objectives To evaluate the risk of bias tool , introduced by the Cochrane Collaboration for assessing the internal validity of r and omised trials , for inter-rater agreement , concurrent validity compared with the Jadad scale and Schulz approach to allocation concealment , and the relation between risk of bias and effect estimates . Design Cross sectional study . Study sample 163 trials in children . Main outcome measures Inter-rater agreement between review ers assessing trials using the risk of bias tool ( weighted κ ) , time to apply the risk of bias tool compared with other approaches to quality assessment ( paired t test ) , degree of correlation for overall risk compared with overall quality scores ( Kendall ’s τ statistic ) , and magnitude of effect estimates for studies classified as being at high , unclear , or low risk of bias ( metaregression ) . Results Inter-rater agreement on individual domains of the risk of bias tool ranged from slight ( κ=0.13 ) to substantial ( κ=0.74 ) . The mean time to complete the risk of bias tool was significantly longer than for the Jadad scale and Schulz approach , individually or combined ( 8.8 minutes ( SD 2.2 ) per study v 2.0 ( SD 0.8 ) , P<0.001 ) . There was low correlation between risk of bias overall compared with the Jadad scores ( P=0.395 ) and Schulz approach ( P=0.064 ) . Effect sizes differed between studies assessed as being at high or unclear risk of bias ( 0.52 ) compared with those at low risk ( 0.23 ) . Conclusions Inter-rater agreement varied across domains of the risk of bias tool . Generally , agreement was poorer for those items that required more judgment . There was low correlation between assessment s of overall risk of bias and two common approaches to quality assessment : the Jadad scale and Schulz approach to allocation concealment . Overall risk of bias as assessed by the risk of bias tool differentiated effect estimates , with more conservative estimates for studies at low risk BACKGROUND This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease , cardiovascular disease , or both . METHODS In a double-blind fashion , we r and omly assigned 8561 patients to aliskiren ( 300 mg daily ) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker . The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation ; nonfatal myocardial infa rct ion ; nonfatal stroke ; unplanned hospitalization for heart failure ; end-stage renal disease , death attributable to kidney failure , or the need for renal-replacement therapy with no dialysis  or transplantation available or initiated ; or doubling of the baseline serum creatinine level . RESULTS The trial was stopped prematurely after the second interim efficacy analysis . After a median follow-up of 32.9 months , the primary end point had occurred in 783 patients ( 18.3 % ) assigned to aliskiren as compared with 732 ( 17.1 % ) assigned to placebo ( hazard ratio , 1.08 ; 95 % confidence interval [ CI ] , 0.98 to 1.20 ; P=0.12 ) . Effects on secondary renal end points were similar . Systolic and diastolic blood pressures were lower with aliskiren ( between-group differences , 1.3 and 0.6 mm Hg , respectively ) and the mean reduction in the urinary albumin-to-creatinine ratio was greater ( between-group difference , 14 percentage points ; 95 % CI , 11 to 17 ) . The proportion of patients with hyperkalemia ( serum potassium level , ≥6 mmol per liter ) was significantly higher in the aliskiren group than in the placebo group ( 11.2 % vs. 7.2 % ) , as was the proportion with reported hypotension ( 12.1 % vs. 8.3 % ) ( P<0.001 for both comparisons ) . CONCLUSIONS The addition of aliskiren to st and ard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful . ( Funded by Novartis ; ALTITUDE Clinical Trials.gov number , NCT00549757 . ) BACKGROUND Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease . We investigated whether treatment with an angiotensin-receptor blocker ( ARB ) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria . METHODS In a r and omized , double-blind , multicenter , controlled trial , we assigned 4447 patients with type 2 diabetes to receive olmesartan ( at a dose of 40 mg once daily ) or placebo for a median of 3.2 years . Additional antihypertensive drugs ( except angiotensin-converting-enzyme inhibitors or ARBs ) were used as needed to lower blood pressure to less than 130/80 mm Hg . The primary outcome was the time to the first onset of microalbuminuria . The times to the onset of renal and cardiovascular events were analyzed as secondary end points . RESULTS The target blood pressure ( < 130/80 mm Hg ) was achieved in nearly 80 % of the patients taking olmesartan and 71 % taking placebo ;  blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group . Microalbuminuria developed in 8.2 % of the patients in the olmesartan group ( 178 of 2160 patients who could be evaluated ) and 9.8 % in the placebo group ( 210 of 2139 ) ; the time to the onset of microalbuminuria was increased by 23 % with olmesartan ( hazard ratio for onset of microalbuminuria , 0.77 ; 95 % confidence interval , 0.63 to 0.94 ; P=0.01 ) . The serum creatinine level doubled in 1 % of the patients in each group . Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events--81 of 2232 patients ( 3.6 % ) as compared with 91 of 2215 patients ( 4.1 % ) (P=0.37)--but a greater number had fatal cardiovascular events--15 patients ( 0.7 % ) as compared with 3 patients ( 0.1 % ) ( P=0.01 ) , a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease ( 11 of 564 patients [ 2.0 % ] vs. 1 of 540 [ 0.2 % ] , P=0.02 ) . CONCLUSIONS Olmesartan was associated with a delayed onset of microalbuminuria , even though blood-pressure control in both groups was excellent according to current st and ards . The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern . ( Funded by Daiichi Sankyo ; Clinical Trials.gov number , NCT00185159 . ) AIMS Major guidelines recommend lowering systolic blood pressure ( SBP ) to < 140 mmHg in all hypertensives , but evidence is missing whether this is beneficial in ( i ) uncomplicated hypertensives , ( ii ) grade 1 hypertensives , and ( iii ) elderly hypertensives . Providing this missing evidence is important to justify efforts and costs of aggressive therapy in all hypertensives . METHODS AND RESULTS Felodipine Event Reduction ( FEVER ) was a double-blind , r and omized trial on 9711 Chinese hypertensives , in whom cardiovascular outcomes  were significantly reduced by more intense therapy ( low-dose hydrochlorothiazide and low-dose felodipine ) achieving a mean of 138 mmHg SBP compared with less-intense therapy ( low-dose hydrochlorothiazide and placebo ) achieving a mean of 142 mmHg . FEVER included older and younger patients , and patients with and without diabetes or cardiovascular disease . In the analyses here reported , Cox regression models assessed outcome differences between more and less-intense treatments in groups of patients with different baseline characteristics . Significant reductions in stroke were found in uncomplicated hypertensives ( -39 % , P = 0.002 ) , in hypertensives with r and omization SBP < 153 mmHg ( -29 % , P = 0.03 ) , and in elderly hypertensives ( -44 % , P < 0.001 ) , when their SBP was lowered by more intense treatment . Significant reductions ( between -29 and -47 % , P = 0.02 to < 0.001 ) were also found in all cardiovascular events and all deaths . Achieving mean SBP values < 140 mmHg by adding a small dose of a generic drug prevented 2.1 ( uncomplicated hypertensives ) and 5.2 ( elderly ) cardiovascular events every 100 patients treated for 3.3 years . CONCLUSIONS These analyses provide strong support , missing so far , to guidelines recommending goal SBP < 140 mmHg in uncomplicated hypertensives , individuals with moderately elevated BP and elderly hypertensives BACKGROUND We investigated whether combination therapy with a statin plus a fibrate , as compared with statin monotherapy , would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease . METHODS We r and omly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo .  The primary outcome was the first occurrence of nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The mean follow-up was 4.7 years . RESULTS The annual rate of the primary outcome was 2.2 % in the fenofibrate group and 2.4 % in the placebo group ( hazard ratio in the fenofibrate group , 0.92 ; 95 % confidence interval [ CI ] , 0.79 to 1.08 ; P=0.32 ) . There were also no significant differences between the two study groups with respect to any secondary outcome . Annual rates of death were 1.5 % in the fenofibrate group and 1.6 % in the placebo group ( hazard ratio , 0.91 ; 95 % CI , 0.75 to 1.10 ; P=0.33 ) . Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex , with a benefit for men and possible harm for women ( P=0.01 for interaction ) , and a possible interaction according to lipid subgroup , with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol ( P=0.057 for interaction ) . CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events , nonfatal myocardial infa rct ion , or nonfatal stroke , as compared with simvastatin alone . These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes . ( Clinical Trials.gov number , NCT00000620 . BACKGROUND It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance . METHODS In this double-blind , r and omized clinical trial with a 2-by-2 factorial design , we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan ( up to 160 mg daily ) or placebo ( and nateglinide or placebo ) in addition to lifestyle modification . We then followed the patients for a median of 5.0 years for the development of diabetes ( 6.5 years for vital status ) . We studied the effects of valsartan on the occurrence of three co primary outcomes : the development of diabetes ; an extended composite outcome of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , hospitalization for heart failure , arterial revascularization , or hospitalization for unstable angina ; and a core composite outcome that excluded unstable angina and revascularization . RESULTS The cumulative incidence of diabetes was 33.1 % in the valsartan group , as compared with 36.8 % in the placebo group ( hazard ratio in the valsartan group , 0.86 ; 95 % confidence interval [ CI ] , 0.80 to 0.92 ; P<0.001 ) . Valsartan , as compared with placebo , did not significantly reduce the incidence of either the extended cardiovascular outcome ( 14.5 % vs. 14.8 % ; hazard ratio , 0.96 ; 95 % CI , 0.86 to 1.07 ; P=0.43 ) or the core cardiovascular outcome ( 8.1 % vs. 8.1 % ; hazard ratio , 0.99 ; 95 % CI , 0.86 to 1.14 ; P=0.85 ) . CONCLUSIONS Among patients with impaired glucose tolerance and cardiovascular disease or risk factors , the use of valsartan for 5 years , along with lifestyle modification , led to a relative reduction of 14 % in the incidence of diabetes but did not reduce the rate of cardiovascular events . ( Clinical Trials.gov number , NCT00097786 . The influence of risk factors on  CHD and all-cause mortality rates in 35- to 57-year-old men is examined by means of data on 325,348 white men who were screened for the MRFIT .  This large data set permits an unusually detailed analysis of factors associated with the 6968 deaths , including 2426 ascribed to CHD , that were detected in the Social Security Administration data set during 6 years of follow-up . Simple cross classification of the data confirms the independent effect of serum cholesterol concentration , diastolic blood pressure , and cigarette smoking as risk factors for CHD and all-cause mortality rates . A distinct escalation of risk is noted for combinations of these risk factors . The strength of the association of each of the risk factors with CHD and all-cause mortality rates diminished with increasing age , although the number of excess deaths attributable to the risk factors increased because of the higher death rates in older men . Comparison of these findings with those observed in the five population s studied in the Pooling Project revealed an overall similarity in the risk relationships . It is estimated that elimination of these risk factors has the potential for reducing the CHD mortality rate by two thirds in 35- to 45-year old men , and by one half in 46- to 57-year-old men Objective To compare the incidence of stroke and other cardiovascular events in hypertensive patients receiving a low-dose diuretic and low-dose calcium antagonist combination with those receiving low-dose diuretic monotherapy  , and assess the effects of a small blood pressure difference at achieved levels lower than those achieved in previous placebo-controlled trials . Methods The Felodipine Event Reduction ( FEVER ) trial was an investigator- design ed , prospect i ve , multicentre , double-blind , r and omized , placebo-controlled , parallel group trial . It enrolled 9800 Chinese patients , of either sex , aged 50–79 years , with one or two additional cardiovascular risk factors or disease , whose blood pressure , 6 weeks after switching from previous antihypertensive therapy to low-dose ( 12.5 mg a day ) hydrochlorothiazide , was in the range 140–180 mmHg ( systolic ) or 90–100 mmHg ( diastolic ) . These patients were r and omly assigned either to low-dose felodipine extended release or placebo , and followed at 3-month intervals for an average of 40 months . Results The intention-to-treat analysis included 9711 r and omly selected patients with only 30 ( 0.3 % ) lost to follow-up . A total of 31 842 patient-years of follow-up were accumulated , with 85.9 % of patients remaining on blinded r and omized treatment . Add-on therapy was given to 33.9 % of the hydrochlorothiazide – felodipine patients and to 42.3 % of the hydrochlorothiazide – placebo patients . In the felodipine  group , systolic blood pressure (SBP)/diastolic blood pressure ( DBP ) decreased ( from r and omization to study end ) from 154.2/91.0 to 137.3/82.5 mmHg , and in the placebo group from 154.4/91.3 to 142.5/85.0 mmHg , with an average difference throughout the trial of 4.2/2.1 mmHg . In the felodipine group , the primary endpoint ( fatal and non-fatal stroke ) was reduced by 27 % ( P = 0.001 ) . Among secondary endpoints , all cardiovascular events were reduced by 27 % ( P < 0.001 ) , all cardiac events by 35 % ( P = 0.012 ) , death by any cause by 31 % ( P = 0.006 ) , coronary events by 32 % ( P = 0.024 ) , heart failure by 30 % ( P = 0.239 ) , cardiovascular death by 33 % ( P = 0.019 ) , cancer by 36 % ( P = 0.017 ) in the felodipine group . No significant differences were found in new-onset diabetes . Both treatments were very well tolerated . Conclusions In moderately complicated hypertensive patients from China even a difference in SBP/DBP as small as 4/2 mmHg , such as that induced by adding low-dose felodipine to low-dose hydrochlorothiazide , is associated with very substantial reductions in the incidence of most types of cardiovascular events . As the SBP achieved in the felodipine group was below the recommended goal of less than 140 mmHg , and SBP in the placebo group was slightly above that level , FEVER provides the required evidence in support of the guidelines recommended goal , even for a hypertensive population not entirely consisting of patients with diabetes or previous cardiovascular events BACKGROUND Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes , and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension . We assessed the effects of the routine administration of an angiotensin converting enzyme ( ACE ) inhibitor-diuretic combination on serious vascular events in patients with diabetes , irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs . METHODS The trial was done by 215 collaborating centres in 20 countries . After a 6-week active run-in period , 11 140 patients with type 2 diabetes were r and omised to treatment with a fixed combination of perindopril and indapamide or matching placebo , in addition to current therapy . The primary endpoints were composites of major macrovascular and microvascular events , defined as death from cardiovascular disease , non-fatal stroke or non-fatal myocardial infa rct ion , and new or worsening renal or diabetic eye disease , and analysis was by intention-to-treat . The macrovascular and microvascular composites were analysed jointly and separately . This trial is registered with Clinical Trials.gov , number NCT00145925 . FINDINGS After a mean of 4.3 years of follow-up , 73 % of those assigned active treatment and 74 % of those assigned control remained on r and omised treatment . Compared with patients assigned placebo , those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg . The relative risk of a major macrovascular or microvascular event was reduced by 9 % ( 861 [ 15.5 % ] active vs 938 [ 16.8 % ] placebo ; hazard ratio 0.91 , 95 % CI 0.83 - 1.00 , p=0.04 ) . The separate reductions in macrovascular and microvascular events were similar but were not independently significant ( macrovascular 0.92 ; 0.81 - 1.04 , p=0.16 ; microvascular 0.91 ; 0.80 - 1.04 , p=0.16 ) . The relative risk of death from cardiovascular disease was reduced by 18 % ( 211 [ 3.8 % ] active vs 257 [ 4.6 % ] placebo ; 0.82 , 0.68 - 0.98 , p=0.03 ) and death from any cause was reduced by 14 % ( 408 [ 7.3 % ] active vs 471 [ 8.5 % ] placebo ; 0.86 , 0.75 - 0.98 , p=0.03 ) . There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline . INTERPRETATION Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events , including death . Although the confidence limits were wide , the results suggest that over 5 years , one death due to any cause would be averted among every 79 patients assigned active therapy BACKGROUND Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke . In addition , inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events , including stroke . However , the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established . We evaluated the effects of therapy with an angiotensin-receptor blocker , telmisartan , initiated early after a stroke . METHODS In a multicenter trial involving 20,332 patients who recently had an ischemic stroke , we r and omly assigned 10,146 to receive telmisartan  ( 80 mg daily ) and 10,186 to receive  placebo . The primary outcome was recurrent stroke . Secondary outcomes were major cardiovascular events ( death from cardiovascular causes , recurrent stroke , myocardial infa rct ion , or new or worsening heart failure ) and new-onset diabetes . RESULTS The median interval from stroke to r and omization was 15 days . During a mean follow-up of 2.5 years , the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group . A total of 880 patients ( 8.7 % ) in the telmisartan group and 934 patients ( 9.2 % ) in the placebo group had a subsequent stroke ( hazard ratio in the telmisartan group , 0.95 ; 95 % confidence interval [ CI ] , 0.86 to 1.04 ; P=0.23 ) . Major cardiovascular events occurred in 1367 patients ( 13.5 % ) in the telmisartan group and 1463 patients ( 14.4 % ) in the placebo group ( hazard ratio , 0.94 ; 95 % CI , 0.87 to 1.01 ; P=0.11 ) . New-onset diabetes occurred in 1.7 % of the telmisartan group and 2.1 % of the placebo group ( hazard ratio , 0.82 ; 95 % CI , 0.65 to 1.04 ; P=0.10 ) . CONCLUSIONS Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke , major cardiovascular events , or diabetes . ( Clinical Trials.gov number , NCT00153062 . Background The prognostic benefits of blood pressure lowering treatment in elderly hypertensive patients were established more than a decade ago , but are less clear in those with mildly to moderately elevated blood pressure . Objective To assess whether c and esartan-based antihypertensive treatment in elderly patients with mildly to moderately elevated blood pressure confers a reduction in cardiovascular events , cognitive decline and dementia . Design Prospect i ve , double-blind , r and omized , parallel-group study conducted in 1997–2002 . Setting and participants The study was of 4964 patients aged 70–89 years , with systolic blood pressure 160–179 mmHg , and /or diastolic blood pressure 90–99 mmHg , and a Mini Mental State Examination ( MMSE ) test score ⩾ 24 . A total of 527 centres in 15 countries participated in the study . Intervention Patients were assigned r and omly to receive the angiotensin receptor blocker c and esartan or placebo , with open-label active antihypertensive therapy added as needed . As a consequence , active antihypertensive therapy was extensively used in the control group ( 84 % of patients ) . Mean follow-up was 3.7 years . Main outcome measures The primary outcome measure was major cardiovascular events , a composite of cardiovascular death , non-fatal stroke and non-fatal myocardial infa rct ion . Secondary outcome measures included cardiovascular death , non-fatal and fatal stroke and myocardial infa rct ion , cognitive function measured by the MMSE and dementia . Results Blood pressure fell by 21.7/10.8 mmHg in the c and esartan group and by 18.5/9.2 mmHg in the control group . A first major cardiovascular event occurred in 242 c and esartan patients and in 268 control patients ; risk reduction with c and esartan was 10.9 % [ 95 % confidence interval ( CI ) , −6.0 to 25.1 , P = 0.19 ] . C and esartan-based treatment reduced non-fatal stroke by 27.8 % ( 95 % CI , 1.3 to 47.2 , P = 0.04 ) , and all stroke by 23.6 % ( 95 % CI , −0.7 to 42.1 , P = 0.056 ) . There were no significant differences in myocardial infa rct ion and cardiovascular mortality . Mean MMSE score fell from 28.5 to 28.0 in the c and esartan group and from 28.5 to 27.9 in the control group ( P = 0.20 ) . The proportions of patients who had a significant cognitive decline or developed dementia were not different in the two treatment groups . Conclusions In elderly hypertensive patients , a slightly more effective blood pressure reduction during c and esartan-based therapy , compared with control therapy , was associated with a modest , statistically non-significant , reduction in major cardiovascular events and with a marked reduction in non-fatal stroke . Cognitive function was well maintained in both treatment groups in the presence of substantial blood pressure reductions . Both treatment regimens were generally well tolerated BACKGROUND Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction , whether or not they have heart failure . We assessed the role of an angiotensin-converting-enzyme inhibitor , ramipril , in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure . METHODS A total of 9297 high-risk patients ( 55 years of age or older ) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were r and omly assigned to receive ramipril ( 10 mg once per day orally ) or matching placebo for a mean of five years . The primary outcome was a composite of myocardial infa rct ion , stroke , or death from cardiovascular causes . The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper . RESULTS A total of 651 patients who were assigned to receive  ramipril ( 14.0 percent ) reached the primary end point , as compared with 826 patients who were assigned to receive placebo ( 17.8 percent ) ( relative risk , 0.78 ; 95 percent confidence interval , 0.70 to 0.86 ; P<0.001 ) . Treatment with ramipril reduced the rates of death from cardiovascular causes ( 6.1 percent , as compared with 8.1 percent in the placebo group ; relative risk , 0.74 ; P<0.001 ) , myocardial infa rct ion ( 9.9 percent vs. 12.3 percent ; relative risk , 0.80 ; P<0.001 ) , stroke ( 3.4 percent vs. 4.9 percent ; relative risk , 0.68 ; P<0.001 ) , death from any cause ( 10.4 percent vs. 12.2 percent ; relative risk , 0.84 ; P=0.005 ) , revascularization procedures ( 16.3 percent vs. 18.8 percent ; relative risk , 0.85 ; P<0.001 ) , cardiac arrest ( 0.8 percent vs. 1.3 percent ; relative risk , 0.62 ; P=0.02 ) , [ corrected ] heart failure ( 9.1 percent vs. 11.6 percent ; relative risk , 0.77 ; P<0.001 ) , and complications related to diabetes ( 6.4 percent vs. 7.6 percent ; relative risk , 0.84 ; P=0.03 ) . CONCLUSIONS Ramipril significantly reduces the rates of death , myocardial infa rct ion , and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure Most patients with type 2 diabetes mellitus develop cardiovascular disease ( CVD ) , with substantial loss of life expectancy . Nonfatal CVD contributes greatly to excess healthcare costs and decreased quality of life in patients with diabetes . The current epidemic of obesity has raised expectations that CVD associated with type 2 diabetes will become an even greater public health challenge . Despite the importance of this health problem , there is a lack of definitive data on the effects of the intensive control of glycemia and other CVD risk factors on CVD event rates in patients with type 2 diabetes . The Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial is a r and omized , multicenter , double 2 x 2 factorial design study involving 10,251 middle-aged and older participants with type 2 diabetes who are at high risk for CVD events because of existing CVD or additional risk factors . ACCORD is testing the effects of 3 medical treatment strategies to reduce CVD morbidity and mortality . All participants are in the glycemia trial , which is testing the hypothesis that a therapeutic strategy that targets a glycosylated hemoglobin ( HbA1c ) level of < 6.0 % will reduce the rate of CVD events more than a strategy that targets an HbA1c level of 7.0%-7.9 % . The lipid trial includes 5,518 of the participants , who receive either fenofibrate or placebo in a double-masked fashion to test the hypothesis of whether , in the context of good glycemic control , a therapeutic strategy that uses a fibrate to increase high-density lipoprotein cholesterol and lower triglyceride levels together with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ( statin ) to lower low-density lipoprotein cholesterol will reduce the rate of CVD events compared with a strategy that uses a statin plus a placebo . The blood pressure trial includes the remaining 4,733 participants and tests the hypothesis that a therapeutic strategy that targets a systolic blood pressure of < 120 mm Hg in the context of good glycemic control will reduce the rate of CVD events compared with a strategy that targets a systolic blood pressure of < 140 mm Hg . The primary outcome measure for all 3 research questions is the first occurrence of a major CVD event , specifically nonfatal myocardial infa rct ion , nonfatal stroke , or cardiovascular death . Upon the expected completion of participant follow-up in 2009 , the ACCORD trial should document for the first time the benefits and risks of intensive glucose control , intensive blood pressure control , and the combination of fibrate and statin drugs in managing blood lipids in high-risk patients with type 2 diabetes This study was performed to investigate whether intensive antihypertensive treatment with achieved blood pressure ( BP ) ≤140/90 mm Hg , as compared with st and ard treatment with achieved BP ≤150/90 mm Hg , could further improve cardiovascular outcomes in Chinese hypertensive patients older than 70 years . A total of 724 participants were r and omly assigned to intensive or st and ard antihypertensive treatment . After a mean follow-up of 4 years , the mean achieved BP was 135.7/76.2 mm Hg in the intensive treatment group and 149.7/82.1 mm Hg in the st and ard treatment group . The visit-to-visit variability in systolic BP and diastolic BP was lower in the intensive group than that in the st and ard group . Intensive antihypertensive treatment , compared with the st and ard treatment , decreased total and cardiovascular mortality by 41.7 % and 50.3 % , respectively , and reduced fatal/nonfatal stroke by 42.0 % and heart failure death by 62.7 % . Cox regression analysis indicated that the mean systolic BP ( P=.020 ; 95 % confidence interval , 1.006 - 1.069 ) and the st and ard deviation of systolic BP ( P=.033 ; 95 % confidence interval , 1.006 - 1.151 ) were risk factors for cardiovascular endpoint events . Intensive antihypertensive treatment with achieved 136/76 mm Hg was beneficial for Chinese hypertensive patients older than 70 years . Long-term visit-to-visit variability in systolic BP was positively associated with the incidence of cardiovascular events BACKGROUND Despite treatment , there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals . Inadequate reduction of their blood pressure is a likely cause , but the optimum target blood pressure is not known . The impact of acetylsalicylic acid ( aspirin ) has never been investigated in patients with hypertension . We aim ed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension . METHODS 18790 patients , from 26 countries , aged 50 - 80 years ( mean 61.5 years ) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg ( mean 105 mm Hg ) were r and omly assigned a target diastolic blood pressure . 6264 patients were allocated to the target pressure < or = 90 mm Hg , 6264 to < or = 85 mm Hg , and 6262 to < or = 80 mm Hg . Felodipine was given as baseline therapy with the addition of other agents , according to a five-step regimen . In addition , 9399 patients were r and omly assigned 75 mg/day acetylsalicylic acid ( Bamycor , Astra ) and 9391 patients were assigned  placebo . FINDINGS Diastolic blood pressure was reduced by 20.3 mm Hg , 22.3 mm Hg , and 24.3 mm Hg , in the < or = 90 mm Hg , < or = 85 mm Hg , and < or = 80 mm Hg target groups , respectively . The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg ; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg . Further reduction below these blood pressures was safe .  In patients with diabetes mellitus there was a 51 % reduction in major cardiovascular events in target group < or = 80 mm Hg compared with target group < or = 90 mm Hg ( p for trend=0.005 ) . Acetylsalicylic acid reduced major cardiovascular events by 15 % ( p=0.03 ) and all myocardial infa rct ion by 36 % ( p=0.002 ) , with no effect on stroke . There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group , and 129 versus 70 non-fatal major bleeds in the two groups , respectively ( p<0.001 ) . INTERPRETATION Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events . The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg . Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infa rct ion . There was no effect on the incidence of stroke or fatal bleeds , but non-fatal major bleeds were twice as common This article introduces the approach of GRADE to rating  quality of evidence .  GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence BACKGROUND Previous trials have shown that the use of statins to lower cholesterol reduces the risk of cardiovascular events among persons without cardiovascular disease . Those trials have involved persons with elevated lipid levels or inflammatory markers and involved mainly white persons . It is unclear whether the benefits of statins can be extended to an intermediate-risk , ethnically diverse population without cardiovascular disease . METHODS In one comparison from a 2-by-2 factorial trial , we r and omly assigned 12,705 participants in 21 countries who did not have cardiovascular disease and were at intermediate risk to receive rosuvastatin at a dose of 10 mg per day or placebo . The first co primary outcome was the composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke , and the second co primary outcome additionally included revascularization , heart failure , and resuscitated cardiac arrest . The median follow-up was 5.6 years . RESULTS The overall mean low-density lipoprotein cholesterol level was 26.5 % lower in the rosuvastatin group than in the placebo group . The first co primary outcome occurred in 235 participants ( 3.7 % ) in the rosuvastatin group and in 304 participants ( 4.8 % ) in the placebo group ( hazard ratio , 0.76 ; 95 % confidence interval [ CI ] , 0.64 to 0.91 ; P=0.002 ) . The results for the second co primary outcome were consistent with the results for the first ( occurring in 277 participants [ 4.4 % ] in the rosuvastatin group and in 363 participants [ 5.7 % ] in the placebo group ; hazard ratio , 0.75 ; 95 % CI , 0.64 to 0.88 ; P<0.001 ) . The results were also consistent in subgroups defined according to cardiovascular risk at baseline , lipid level , C-reactive protein level , blood pressure , and race or ethnic group . In the rosuvastatin group , there was no excess of diabetes or cancers , but there was an excess of cataract surgery ( in 3.8 % of the participants , vs. 3.1 % in the placebo group ; P=0.02 ) and muscle symptoms ( in 5.8 % of the participants , vs. 4.7 % in the placebo group ; P=0.005 ) . CONCLUSIONS Treatment with rosuvastatin at a dose of 10 mg per day result ed in a significantly lower risk of cardiovascular events than placebo in an intermediate-risk , ethnically diverse population without cardiovascular disease . ( Funded by the Canadian Institutes of Health Research and AstraZeneca ; HOPE-3 Clinical Trials.gov number , NCT00468923 . ) Angiotensin-converting enzyme inhibitors improve endothelial function , inhibit experimental atherogenesis , and decrease ischemic events . The Quinapril Ischemic Event Trial was design ed to test the hypothesis that quinapril 20 mg/day would reduce ischemic events ( the occurrence of cardiac death , resuscitated cardiac arrest , nonfatal myocardial infa rct ion , coronary artery bypass grafting , coronary angioplasty , or hospitalization for angina pectoris ) and the angiographic progression of coronary artery disease in patients without systolic left ventricular dysfunction . A total of 1,750 patients were r and omized to quinapril 20 mg/day or placebo  and followed a mean of 27 + /- 0.3 months . The 38 % incidence of ischemic events was similar for both groups ( RR 1.04 ; 95 % confidence interval 0.89 to 1.22 ; p = 0.6 ) . There was also no significant difference in the incidence of patients having angiographic progression of coronary disease ( p = 0.71 ) . The rate of development of new coronary lesions was also similar in both groups ( p = 0.35 ) . However , there was a difference in the incidence of angioplasty for new ( previously unintervened ) vessels ( p = 0.018 ) . Quinapril was well tolerated in patients after angioplasty with normal left ventricular function . Quinapril 20 mg did not significantly affect the overall frequency of clinical outcomes or the progression of coronary atherosclerosis . However , the absence of the demonstrable effect of quinapril may be due to several limitations in study design BACKGROUND Treatment with angiotensin-converting-enzyme ( ACE ) inhibitors reduces the rate of cardiovascular events among patients with left-ventricular dysfunction and those at high risk of such events . We assessed whether the ACE inhibitor perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease and no apparent heart failure . METHODS We recruited patients from October , 1997 , to June , 2000 . 13655 patients were registered with previous myocardial infa rct ion ( 64 % ) , angiographic evidence of coronary artery disease ( 61 % ) , coronary revascularisation ( 55 % ) , or a positive stress test only ( 5 % ) . After a run-in period of 4 weeks , in which all patients received perindopril , 12218 patients were r and omly assigned perindopril 8 mg once daily ( n=6110 ) , or matching placebo ( n=6108 ) . The mean follow-up was 4.2 years , and the primary endpoint was cardiovascular death , myocardial infa rct ion , or cardiac arrest . Analysis was by intention to treat . FINDINGS Mean age of patients was 60 years ( SD 9 ) , 85 % were male , 92 % were taking platelet inhibitors , 62 % beta blockers , and 58 % lipid-lowering therapy . 603 ( 10 % ) placebo and 488 ( 8 % ) perindopril patients experienced the primary endpoint , which yields a 20 % relative risk reduction ( 95 % CI 9 - 29 , p=0.0003 ) with perindopril . These benefits were consistent in all predefined subgroups and secondary endpoints . Perindopril was well tolerated . INTERPRETATION Among patients with stable coronary heart disease without apparent heart failure , perindopril can significantly improve outcome . About 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event . Treatment with perindopril , on top of other preventive medications , should be considered in all patients with coronary heart disease BACKGROUND Diabetes is the most common cause of renal failure in the United States , and data regarding the effects of aggressive blood pressure ( BP ) therapy in normotensive patients with type 2 diabetes are inadequate . METHODS A total of 129 type 2 diabetic patients with a BP of < 140/80 to 90 mm Hg without overt albuminuria were r and omized to either intensive BP control ( diastolic BP goal 75 mm Hg ) using an angiotensin II receptor blocker , valsartan , versus moderate BP control ( diastolic BP 80 to 90 mm Hg with placebo initially ) to evaluate the effect on the change in urinary albumin excretion ( UAE ) from baseline . RESULTS The mean entrance BP was 126 + /- 8.8/84 + /- 2.4 mm Hg . The mean follow-up period was 1.9 + /- 1.0 years . During the follow-up period , the mean BP was 118 + /- 10.9/75 + /- 5.7 for the intensive v 124 10.9/80 6.5 mm Hg for the moderate BP groups ( P < .001 ) . No difference was observed in change in creatinine clearance or serum creatinine from baseline between the two groups . An analysis of covariance model for change in log ( UAE + 1 ) , adjusting for age , HBA(1c ) , duration of diabetes , baseline log ( UAE + 1 ) , sex , and ethnicity result ed in a significant treatment difference at 2 years ( P = .007 ) with intensive BP control reducing log ( UAE+1 ) compared with moderate BP control . CONCLUSION Intensive BP control with valsartan to < 120/80 mm Hg in normotensive patients with type 2 diabetes and normo- or microalbuminuria significantly decreased the progression of UAE and in some cases caused regression of UAE The associations of  diastolic blood pressure ( DBP )  with  stroke  and with coronary heart disease ( CHD ) were investigated in nine major prospect i ve observational studies : total 420,000 individuals , 843 strokes , and 4856 CHD events , 6 - 25 ( mean 10 ) years of follow-up . The combined results demonstrate positive , continuous , and apparently independent associations , with no significant heterogeneity of effect among different studies . Within the range of DBP studied ( about 70 - 110 mm Hg ) , there was no evidence of any " threshold " below which lower levels of DBP were not associated with lower risks of stroke and of CHD . Previous analyses have described the uncorrected associations of DBP measured just at " baseline " with subsequent disease rates . But , because of the diluting effects of r and om fluctuations in DBP , these substantially underestimate the true associations of the usual DBP ( ie , an individual 's long-term average DBP ) with disease . After correction for this " regression dilution " bias , prolonged differences in usual DBP of 5 , 7.5 , and 10 mm Hg were respectively associated with at least 34 % , 46 % , and 56 % less stroke and at least 21 % , 29 % , and 37 % less CHD . These associations are about 60 % greater than in previous uncorrected analyses . ( This regression dilution bias is quite general , so analogous corrections to the relations of cholesterol to CHD or of various other risk factors to CHD or to other diseases would likewise increase their estimated strengths . ) The DBP results suggest that for the large majority of individuals , whether conventionally " hypertensive " or " normotensive " , a lower blood pressure should eventually confer a lower risk of vascular disease BACKGROUND Microalbuminuria and hypertension are risk factors for diabetic nephropathy . Blockade of the renin-angiotensin system slows the progression to diabetic nephropathy in patients with type 1 diabetes , but similar data are lacking for hypertensive patients with type 2 diabetes . We evaluated the renoprotective effect of the angiotensin-II-receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria . METHODS A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this multinational , r and omized , double-blind , placebo-controlled study of irbesartan , at a dose of either 150 mg daily or 300 mg daily , and were followed for two years . The primary outcome was the time to the onset of diabetic nephropathy , defined by persistent albuminuria in overnight specimens , with a urinary albumin excretion rate that was greater than 200 microg per minute and at least 30 percent higher than the base-line level . RESULTS The base-line characteristics in the three groups were similar . Ten of the 194 patients in the 300-mg group ( 5.2 percent ) and 19 of the 195 patients in the 150-mg group ( 9.7 percent ) reached the primary end point , as compared with 30 of the 201 patients in the placebo group ( 14.9 percent ) ( hazard ratios , 0.30 [ 95 percent confidence interval , 0.14 to 0.61 ; P < 0.001 ] and 0.61 [ 95 percent confidence interval , 0.34 to 1.08 ; P=0.081 for the two irbesartan groups , respectively ) . The average blood pressure during the course of the study was 144/83 mm Hg in the placebo group , 143/83 mm Hg in the 150-mg group , and 141/83 mm Hg in the 300-mg group ( P=0.004 for the comparison of systolic blood pressure between the placebo group and the combined irbesartan groups ) . Serious adverse events were less frequent among the patients treated with irbesartan ( P=0.02 ) . CONCLUSIONS Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria BACKGROUND Angiotensin-converting-enzyme ( ACE ) inhibitors are effective in reducing the risk of heart failure , myocardial infa rct ion , and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure . ACE inhibitors have also been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure . METHODS In the Prevention of Events with Angiotensin Converting Enzyme Inhibition ( PEACE ) Trial , we tested the hypothesis that patients with stable coronary artery disease and normal or slightly reduced left ventricular function derive therapeutic benefit from the addition of ACE inhibitors to modern conventional therapy . The trial was a double-blind , placebo-controlled study in which 8290 patients were r and omly assigned to receive either  tr and olapril  at a target dose of  4 mg  per  day ( 4158 patients ) or matching placebo ( 4132 patients ) . RESULTS The mean ( + /-SD ) age of the patients was 64+/-8 years , the mean blood pressure 133+/-17/78+/-10 mm Hg , and the mean left ventricular ejection fraction 58+/-9 percent . The patients received intensive treatment , with 72 percent having previously undergone coronary revascularization and 70 percent receiving lipid-lowering drugs . The incidence of the primary end point -- death from cardiovascular causes , myocardial infa rct ion , or coronary revascularization -- was 21.9 percent in the tr and olapril group , as compared with 22.5 percent in the placebo group ( hazard ratio in the tr and olapril group , 0.96 ; 95 percent confidence interval , 0.88 to 1.06 ; P=0.43 ) over a median follow-up period of 4.8 years . CONCLUSIONS In patients with stable coronary heart disease and preserved left ventricular function who are receiving " current st and ard " therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease , there is no evidence that the addition of an ACE inhibitor provides further benefit in terms of death from cardiovascular causes , myocardial infa rct ion , or coronary revascularization The benefits of lowering a systolic blood pressure below 140 mmHg in elderly hypertension remain controversial . This study is a prospect i ve , r and omized , open-label study with blinded assessment of endpoints to compare the 2-year effect of strict treatment to maintain systolic blood pressure below 140 mmHg with that of mild treatment to maintain systolic blood pressure below 160 but at or above 140 mmHg in elderly hypertensive patients . Patients with essential hypertension ( 65–85 years old , with a pretreatment systolic blood pressure of above 160 mmHg ) were r and omly assigned to receive strict treatment ( n=2,212 ) or mild treatment ( n=2,206 ) . The baseline drug was efonidipine hydrochloride , a long-acting calcium antagonist . The primary endpoint was the combined incidence of cardiovascular disease and renal failure , and the secondary endpoints were total deaths and any safety problems . Although final blood pressures ( systolic/diastolic ) were significantly lower in the strict-treatment group compared with the mild-treatment group ( 135.9/74.8 vs. 145.6/78.1 mmHg ; p<0.001 ) , the incidence of the primary endpoint was similar in the two groups ( 86 patients in each group ; p=0.99 ) . Total deaths were 54 in the strict-treatment group vs. 42 in the mild-treatment group ( p=0.22 ) , and treatment was withdrawn because of adverse events in 36 patients in each group ( p=0.99 ) . An interaction between age and treatment for the primary endpoints ( p=0.03 ) was seen . Complex clinical features associated with aging seem to have obscured the difference in effect between the two treatments . Further studies are needed to assess the optimal treatment strategy for hypertension in the elderly In 1972 - -1973 , 785 symptom-free men , aged 40 to 49 years , without target organ damage , with systolic blood pressures between 150 and 179 mm Hg and diastolic blood pressure below 110 mm Hg , were assigned at r and om to one of two groups : ( 406 to a drug treatment group and 379 to a control group ) for a five-year controlled drug treatment trial to evaluate the effect of therapy on cardiovascular complications . Drug treatment started with hydrochlorothiazide . If systolic blood pressure remained above 140 mm Hg and /or diastolic blood pressure above 90 mm Hg , alphamethyldopa was added . If there were side effects , methyldopa was replaced with propranolol . The control group was not given a placebo . The mean observation time was 66 months ( range 60 to 78 months ) . A difference in blood pressure between groups of about 17 mm Hg systolic and 10 mm Hg diastolic was maintained throughout the study . The study protocol had a rather low " ethical " blood pressure roof , 180 mm Hg systolic and /or 110 mm Hg diastolic . Seventeen percent of the control group had an increase in blood pressure above this level during the trial , and drug treatment was started . There was no effect on major cardiovascular morbidity comparing groups as established by r and omization , with 18 events in the treatment group and 20 events in the control group . There was no difference between the groups in total mortality and mortality from cardiovascular events . However , in the subgroups with diastolic blood pressure greater than or equal to 100 mm Hg before r and omization , there was a probable reduction in total morbidity from cardiovascular events in favor or the group receiving drug therapy , 7.6 and 16.4 percent events in the treated and control groups , respectively . Cerebrovascular events occurred only in the control group , 7 versus 0 . Two cases of fatal aortic aneurysms also occurred in the control group . Other " pressure " complications , such as marked left ventricular hypertrophy in the electrocardiogram and left ventricular failure , occurred only in the control group . However , regarding coronary heart disease , including sudden death , the incidence tended to be higher in the treated group , although it was not statistically significant . Only 13 men ( 1.7 percent ) failed to meet for regular examinations . At the end of the study these men were also followed up with regard to possible cardiovascular events Abstract Blood pressure treatment has shown great efficacy in reducing cardiovascular events in r and omized controlled trials . If this is effective in reducing cardiovascular disease in the general population , is less studied . Between 2001 and 2009 we performed an intervention to improve blood pressure control in the county of Västerbotten , using Södermanl and County as a control . The intervention was directed towards primary care physicians and included lectures on blood pressure treatment , a computerized decision support system with treatment recommendations , and yearly feed back on hypertension control .  Each county had approximately 255 000 inhabitants . Differences in age and incidence of cardiovascular disease were small . During follow-up , more than 400 000 patients had their blood pressure recorded . The mean number of measurements was eight per patient , yielding a total of 3.4 million blood pressure recordings . The effect of the intervention will be estimated combining the blood pressure data collected from the electronic medical records , with data on stroke , myocardial infa rct ion and mortality from Swedish health registers . Additional variables , from health registers and Statistics Sweden , will be collected to address for confounders . The blood pressure data collected within this study will be an important asset for future epidemiological studies within the field of hypertension BP is an important determinant of kidney disease among patients with diabetes . The recommended thresholds to initiate treatment to lower BP are 130/80 and 125/75 mmHg for people with diabetes and nephropathy , respectively . We sought to determine the effects of lowering BP below these currently recommended thresholds on renal outcomes among 11,140 patients who had type 2 diabetes and participated in the Action in Diabetes and Vascular disease : preterAx and diamicroN-MR Controlled Evaluation ( ADVANCE ) study . Patients were r and omly assigned to fixed combination perindopril-indapamide or placebo , regardless of their BP at entry . During a mean follow-up of 4.3 yr , active treatment reduced the risk for renal events by 21 % ( P < 0.0001 ) , which was driven by reduced risks for developing microalbuminuria and macroalbuminuria ( both P < 0.003 ) . Effects of active treatment were consistent across subgroups defined by baseline systolic or diastolic BP . Lower systolic BP levels during follow-up , even to < 110 mmHg , was associated with progressively lower rates of renal events . In conclusion , BP-lowering treatment with perindopril-indapamide administered routinely to individuals with type 2 diabetes provides important renoprotection , even among those with initial BP < 120/70 mmHg . We could not identify a BP threshold below which renal benefit is lost Background Hypertension guidelines advise aggressive blood pressure ( BP ) lowering in patients with diabetes or high cardiovascular risk , but supporting evidence is limited . We analysed the impact of BP on cardiovascular events in well treated high-risk patients enrolled in a large clinical trial ( Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial ) . Methods Twenty-five thous and five hundred and eighty-eight patients with atherosclerotic disease or diabetes with organ damage , tolerant to angiotensin-converting enzyme inhibitors , were r and omized to ramipril , telmisartan or both . We related the primary composite outcome and its components to : baseline SBP ; SBP changes from baseline to event ; and average in-trial SBP . Results The risk of myocardial infa rct ion did not increase with baseline SBP and was unaffected by subsequent SBP change . In contrast , stroke risk progressively increased with baseline SBP ( P for trend < 0.0001 ) and decreased with reduction . In patients with  baseline SBP  less than 130 mmHg , adjusted for several covariates , cardiovascular mortality increased with further SBP reduction ( P < 0.0001 ) . A J-curve ( nadir around 130 mmHg ) occurred in the relationship between in-treatment SBP and all outcomes except stroke . Conclusion In high-risk patients , the benefits from SBP lowering below 130 mmHg are driven mostly by a reduction of stroke ; myocardial infa rct ion is unaffected and cardiovascular mortality is unchanged or increased . Future trials should be design ed to test the value of SBP lowering in high-risk patients with SBP in the range of 130–150 mmHg Abstract Aims /hypothesisThe renal and cardiovascular protective effects of angiotensin receptor blocker ( ARB ) remain controversial in type 2 diabetic patients treated with a contemporary regimen including an angiotensin converting enzyme inhibitor ( ACEI ) . Methods We examined the effects of olmesartan , an ARB , on primary composite outcome of doubling of serum creatinine , endstage renal disease and death in type 2 diabetic patients with overt nephropathy . Secondary outcome included composite cardiovascular outcomes , changes in renal function and proteinuria . R and omisation and allocation to trial group were carried out by a central computer system . Participants , caregivers , the people carrying out examinations and people assessing the outcomes were blinded to group assignment . Results Five hundred and seventy-seven ( 377 Japanese , 200 Chinese ) patients treated with antihypertensive therapy ( 73.5 % [ n = 424 ] received concomitant ACEI ) , were given either once-daily olmesartan ( 10–40 mg ) ( n = 288 ) or placebo ( n = 289 ) over 3.2 ± 0.6 years ( mean±SD ) . In the olmesartan group , 116 developed the primary outcome ( 41.1 % ) compared with 129 ( 45.4 % ) in the placebo group ( HR 0.97 , 95 % CI 0.75 , 1.24 ; p = 0.791 ) . Olmesartan significantly decreased blood pressure , proteinuria and rate of change of reciprocal serum creatinine . Cardiovascular death was higher in the olmesartan group than the placebo group ( ten vs three cases ) , whereas major adverse cardiovascular events ( cardiovascular death plus non-fatal stroke and myocardial infa rct ion ) and all-cause death were similar between the two groups ( major adverse cardiovascular events 18 vs 21 cases , all-cause deaths ; 19 vs 20 cases ) . Hyperkalaemia was more frequent in the olmesartan group than the placebo group ( 9.2 % vs 5.3 % ) . Conclusions /interpretationOlmesartan was well tolerated but did not improve renal outcome on top of ACEI . Trial registration : Clinical Trials.gov NCT00141453 Funding : The ORIENT study was supported by a research grant from Daiichi Sankyo The concept of microalbuminuria has had a major impact on diabetes research and clinical care of patients with diabetes [ 1 - 5 ] . Initial albuminuria is regarded by most research ers as an independent predictor of subsequent progression of nephropathy and risk for cardiovascular morbidity and mortality [ 6 - 8 ] . Angiotensin-converting enzyme ( ACE ) inhibitors have been found to attenuate progression of nephropathy in both types of diabetes in hypertensive [ 9 - 12 ] and normotensive patients [ 13 - 15 ] with microalbuminuria . They were also found to lower urinary albumin excretion in normotensive and normoalbuminuric patients with type 1 diabetes [ 16 ] . The relation between albuminuria and later progression of nephropathy in these patients has not been established , possibly because of short follow-up periods . No data are available on the effect of early introduction of ACE inhibitors in normotensive and normoalbuminuric patients with type 2 diabetes mellitus . We design ed a r and omized , double-blind , placebo-controlled trial of the effect of ACE inhibition on the course of nephropathy in 156 patients with type 2 diabetes . These patients had normal blood pressure and normal urinary albumin excretion at baseline . Methods Patients Potential c and i date s were identified through the computerized records of the central regional laboratory for the northern part of the greater Tel-Aviv area . Persons with hyperglycemia and normal urinalysis results were located through their family physicians . Consent was sought once eligibility was established . Inclusion criteria were age younger than 60 years ; age 40 years or older at diagnosis ; duration of diabetes mellitus less than 10 years with no clinical evidence of malignant , autoimmune , hepatic , cardiovascular , or renal disease ; body mass index less than 30 kg/m2 ; normal blood pressure on at least two consecutive visits ( systolic pressure 140 mm Hg and diastolic pressure 90 mm Hg ; mean pressure 107 mm Hg ) ; serum creatinine concentration of 123 mol/L or less ; and urinary albumin excretion of 30 mg/24 h or less . All baseline data were obtained twice during the run-in prer and omization period . Patients were eligible only if values within the predetermined range were found on both examinations . The average of the values was used as the baseline value . A total of 255 patients who had type 2 diabetes according to World Health Organization criteria [ 17 ] and attended one of eight clinics in the greater Tel-Aviv area were found to be eligible and were contacted during 1990 and 1991 . Of these patients , 214 gave informed consent to participate . Twenty patients were excluded during the observation period : Six had blood pressure values above normal , 5 had microalbuminuria , 3 had serum creatinine concentrations above the trial criterion , 1 patient developed unstable angina pectoris , and 5 withdrew consent . Of the 194 patients included in the study , 102 were women and 92 were men ( mean age SD , 54.9 3.2 years [ range , 37 to 59 years ] ) . The known duration of diabetes was 0 to 9 years ( mean duration , 5.75 2.8 years ) . Patients were instructed to use the st and ard isocaloric diet recommended by the Israeli Diabetic Association , and 69 study patients used diet alone to control their hyperglycemia . Pharmacologic therapy for diabetes was insulin in 34 patients and oral hypoglycemic agents in 91 patients . Protocol The protocol was approved by the hospital review board . After a 2-month observation period , patients were r and omly assigned in a double-blind manner to receive enalapril ( Assia-Riezel Ltd. , Ramat-Gan , Israel ) , 10 mg/d , or placebo .  Ninety-seven patients were assigned to receive enalapril  , and 97 were assigned to receive placebo . R and omization was done central ly by telephone with a r and om number table [ 18 ] . Patient allocation to placebo or enalapril was recorded and kept by one of the authors . The placebo tablets were similar in appearance to the enalapril tablets . The medications , which came in sealed , numbered packages , were central ly prepared and were given to the patients at each visit by one nurse who was otherwise not involved in the study . Patients were followed by their family physicians , who were unaware of allocation . Two semiannual prescheduled visits took place each year , and interim visits were scheduled as clinical ly indicated . At the semiannual visits , hemoglobin A1c values , serum creatinine concentrations , serum electrolyte levels , and 24-hour albumin excretion and urinary creatinine concentrations were measured . Blood pressure was measured by the physicians twice at each visit by using mercury sphygmomanometers with the patients seated after a 5-minute rest ; physicians recorded the average of the two values . The diastolic pressure was determined at Korotkoff phase V. If a systolic blood pressure of 145 mm Hg or more or a diastolic blood pressure of 95 mm Hg or more was found , measurements were repeated weekly . If elevated values persisted on two consecutive visits , a long-acting calcium-channel blocker ( diltiazem or verapamil ) , hydrochlorothiazide , or both were administered . If systolic blood pressure values of 100 mm Hg or less were repeatedly found , the enalapril dosage was reduced to 5 mg/d ( half of a 10-mg enalapril tablet or half of a placebo tablet ) . Fundoscopy was done yearly by an ophthalmologist , and the presence of retinopathy was recorded . For each patient , follow-up was terminated 6 years after r and omization . Measurements All blood and urine sample s were examined by a central laboratory . Assays were not changed during the study period . Glycosylated hemoglobin values were measured by affinity chromatography with a commercial kit ( Isolab , Biochemical Methodology , Akron , Ohio ) . The normal range of this assay is a hemoglobin A1c value of 3.5 % to 5.6 % and an intra-assay and interassay coefficient of variability of less than 3 % . Urinary albumin concentration was measured twice in 24-hour urine sample s by an automated immunoturbidimetric method [ 19 ] . This procedure has intra-assay and interassay coefficients of variability of 5.9 % and 7.6 % , respectively . Creatinine concentrations were determined by using the automated method of Bartels and colleagues [ 20 ] . Creatinine clearance , normalized for 1.73 m2 of body surface area , was calculated for each visit by using the st and ard formula ( urine creatinine x urine volume/plasma creatinine ) . The mean blood pressure ( defined as the diastolic pressure plus one third of the pulse pressure ) was calculated at each visit . Statistical Analysis Data are expressed as the mean ( SD ) with ranges . A P value less than 0.05 was considered significant . On the basis of the assumptions that 15 % of normotensive , normoalbuminuric patients with type 2 diabetes will develop microalbuminuria during 6 years and that treatment with enalapril will reduce the risk for microalbuminuria by 12 % , we calculated that 69 patients were required in each group for a type 1 error of 0.05 and a power of 0.80 [ 21 ] . To test for adequate r and omization and to compare the patients who completed the trial with those who did not complete the trial , the enalapril and placebo groups and the 38 patients who dropped out were compared for mean age ; mean duration of diabetes ; and mean baseline albumin excretion , creatinine clearance , glycosylated hemoglobin value , and blood pressure by using pooled-variance Student t-tests for independent groups and one-way analysis of variance . To compare the annual means of the various measurements between the two groups and within each group , one between-group factor and one repeated- measures factor were used in analysis of variance . For variables shown to be different by analysis of variance , unpaired t-tests were used for between-group parallel annual means and paired t-tests were used for comparison of intragroup sequential annual means . The rate of decrease of creatinine clearance and the rate of increase of albumin excretion were computed by doing linear regression analysis with all of the semiannual values included in the equation . Urinary albumin values were logarithmically transformed before analysis . The degree of albuminuria at baseline was used as a covariate . The funding source had no involvement in the design , conduct , or reporting of the trial . Results Figure 1 shows the flow of participants during the trial . Thirty-eight patients did not complete the trial . Five patients died ( 3 in the enalapril group and 2 in the placebo group ) ; death was related to coronary heart disease in 3 patients , stroke in 1 patient , and ovarian carcinoma in 1 patient . Six patients violated the protocol ( 2 patients in the enalapril group stopped taking their medication for more than 6 months , and 4 patients in the placebo group took an ACE inhibitor prescribed by consultant physicians for more than 6 months ) . Ten patients were lost to follow-up ( 6 in the enalapril group and 4 in the placebo group ) . The trial medication was discontinued in 12 patients : Six developed a disturbing cough ( 4 in the enalapril group and 2 in the placebo group ) , 4 had an allergic skin reaction ( 2 in the enalapril group and 2 in the placebo group ) , 1 patient in the enalapril group developed leukopenia , and 1 patient in the placebo group developed hyperkalemia . Finally , 5 patients developed severe urinary tract infections that had a detectable influence on renal function ( 2 in the enalapril group and 3 in the placebo group ) . A total of 156 patients completed the trial , of whom 77 received enalapril and 79 received placebo . Figure 1 . Flow of participants through the trial . Baseline data for the two groups and for patients who did not complete the trial are shown in Table 1 . The baseline characteristics of patients in the study groups and those who dropped out did not differ significantly . A modest but steady decrease in hemoglobin A1c values was seen in the enalapril and the placebo groups and may reflect the change in attitude toward glucose control among family physicians in the early 1990s . However , Review articles are an important element of most medical journals and a popular source of information for clinicians ( 1 ) . Given the increasing volume of medical literature and the limited time for reading that busy clinicians have , reliance on review articles is likely to increase . However , concerns have been raised that narrative , non systematic review articles may produce biased conclusions ( 2 , 3 ) . Mulrow ( 4 ) examined 50 review articles published in four major medical journals ( The New Engl and Journal of Medicine , Annals of Internal Medicine , JAMA , and Archives of Internal Medicine ) in 1985 - 1986 and found that none fulfilled 8 explicit criteria for scientifically sound summaries of the evidence . As a result , she and others ( 5 , 6 ) proposed criteria for conducting and evaluating review articles that would improve their quality ; these criteria are the first 10 listed in the Appendix Table . In a study of 36 review articles done by nine content experts and method ologists , these criteria were shown to yield reliable and valid estimates of the scientific quality of review s ( 7 , 8) . We sought to describe the methods used in recently published review articles and determine whether the attention paid to the method ologic shortcomings of review articles has led to improvements in their scientific quality . Methods By using the Science Citation Index ( 9 ) , we stratified the 12 general medicine journals that are considered core journals for ACP Journal Club ( 10 ) into those with high impact factors ( scores 5 ) and those with lower impact factors . We r and omly selected 3 ( The New Engl and Journal of Medicine , Annals of Internal Medicine , and JAMA ) of the 4 high-impact core journals and 3 ( British Medical Journal , American Journal of Medicine , and Journal of Internal Medicine ) of the 8 core journals with lower impact factors . The sampling frame included 3 of the 4 journals examined in Mulrow 's original study ( 4 ) . All 6 journals were h and - search ed by two of the investigators independently , and review articles published between January and December 1996 were retrieved . Review articles were defined as full-text articles published under the banner review that dealt with disease states ; had the words review , overview , or meta- analysis in the title or abstract ; or indicated in the text that the intention was to review or summarize the literature about a clinical topic . Editorials , correspondence , and conference summaries were excluded . Disagreements on article eligibility ( which occurred in five cases ) were resolved by consensus . After training with a test set of articles , five of the authors used explicit criteria ( Appendix Table ) to rate the identified review articles . So that the raters ' assessment s would be blinded , the articles ' authors , author affiliations , and sources of articles were masked . The first 10 criteria in the Appendix Table ( hereafter referred to as method ologic criteria ) have been previously vali date d ( 7 ) and assess method ologic rigor , whereas the last five criteria were developed for this study to evaluate the scientific basis of treatment recommendations . Because inter-rater agreement was excellent on the test set ( overall agreement , 94 % ) , each rater was assigned a r and om sample of 20 % of the articles . One rater independently evaluated a r and om sample of five articles from each rater to assess inter-rater reliability for the criteria . The mean value was 0.79 , indicating substantial agreement ; overall agreement was 95 % and ranged from 84 % for criteria 1 and 6 to 100 % for criteria 2 , 3 , and 5 . After we determined the number of criteria fulfilled by each article , the number of articles meeting each criterion was ascertained . The proportion of review s from high-impact journals and from lower-impact journals that met each criterion were compared . Only the subset of review s containing treatment recommendations were used for the comparisons for criteria 7 to 15 . The chi-square test was used and 95 % CIs for the observed differences were calculated for all comparisons . In addition , articles identified as meta-analyses , systematic review s , or overviews in their title , abstract , or text were compared with the remaining review articles for each criterion ( again by using the chi-square test and by limiting analysis to those that included treatment recommendations for criteria 7 to 15 ) . Logistic regression analysis was used to adjust for journal of publication . The funding organizations were not involved in the design , conduct , analysis , or reporting of this study . Results A total of 158 review articles were identified : 60 from The New Engl and Journal of Medicine , 33 from Annals of Internal Medicine , 24 from British Medical Journal , 18 from American Journal of Medicine , 13 from JAMA , and 10 from Journal of Internal Medicine . ( A full list of the included articles is available from Dr. McAlister on request . ) Most review s were written by more than one author ( median number of authors , 2 [ range , 1 to 10 authors ] ) , and 111 review s ( 70 % ) made treatment recommendations . Although most articles had sections review ing the relevant pathophysiology and pharmacodynamics , 19 articles ( 12 % ) were largely basic science review s. Only 2 review s met all 10 method ologic criteria ; the median number of criteria fulfilled was one ( Figure ) . Nineteen ( 12 % ) of the review articles were described as meta- analysis , systematic review , or overview in the title or abstract ; 12 of these 19 articles were published in high-impact journals . A higher proportion of these articles met the method ologic criteria ( Appendix Table ) ; the comparisons for all but criterion 6 were statistically significant , even after adjustment for journal of publication ( P<0.005 for all comparisons ) . Although there was significant heterogeneity among journals ( P<0.005 for criteria 1 to 5 , 7 , and 8) , review articles published in high-impact journals did not meet method ologic criteria more frequently than those published in other journals ( Table ) . Exclusion of the review s from one journal with method ologic scores that were significantly lower than the rest ( P<0.001 for all comparisons ) resolved much of the interjournal heterogeneity and revealed that review s published in the remaining high-impact journals more often met some ( but not all ) of the method ologic criteria ( Table ) . Figure . Percentage of 158 review articles published in 1996 that fulfilled specific method ologic criteria . Table . Comparison of Methods Used in 1996 Review Articles , by Journal Impact Factor The 44 articles that described how evidence was located used the following sources ( which were not mutually exclusive ) : MEDLINE ( 42 articles ) , h and search of reference lists from published studies or review articles ( 30 articles ) , other electronic data bases ( 14 articles ) , contact with experts in the field ( 10 articles ) , h and search of relevant journals ( 7 articles ) , and contact with the pharmaceutical industry ( 5 articles ) . Of the 22 review s that included a description of the electronic search strategy , the search was restricted to English- language publications in 11 . Of the 111 review s in which treatment recommendations were made , a median of 3 therapies ( range , 1 to 23 therapies ) were discussed . The 16 meta-analyses that included treatment recommendations were more focused , examining a median of 1 therapy ( range , 1 to 6 therapies ) . The scientific basis of these recommendations is outlined in the last five criteria of the Appendix Table . Discussion In summary , only a minority of the review articles published in six widely read general medical journals specified rigorous , systematic methods of identifying , evaluating , and synthesizing the evidence , thereby raising concerns about the validity of their conclusions and recommendations ( 11 ) . Furthermore , although most review articles made recommendations for therapeutic options , their clinical relevance may be limited : Only one third discussed benefits and harms of the treatment options , only 6 % mentioned the relative or absolute costs of the various options , less than half provided an estimate of the anticipated treatment effect , and very few presented the results in clinical ly relevant formats that would be easily understood by clinicians . Although there is still substantial room for improvement , these results do represent progress from the situation in 1985 - 1986 ( Appendix Table ) . A higher proportion of recently published review s specify how the evidence was identified and synthesized . This same pattern was observed in a recent study of oncology review articles published in a single journal between 1983 and 1995 ( 12 ) . Similarly , our findings for meta-analyses published in these journals in 1996 are consistent with contemporaneous investigations in other fields and represent substantial improvement over the state of affairs in the mid-1980s ( 13 , 14 ) . Our study had several potential limitations . First , the authors of articles in which systematic methods were not specified may have used such methods but not reported them ( or the journal may have removed the details of the methods in prepublication ) . However , preliminary evidence suggests that there is little difference between the conduct of studies and their published methods ( 7 , 15 ) . In other words , if what was done is not reported , there is a good chance that it was not done rigorously ( 7 ) . Second , our finding that meta-analyses are more scientifically rigorous than other review s may be seen as tautological because the criteria used in this study may be used by meta-analysts in performing their studies . However , meta-analysts disagree over some issues of methodology , and published meta-analyses often vary in the quality of their reports ( 13 ) . Third , the practical importance of the method ologic flaws identified in these review s is difficult to ascertain . We lack empirical evidence that review s with explicit , systematic methods yield results closer to the truth , but it is known that non systematic review s are more prone to r and om and Objectives To address whether nondihydropyridine calcium-channel blocker added-on angiotensin-converting-enzyme inhibitor therapy ameliorates albuminuria and cardiovascular outcomes in type 2 diabetes patients . Design The Bergamo Nephrologic Diabetes Complications Trial-B was a multicentre , prospect i ve , double-blind , parallel-group trial comparing renal and cardiovascular outcomes in 281 hypertensive type 2 diabetes patients with microalbuminuria r and omized to at least 2-year VeraTran ( verapamil/tr and olapril 180 mg/2 mg daily ) or tr and olapril ( 2 mg daily , identical image ) treatment . Main outcome was persistent macroalbuminuria ( albuminuria > 200 μg/min in two consecutive visits ) . Treatment targets were SBP/DBP less than 120/80 mmHg and HbA1C less than 7 % . Results Over a median follow-up of 4.5 years , 18 patients ( 13 % ) on VeraTran vs. 15 ( 10.5 % ) on tr and olapril [ unadjusted hazard ratio ( 95 % confidence interval [ CI ] ) 1.07 ( 0.54–2.12 ) , P = 0.852 ] progressed to macroalbuminuria , respectively ; 62 ( 44.9 % ) vs. 71 ( 49.7 % ) [ 0.80 ( 0.57–1.12 ) , P = 0.198 ] regressed to normoalbuminuria ( urinary albumin excretion < 20 μg/min ) , and 20 ( 14.5 % ) vs. 21 ( 14.7 % ) [ hazard ratio 0.93 ( 0.50–1.72 ) , P = 0.816 ] had major cardiovascular events . BP and metabolic control were similar between groups . Patients with cardiovascular events were significantly less [ 13 ( 9.8 % ) vs. 28 ( 18.9 % ) , hazard ratio : 0.37 ( 0.19–0.71 ) , P = 0.003 ] among those regressing to normoalbuminuria than those without regression . Difference was independent of treatment allocation and was significant also after adjusting for baseline characteristics [ 0.40 ( 0.20–0.79 ) , P = 0.009 ] , follow-up SBP [ 0.40 ( 0.20–0.80 ) , P = 0.010 ] or DBP [ 0.36 ( 0.18–0.73 ) , P = 0.004 ] BP or HbA1C [ 0.43 ( 0.21–0.88 ) , P = 0.021 ] . Conclusion In hypertensive type 2 diabetes patients with microalbuminuria , verapamil added-on tr and olapril did not improve renal or cardiovascular outcomes . Independent of verapamil , tr and olapril normalized albuminuria in half of patients and this translated into significant cardioprotection AIMS The aim of this study was to assess the effect of the angiotensin converting enzyme inhibitor perindopril on cardiovascular events in diabetic patients with coronary artery disease . METHODS AND RESULTS A total of 1502 diabetic patients with known coronary artery disease and without heart failure of 12 218 overall in the EUropean trial on Reduction Of cardiac events with Perindopril  in stable coronary Artery ( EUROPA ) disease were r and omized in a double-blinded manner to perindopril 8 mg once daily or placebo . Follow-up was for a median of 4.3 years . The primary end point was cardiovascular death , non-fatal myocardial infa rct ion , and resuscitated cardiac arrest .  Perindopril treatment was associated with a non-significant reduction in the primary endpoint in the diabetic population , 12.6 vs. 15.5 % , relative risk reduction 19 % [ ( 95 % CI , -7 to 38 % ) , P=0.13 ] . This was of similar relative magnitude to the 20 % risk reduction observed in the main EUROPA population . CONCLUSION Perindopril tends to reduce major cardiovascular events in diabetic patients with coronary disease in addition to other preventive treatments and the trend towards reduction was of a similar relative magnitude to that observed the general population with coronary artery disease BACKGROUND Although several important studies have been performed in hypertensive type 2 diabetic patients , it is not known whether lowering blood pressure in normotensive ( BP < 140/90 mm Hg ) patients offers any beneficial results on vascular complications . The current study evaluated the effect of intensive versus moderate diastolic blood pressure ( DBP ) control on diabetic vascular complications in 480 normotensive type 2 diabetic patients . METHODS The current study was a prospect i ve , r and omized controlled trial in normotensive type 2 diabetic subjects . The subjects were r and omized to intensive ( 10 mm Hg below the baseline DBP ) versus moderate ( 80 to 89 mm Hg ) DBP control . Patients in the moderate therapy group were given placebo , while the patients r and omized to intensive therapy received either nisoldipine or enalapril in a blinded manner as the initial antihypertensive medication . The primary end point evaluated was the change in creatinine clearance with the secondary endpoints consisting of change in urinary albumin excretion , progression of retinopathy and neuropathy and the incidence of cardiovascular disease . RESULTS The mean follow-up was 5.3 years . Mean BP in the intensive group was 128 + /- 0.8/75 + /- 0.3 mm Hg versus 137 + /- 0.7/81 + /- 0.3 mm Hg in the moderate group , P < 0.0001 . Although no difference was demonstrated in creatinine clearance ( P = 0.43 ) , a lower percentage of patients in the intensive group progressed from normoalbuminuria to microalbuminuria ( P = 0.012 ) and microalbuminuria to overt albuminuria ( P = 0.028 ) . The intensive BP control group also demonstrated less progression of diabetic retinopathy ( P = 0.019 ) and a lower incidence of strokes ( P = 0.03 ) . The results were the same whether enalapril or nisoldipine was used as the initial antihypertensive agent . CONCLUSION Over a five-year follow-up period , intensive ( approximately 128/75 mm Hg ) BP control in normotensive type 2 diabetic patients : ( 1 ) slowed the progression to incipient and overt diabetic nephropathy ; ( 2 ) decreased the progression of diabetic retinopathy ; and ( 3 ) diminished the incidence of stroke BACKGROUND Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently . We studied the effect of an angiotensin-converting-enzyme inhibitor , enalapril , on mortality and hospitalization in patients with chronic heart failure and ejection fractions less than or equal to 0.35 . METHODS Patients receiving conventional treatment for heart failure were r and omly assigned to receive either placebo ( n = 1284 ) or enalapril ( n = 1285 ) at doses of 2.5 to 20 mg per day in a double-bind trial . Approximately 90 percent of the patients were in New York Heart Association functional classes II and III . The follow-up averaged 41.4 months . RESULTS There were 510 deaths in the placebo group ( 39.7 percent ) , as compared with 452 in the enalapril group ( 35.2 percent ) ( reduction in risk , 16 percent ; 95 percent confidence interval , 5 to 26 percent ; P = 0.0036 ) . Although reductions in mortality were observed in several categories of cardiac deaths , the largest reduction occurred among the deaths attributed to progressive heart failure ( 251 in the placebo group vs. 209 in the enalapril group ; reduction in risk , 22 percent ; 95 percent confidence interval , 6 to 35 percent ) . There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure . Fewer patients died or were hospitalized for worsening heart failure ( 736 in the placebo group and 613 in the enalapril group ; risk reduction , 26 percent ; 95 percent confidence interval , 18 to 34 percent ; P less than 0.0001 ) . CONCLUSIONS The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions Background Recent trials question previously accepted low blood pressure targets in type 2 diabetes to reduce complication risk . We explored this question in the DIabetic REtinopathy C and esartan Trials-Protect 2 clinical trial . Methods A total of 1905 normoalbuminuric participants with type 2 diabetes and mild-moderate retinopathy were r and omized to c and esartan or placebo .  Participants were normotensive [ untreated , blood pressure ( BP ) < 130/85 mmHg ] or treated hypertensive [ ( 62 % ) , BP < 160/90 mmHg ] . The effects of c and esartan on microvascular and macrovascular endpoints alone and in combination were analysed , including subgroup analyses by baseline hypertension status . Results Mean age was 57 ± 8 years , 50 % were men , mean diabetes duration was 9 ± 5 years and baseline HbA1c was 8.2 ± 1.6 % . Mean r and omization BP was 123/75 mmHg in the normotensive , and 139/79 mmHg in the treated hypertensive subgroups . During the median 4.7-year follow-up , achieved systolic pressure on c and esartan was 128 mmHg in baseline normotensive individuals , and 136 mmHg in treated hypertensive patients . C and esartan reduced combined macrovascular and microvascular complication risk ; the age and baseline SBP overall adjusted hazard ratio for c and esartan vs. placebo was 0.85 [ 95 % confidence interval ( CI ) 0.72–0.99 ] , P = 0.040 , reflecting hazard ratios of 0.86 ( 0.66–1.13 ) for baseline normotensive individuals and 0.83 ( 0.68–1.02 ) for hypertensive patients . Hazard ratios were 0.87 ( 0.74–1.04 ) for microvascular and 0.84 ( 0.57–1.25 ) for macrovascular complications , when analysed separately . However , an interaction ( P = 0.06 ) between hypertensive [ hazard ratio 0.67 ( 0.42–1.07 ) ] and normotensive ( 1.45 , 0.71–2.94 ) subgroups was observed for macrovascular events . Conclusion C and esartan modestly reduces vascular complication risk in treated hypertensive diabetic individuals at low risk of cardiovascular disease . Separate analyses of microvascular and macrovascular events suggest that c and esartan may not reduce macrovascular events in normotensive persons with type 2 diabetes . Clinical trial registration : http:// clinical trials.gov/ct2/show/NCT00252694 BACKGROUND There is no evidence from r and omized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus . We investigated whether therapy targeting normal systolic pressure ( i.e. , < 120 mm Hg ) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events . METHODS A total of 4733 participants with type 2 diabetes were r and omly assigned to intensive therapy , targeting a systolic pressure of less than 120 mm Hg , or st and ard therapy , targeting a systolic pressure of less than 140 mm Hg . The primary composite outcome was nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The mean follow-up was 4.7 years . RESULTS After 1 year , the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the st and ard-therapy group . The annual rate of the primary outcome was 1.87 % in the intensive-therapy group and 2.09 % in the st and ard-therapy group ( hazard ratio with intensive therapy , 0.88 ; 95 % confidence interval [ CI ] , 0.73 to 1.06 ; P=0.20 ) . The annual rates of death from any cause were 1.28 % and 1.19 % in the two groups , respectively ( hazard ratio , 1.07 ; 95 % CI , 0.85 to 1.35 ; P=0.55 ) . The annual rates of stroke , a prespecified secondary outcome , were 0.32 % and 0.53 % in the two groups , respectively ( hazard ratio , 0.59 ; 95 % CI , 0.39 to 0.89 ; P=0.01 ) . Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group ( 3.3 % ) and 30 of the 2371 participants in the st and ard-therapy group ( 1.3 % ) ( P<0.001 ) . CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events , targeting a systolic blood pressure of less than 120 mm Hg , as compared with less than 140 mm Hg , did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events . ( Clinical Trials.gov number , NCT00000620 . is well recognized that hypertensives are especially prone to clinical manifestations of atherosclerosis in general and to coronary heart disease ( CHD ) in particular . Prospect i ve epidemiologic investigation of the circumstances under which CHD evolves in hypertensives compared to their more normotensive cohorts has revealed a number of misconceptions concerning the nature of the relationship of blood pressure to atherosclerotic vascular disease . This report is concerned with a detailed examination of the relationship of  blood pressure  to the development of the various clinical manifestations of CHD  in each sex at varying ages . The IMPORTANCE Hypertension is the most important preventable cause of morbidity and mortality globally , yet there are relatively few data collected using st and ardized methods . OBJECTIVE To examine hypertension prevalence , awareness , treatment , and control in participants at baseline in the Prospect i ve Urban Rural Epidemiology ( PURE ) study . DESIGN , SETTING , AND PARTICIPANTS A cross-sectional study of 153,996 adults ( complete data for this analysis on 142,042 ) aged 35 to 70 years , recruited between January 2003 and December 2009 . Participants were from 628 communities in 3 high-income countries ( HIC ) , 10 upper-middle-income and low-middle-income countries ( UMIC and LMIC ) , and 4 low-income countries ( LIC ) . MAIN OUTCOMES AND MEASURES Hypertension was defined as individuals with self-reported treated hypertension  or with an average of 2 blood pressure measurements of at least 140/90 mm Hg using an automated digital device . Awareness was based on self-reports , treatment was based on the regular use of blood pressure-lowering medications , and control was defined as individuals with blood pressure lower than 140/90 mm Hg . RESULTS Among the 142,042 participants , 57,840 ( 40.8 % ; 95 % CI , 40.5%-41.0 % ) had hypertension and 26,877 ( 46.5 % ; 95 % CI , 46.1%-46.9 % ) were aware of the diagnosis . Of those who were aware of the diagnosis , the majority ( 23,510 [ 87.5 % ; 95 % CI , 87.1%-87.9 % ] of those who were aware ) were receiving pharmacological treatments , but only a minority of those receiving treatment were controlled ( 7634 [ 32.5 % ; 95 % CI , 31.9%-33.1 % ] ) . Overall , 30.8 % , 95 % CI , 30.2%-31.4 % of treated patients were taking 2 or more types of blood pressure-lowering medications . The percentages aware ( 49.0 % [ 95 % CI , 47.8%-50.3 % ] in HICs , 52.5 % [ 95 % CI , 51.8%-53.2 % ] in UMICs , 43.6 % [ 95 % CI , 42.9%-44.2 % ] in LMICs , and 40.8 % [ 95 % CI , 39.9%-41.8 % ] in LICs ) and treated ( 46.7 % [ 95 % CI , 45.5%-47.9 % ] in HICs , 48.3 % , [ 95 % CI , 47.6%-49.1 % ] in UMICs , 36.9 % , [ 95 % CI , 36.3%-37.6 % ] in LMICs , and 31.7 % [ 95 % CI , 30.8%-32.6 % ] in LICs ) were lower in LICs compared with all other countries for awareness ( P < .001 ) and treatment ( P < .001 ) . Awareness , treatment , and control of hypertension were higher in urban communities compared with rural ones in LICs ( urban vs rural , P < .001 ) and LMICs ( urban vs rural , P < .001 ) , but similar for other countries . Low education was associated with lower rates of awareness , treatment , and control in LICs , but not in other countries . CONCLUSIONS AND RELEVANCE Among a multinational study population , 46.5 % of participants with hypertension were aware of the diagnosis , with blood pressure control among 32.5 % of those being treated . These findings suggest substantial room for improvement in hypertension diagnosis and treatment The Study on COgnition and Prognosis in the Elderly ( SCOPE ) assessed the effect of c and esartan on cardiovascular outcomes in elderly patients with mild to moderate hypertension . Patients were r and omized to c and esartan 8–16 mg daily ( n = 2477 ) or placebo ( n = 2460 ) . Due to extensive add‐on therapy , blood pressure reduction was only about 3/2 mmHg greater in the c and esartan group than in the control group . Nevertheless , non‐fatal stroke was reduced by 28 % ( p = 0.04 ) in the c and esartan group compared to the control group , and there was a non‐significant 11 % reduction in major cardiovascular events ( p = 0.19 ) . This report provides results in pre‐specified subgroups of patients ( age , gender , diabetes , history of stroke , smoking and cardiovascular risk at r and omization ) . Reductions in major cardiovascular events and stroke  with c and esartan‐based therapy were indicated in all subgroups . A significant interaction between treatment and subgroups was found for one pair of subgroups only ; the reduction in major cardiovascular events with c and esartan  was greater in patients with a previous stroke ( 64 % reduction , p = 0.004 ) than in those without ( 5 % reduction , p>0.20 ) . In conclusion , this analysis indicates consistent favourable effects of c and esartan‐based  therapy on major cardiovascular events and stroke across the different subgroups of patients . However , the benefit was particularly pronounced in patients who entered the study with a previous stroke OBJECTIVE To assess if low ( 1.25 mg ) and /or st and ard ( 5 mg ) doses of the ACE inhibitor ramipril could prevent progression of microalbuminuria ( incipient diabetic nephropathy ) in normotensive type 1 diabetic patients . RESEARCH DESIGN AND METHODS This study , using a multicenter r and omized placebo-controlled double-blind parallel group , was conducted over 2 years in 28 outpatient diabetic clinics in the U.K. and Irel and . We screened 334 type 1 diabetic patients with suspected microalbuminuria and normal blood pressure ; of these , 140 patients 18 - 65 years of age with a diagnosis of type 1 diabetes and persistent microalbuminuria , defined as urinary albumin excretion rate ( AER ) of 20 - 200 microg/min , were enrolled in the study . RESULTS The proportion of patients progressing to macroalbuminuria was reduced in the ramipril groups but did not reach statistical significance over 2 years . AER was significantly lower at year 2 in the combined ramipril-treated patients versus placebo ( P = 0.013 ) . More patients on ramipril regressed to normoalbuminuria ( < 20 microg/min ) , with 11 % for 1.25 mg ramipril , 20 % for 5 mg ramipril , and 4 % for placebo ( P = 0.053 ) . Blood pressure was significantly reduced to a similar extent with both 1.25 and 5 mg ramipril . Supine systolic blood pressure increased from 130 to 134 mmHg in the placebo group and fell in the 1.25 mg ramipril group ( from 132 to 129 mmHg ) and in the 5 mg ramipril group ( from 134 to 130 mmHg ) ( P = 0.003 , compared with placebo ) . No statistically significant changes were observed in glomerular filtration rate ( GFR ) between the placebo- and ramipril-treated groups during the 2-year period . CONCLUSIONS Microalbuminuria is reduced significantly by ramipril treatment in type 1 diabetic patients without hypertension . Although the magnitude of the response was greater , there is no significant difference between responses to 1.25 or 5 mg ramipril . Small but highly significant reductions in systolic and mean arterial pressures occur in ramipril-treated patients . GFR is stable at this stage of the evolution of diabetic nephropathy and is unaffected by ramipril treatment for 2 years Summary The latter was due to a reduction in cardiac mortality ( −38 % , p=0.036 ) and a nonsignificant decrease in cerebrovascular mortality ( −32 % , p=0.16 ) . In the double-blind part of the trial , the total mortality rate was not significantly reduced ( −26 % , p=0.077 ) . However , cardiovascular mortality was reduced in the actively treated group ( −38 % , p=0.023 ) , owing to a reduction in cardiac deaths ( −47 % , p=0.048 ) and a non-significant decrease in cerebrovascular mortality ( −43 % , p=0.15 ) . Deaths from myocardial infa rct ion were reduced ( −60 % , p=0.043 ) , and study -terminating morbid cardiovascular events were significantly reduced by active treatment ( −60 % , p=0.0064 ) . Non-terminating cerebrovascular events were reduced ( −52 % , p=0.026 ) , but the non-terminating cardiac events were not ( + 3 % , p=0.98 ) . In the patients r and omised to active treatment there were 29 fewer cardiovascular events and 14 fewer cardiovascular deaths per 1000 patient years during the double-blind part of the trial . A double-blind r and omised placebo-controlled trial of antihypertensive treatment was conducted in patients over the age of 60 . Entry criteria included both a sitting diastolic blood pressure on placebo treatment in the range 90 to 119 mm Hg and a systolic pressure in the range 160 to 239 mm Eg . 840 patients were r and omised either to active treatment ( hydrochlorothiazide and triamterene ) or to  matching placebo  . If the blood pressure remained raised , methyldopa was added to the active regimen and matching placebo in the placebo group . An overall intention-to-treat analysis , combining the double-blind part of the trial and all subsequent follow-up , revealed a non-significant change in total mortality rate ( −9 % , p=0.41 ) but a significant reduction in cardiovascular mortality rate ( −27 % , p=0.037 ) BACKGROUND Left ventricular dilatation and dysfunction after myocardial infa rct ion are major predictors of death . In experimental and clinical studies , longterm therapy with the angiotensin-converting -- enzyme inhibitor captopril attenuated ventricular dilatation and remodeling . We investigated whether captopril could reduce morbidity and mortality in patients with left ventricular dysfunction after a myocardial infa rct ion . METHODS Within 3 to 16 days after myocardial infa rct ion , 2231 patients with ejection fractions of 40 percent or less but without overt heart failure or symptoms of myocardial ischemia were r and omly assigned to receive doubleblind treatment with either placebo ( 1116 patients ) or captopril ( 1115 patients ) and were followed for an average of 42 months . RESULTS Mortality from all causes was significantly reduced in the captopril group ( 228 deaths , or 20 percent ) as compared with the placebo group ( 275 deaths , or 25 percent ) ; the reduction in risk was 19 percent ( 95 percent confidence interval , 3 to 32 percent ; P = 0.019 ) . In addition , the incidence of both fatal and nonfatal major cardiovascular events was consistently reduced in the captopril group . The reduction in risk was 21 percent ( 95 percent confidence interval , 5 to 35 percent ; P = 0.014 ) for death from cardiovascular causes , 37 percent ( 95 percent confidence interval , 20 to 50 percent ; P less than 0.001 ) for the development of severe heart failure , 22 percent ( 95 percent confidence interval , 4 to 37 percent ; P = 0.019 ) for congestive heart failure requiring hospitalization , and 25 percent ( 95 percent confidence interval , 5 to 40 percent ; P = 0.015 ) for recurrent myocardial infa rct ion . CONCLUSIONS In patients with asymptomatic left ventricular dysfunction after myocardial infa rct ion , long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events . These benefits were observed in patients who received thrombolytic therapy , aspirin , or beta-blockers , as well as those who did not , suggesting that treatment with captopril leads to additional improvement in outcome among selected survivors of myocardial infa rct ion Background : The Reduction in ENdpoints with the Angiotensin Antagonist Losartan ( RENAAL ) study reported that losartan delayed the progression of renal disease in patients with type 2 diabetes and nephropathy . Diabetic or renally impaired patients are at high cardiovascular risk , a risk potentially increased in patients with both conditions At the end of a long week in the office , you sink back into your chair , reflecting on some of the more memorable patients you cared for and counseled . Through gentle history taking , you discovered that urinary incontinence is the underlying cause of an elderly patient 's increasing social isolation . During a careful physical examination , you detected bruising on the torso of a woman with chronic headaches and began to explore the longst and ing abusive relationship between the woman and her alcoholic partner . You discontinued procainamide therapy in a 72-year-old man who had asymptomatic premature ventricular contractions after myocardial infa rct ion . To prevent bleeding from esophageal varices , you started -blocker therapy in a woman with long-st and ing cryptogenic cirrhosis and portal hypertension . In couples ' therapy , discussing the future quality of life of a middle-aged gay man with human immunodeficiency virus infection , you journeyed through emotionally intense dialogue about advance directives . You presented the risk factors for major and minor bleeding to a 39-year-old woman who was considering warfarin therapy because of recently diagnosed atrial fibrillation and valvular heart disease . You listened to , made diagnoses for , treated , advised , and comforted many patients . Yet there were some hiccoughs in your practice along the way . You stumbled while debating the pros and cons of breast cancer screening with a healthy 48-year-old woman who has been staying current with information on the Internet . You question ed the merits of a personalized walking program suggested to you by a motivated 66-year-old man with severe claudication . Explaining that you wanted to review the best current evidence on these issues , you resolved to address your uncertainties before these patients made their next office visits , in a week 's time . Sighing deeply , you acknowledge that you have little time to read . You subscribe to three journals , which you browse months after they arrive-either when your journal stack becomes precariously high or when your guilt is sufficiently motivational . You sometimes find the conclusions of individual articles conflicting or confusing . You know that some of the decisions and suggestions you made this week , specifically your decisions about stopping procainamide therapy and starting -blocker therapy and your advice about bleeding risks from anticoagulant therapy , were based on the best current research evidence [ 1 - 3 ] . On the other h and , your patients ' inquiries about breast cancer screening and exercise treatment for claudication highlight your need for a concise , current , rigorous synthesis of the best available evidence on each of these topics : in brief , a systematic review [ 4 , 5 ] . Incorporating Research Evidence into Clinical Decision Making The foregoing scenario is familiar to practitioners . In a typical week , we encounter patients with diverse problems ; exercise numerous clinical , interpersonal , and technical skills ; and make many decisions . The factors that affect these decisions and their outcomes are complex . For instance , each patient has unique sociodemographic characteristics , cultural circumstances , and personal preferences . Each physician has unique knowledge , experiences , and values . Moreover , practitioners and their patients make decisions within the context of a rapidly changing health care system that influences the availability , accessibility , and cost of diagnostic tests and therapies [ 6 ] . Timely , useful evidence from the biomedical literature should be an integral component of clinical decision making . If one treatment has been shown to be better than another , we need to know , so that we can recommend the treatment to the appropriate patients . The worldwide effort to develop new tests and treatments , and to determine their usefulness , has never been stronger , and our patients and their families expect us to be fonts of the knowledge that results from this effort [ 7 ] . Unfortunately , it is easy for current best research evidence to pass us by [ 8 ] . We may lack the time , motivation , and basic skills needed to find , critically appraise , and synthesize information , all of which we must do if we are to integrate the results of original studies into our practice . Fortunately , several potent methods are emerging that can greatly enhance our ability to interpret and apply research evidence ; foremost among them is the systematic review . This article begins a series in Annals that will examine systematic review s in detail and explore their many applications . Systematic review s represent the best chance that most practitioners will have to underst and and accurately apply the key signals arising from the robust and increasingly productive search for solutions to medical problems . A properly conducted systematic review faithfully summarizes the evidence from all relevant studies on the topic of interest , and it does so concisely and transparently . What Is a Systematic Review ? Systematic review s are scientific investigations in themselves , with pre-planned methods and an assembly of original studies as their subjects . They synthesize the results of multiple primary investigations by using strategies that limit bias and r and om error [ 9 , 10 ] . These strategies include a comprehensive search of all potentially relevant articles and the use of explicit , reproducible criteria in the selection of articles for review . Primary research design s and study characteristics are appraised , data are synthesized , and results are interpreted . When the results of primary studies are summarized but not statistically combined , the review may be called a qualitative systematic review . A quantitative systematic review , or meta- analysis , is a systematic review that uses statistical methods to combine the results of two or more studies . The term overview is sometimes used to denote a systematic review , whether quantitative or qualitative . Summaries of research that lack explicit descriptions of systematic methods are often called narrative review s. Review articles are one type of integrative publication ; practice guidelines , economic evaluations , and clinical decision analyses are others . These other types of integrative articles often incorporate the results of systematic review s. For example , practice guidelines are systematic ally developed statements intended to assist practitioners and patients with decisions about appropriate health care for specific clinical circumstances [ 11 ] . Evidence -based practice guidelines are based on systematic review s of the literature , appropriately adapted to local circumstances and values . Economic evaluations compare both the costs and the consequences of different courses of action ; the knowledge of consequences that are considered in these evaluations is often generated by systematic review s of primary studies . Decision analyses quantify both the likelihood and the valuation of the expected outcomes associated with competing alternatives . Differences between Systematic and Narrative Review s All review s , narrative and systematic alike , are retrospective , observational research studies and are therefore subject to systematic and r and om error . Accordingly , the quality of a review - and thus its worth-depends on the extent to which scientific review methods have been used to minimize error and bias . This is the key feature that distinguishes traditional narrative review s from systematic review s ( Table 1 ) . If a review is prepared according to the steps outlined in the right column of Table 1 , it is more likely to be systematic and to provide unbiased conclusions . If review methods approximate those found in the middle column of Table 1 , the article is more likely to be a narrative review , and the conclusions are less likely to be based on an unbiased summary of all relevant evidence . Table 1 . Differences between Narrative Review s and Systematic Review s Systematic review s are generated to answer specific , often narrow , clinical questions in depth . These questions can be formulated explicitly according to four variables : a specific population and setting ( such as elderly out patients ) , the condition of interest ( for example , hypertension ) , an exposure to a test or treatment ( such as pharmacologic management ) , and one or more specific outcomes ( such as cardiovascular and cerebrovascular events and mortality ) [ 12 ] . Thus , an example of a well-formulated , clinical ly relevant question is , Does pharmacologic treatment of hypertension in the elderly prevent strokes and myocardial infa rct ions or delay death ? If the question that is driving the review is not clear from the title , abstract , or introduction , or if no methods section is included , the paper is more likely to be a narrative review than a systematic review [ 13 ] . Most narrative review articles deal with a broad range of issues related to a given topic rather than addressing a particular issue in depth [ 9 ] . For example , a narrative review on diabetes ( such as that which might be found in a textbook chapter ) might include sections on the physiology and pathophysiology of carbohydrate , lipid , and protein metabolism ; the epidemiology of and prognosis associated with diabetes ; diagnostic and screening approaches ; and preventive , therapeutic , rehabilitative , and palliative interventions . Thus , narrative review s may be most useful for obtaining a broad perspective on a topic ; they are less often useful in furnishing quantitative answers to specific clinical questions . Narrative review s are appropriate for describing the history or development of a problem and its management . Narrative review s may better describe cutting-edge developments if research is scant or preliminary or if studies are very limited by flawed design or execution [ 13 ] . They may be particularly useful for discussing data in light of underlying theory and context . Narrative review s can draw analogies and can conceptually integrate two independent fields of research , such as BACKGROUND The aim of this study is to compare the long-term effect of amlodipine and fosinopril in monotherapy or in combination on urinary albumin excretion ( UAE ) in hypertensive diabetic patients . METHODS We selected 453 hypertensive patients with type 2 diabetes and microalbuminuria and r and omized them to amlodipine ( 5 to 15 mg/day ) , fosinopril ( 10 to 30 mg/day ) , or amlodipine plus fosinopril ( 5/10 to 15/30 mg/day ) for a 3-month titration period . The nonresponder patients or those complaining of side effects during the titration period were discontinued ( n = 144 ) ; the remaining 309 patients were enrolled in the trial and treated with the same therapy for 4 years . Every 6 months , blood pressure ( BP ) , heart rate ( HR ) , UAE , creatinine clearance , and glycosylated hemoglobin ( HbA1c ) were evaluated . RESULTS The combination therapy was more effective in reducing BP than either drug alone at any time of the study without affecting glucose homeostasis . All three treatments provided a significant decrease in UAE during the 48-month study period . However , this effect was more pronounced and became evident earlier with fosinopril than with amlodipine monotherapy ( after 3 v 18 months of therapy ) . In addition , the combination therapy provided a greater antialbuminuric effect than the single drugs . This could be due to the greater antihypertensive effects , although other drug-specific effects can not be excluded . The cardiovascular outcomes were similar in the amlodipine and in the fosinopril group , but they were lower in the combination group . CONCLUSIONS These results strengthen the rationale to use a calcium-antagonist/angiotensin converting enzyme inhibitor combination in the treatment of hypertensive patients with type 2 diabetes BACKGROUND The objective of the current study was to examine the efficacy and tolerability of the beta-blocker metoprolol succinate controlled release/extended release ( CR/XL ) in patients with diabetes in the Metoprolol CR/XL R and omized Intervention Trial in Chronic Heart Failure ( MERIT-HF ) . METHODS The Cox proportional hazards model was used to calculate hazard ratios ( HR ) for convenience expressed as relative risks ( risk reduction = 1-HR ) , and 95 % confidence intervals ( CI ) . RESULTS The risk of hospitalization for heart failure was 76 % higher in diabetics compared to non-diabetics ( 95 % CI 38 % to 123 % ) . Metoprolol CR/XL was well tolerated and reduced the risk of hospitalization for heart failure by 37 % in the diabetic group ( 95 % CI 53 % to 15 % ) , and by 35 % in the non-diabetic group ( 95 % CI 48 % to 19 % ) . Pooling of mortality data from the Cardiac Insufficiency Bisoprolol Study II ( CIBIS II ) , MERIT-HF , and the Carvedilol Prospect i ve R and omized Cumulative Survival Study ( COPERNICUS ) showed similar survival benefits in patients with diabetes ( 25 % ; 95 % CI 40 % to 4 % ) and without diabetes ( 36 % ; 95 % CI 44 % to 27 % ) ; test of diabetes by treatment interaction was non-significant . Adverse events were reported more often on placebo than on metoprolol CR/XL . CONCLUSIONS Patients with heart failure and diabetes have a much higher risk of hospitalization than patients without diabetes . Regardless of diabetic status , a highly significant reduction in hospitalizations for heart failure was observed with metoprolol CR/XL therapy , which was very well tolerated also by patients with diabetes . Furthermore , the pooled data showed a statistically significant survival benefit in patients with diabetes BACKGROUND Diabetic nephropathy is the leading cause of end-stage renal disease . Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes , but similar data are not available for patients with type 2 , the most common form of diabetes . We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy . METHODS A total of 1513 patients were enrolled in this r and omized , double-blind study comparing losartan ( 50 to 100 mg once daily ) with placebo , both taken in addition to conventional antihypertensive treatment ( calcium-channel antagonists , diuretics , alpha-blockers , beta-blockers , and central ly acting agents ) , for a mean of 3.4 years . The primary outcome was the composite of a doubling of the base-line serum creatinine concentration , end-stage renal disease , or death . Secondary end points included a composite of morbidity and mortality from cardiovascular causes , proteinuria , and the rate of progression of renal disease . RESULTS A total of 327 patients in the losartan group reached the primary end point , as compared with 359 in the placebo group ( risk reduction , 16 percent ; P=0.02 ) . Losartan reduced the incidence of a doubling of the serum creatinine concentration ( risk reduction , 25 percent ; P=0.006 ) and end-stage renal disease ( risk reduction , 28 percent ; P=0.002 ) but had no effect on the rate of death . The benefit exceeded that attributable to changes in blood pressure . The composite of morbidity and mortality from cardiovascular causes was similar in the two groups , although the rate of first hospitalization for heart failure was significantly lower with losartan ( risk reduction , 32 percent ; P=0.005 ) . The level of proteinuria declined by 35 percent with losartan ( P<0.001 for the comparison with placebo ) . CONCLUSIONS Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy , and it was generally well tolerated Blood-pressure and cholesterol lowering in persons without cardiovascular disease Elevated blood pressure and elevated low-density lipoprotein ( LDL ) cholesterol increase the risk of cardiovascular disease . Lowering both should reduce the risk of cardiovascular events substantially . This proposition is examined in this r and omised trial in which patients without cardiovascular disease were r and omised to receive such treatments compared with placebos . The combination of rosuvastatin ( 10 mg per day ) , c and esartan ( 16 mg per day ) , and hydrochlorothiazide ( 12.5 mg per day ) was associated with a significantly lower rate of cardiovascular events than dual placebo among persons at intermediate risk who did not have cardiovascular disease .  Muscle weakness and dizziness were more common in the combined therapy group , but the rate of discontinuation was similar in the two groups Hypertension is the most common condition seen in primary care and leads to myocardial infa rct ion , stroke , renal failure , and death if not detected early and treated appropriately . Patients want to be assured that blood pressure ( BP ) treatment will reduce their disease burden , while clinicians want guidance on hypertension management using the best scientific evidence . This report takes a rigorous , evidence -based approach to recommend treatment thresholds , goals , and medications in the management of hypertension in adults . Evidence was drawn from r and omized controlled trials , which represent the gold st and ard for determining efficacy and effectiveness . Evidence quality and recommendations were grade d based on their effect on important outcomes . There is strong evidence to support treating hypertensive persons aged 60 years or older to a  BP goal  of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg ; however , there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal , or in those younger than 30 years for a diastolic goal , so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion . The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease ( CKD ) as for the general hypertensive population younger than 60 years . There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor , angiotensin receptor blocker , calcium channel blocker , or thiazide-type diuretic in the nonblack hypertensive population , including those with diabetes . In the black hypertensive population , including those with diabetes , a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy . There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes . Although this guideline provides evidence -based recommendations for the management of high BP and should meet the clinical needs of most patients , these recommendations are not a substitute for clinical judgment , and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient BACKGROUND Combination therapy with angiotensin-converting-enzyme ( ACE ) inhibitors and angiotensin-receptor blockers ( ARBs ) decreases proteinuria ; however , its safety and effect on the progression of kidney disease are uncertain . Methods We provided losartan ( at a dose of 100 mg per day ) to patients with type 2 diabetes , a urinary albumin-to-creatinine ratio ( with albumin measured in milligrams and creatinine measured in grams ) of at least 300 , and an estimated glomerular filtration rate ( GFR ) of 30.0 to 89.9 ml per minute per 1.73 m(2 ) of body-surface area and then r and omly assigned them to receive lisinopril ( at a dose of 10 to 40 mg per day ) or placebo . The primary end point was the first occurrence of a change in the estimated GFR ( a decline of ≥ 30 ml per minute per 1.73 m(2 ) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2 ) or a decline of ≥ 50 % if the initial estimated GFR was < 60 ml per minute per 1.73 m(2 ) ) , end-stage renal disease ( ESRD ) , or death . The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD . Safety outcomes included mortality , hyperkalemia , and acute kidney injury . Results The study was stopped early owing to safety concerns . Among 1448 r and omly assigned patients with a median follow-up of 2.2 years , there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group ( hazard ratio with combination therapy , 0.88 ; 95 % confidence interval [ CI ] , 0.70 to 1.12 ; P=0.30 ) . A trend toward a benefit from combination therapy with respect to the secondary end point ( hazard ratio , 0.78 ; 95 % CI , 0.58 to 1.05 ; P=0.10 ) decreased with time ( P=0.02 for nonproportionality ) . There was no benefit with respect to mortality ( hazard ratio for death , 1.04 ; 95 % CI , 0.73 to 1.49 ; P=0.75 ) or cardiovascular events . Combination therapy increased the risk of hyperkalemia ( 6.3 events per 100 person-years , vs. 2.6 events per 100 person-years with monotherapy ; P<0.001 ) and acute kidney injury ( 12.2 vs. 6.7 events per 100 person-years , P<0.001 ) . Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events  among patients with diabetic nephropathy . ( Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development ; VA NEPHRON-D Clinical Trials.gov number , NCT00555217 . ) BACKGROUND Antihypertensive therapy reduces the risk of cardiovascular events among high-risk persons and among those with a systolic blood pressure of 160 mm Hg or higher , but its role in persons at intermediate risk and with lower blood pressure is unclear . METHODS In one comparison from a 2-by-2 factorial trial , we r and omly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to receive either c and esartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo . The first co primary outcome was the composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke ; the second co primary outcome additionally included resuscitated cardiac arrest , heart failure , and revascularization . The median follow-up was 5.6 years . RESULTS The  mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg ; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo group . The first co primary outcome occurred in 260 participants ( 4.1 % ) in the active-treatment group and in 279 ( 4.4 % ) in the placebo group ( hazard ratio , 0.93 ; 95 % confidence interval [ CI ] , 0.79 to 1.10 ; P=0.40 ) ; the second co primary outcome occurred in 312 participants ( 4.9 % ) and 328 participants ( 5.2 % ) , respectively ( hazard ratio , 0.95 ; 95 % CI , 0.81 to 1.11 ; P=0.51 ) . In one of the three prespecified hypothesis-based subgroups , participants in the subgroup for the upper third of systolic blood pressure ( > 143.5 mm Hg ) who were in the active-treatment group had significantly lower rates of the first and second co primary outcomes than those in the placebo group ; effects were neutral in the middle and lower thirds ( P=0.02 and P=0.009 , respectively , for trend in the two outcomes ) . CONCLUSIONS Therapy with c and esartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who did not have cardiovascular disease . ( Funded by the Canadian Institutes of Health Research and AstraZeneca ; Clinical Trials.gov number , NCT00468923 . ) BACKGROUND The optimal systolic blood pressure ( SBP ) treatment goal is in question , with SPRINT ( Systolic Blood Pressure Intervention Trial ) suggesting benefit for 120 mm Hg . However , achieving an SBP this low may reduce diastolic blood pressure ( DBP ) to levels that could compromise myocardial perfusion . OBJECTIVES This study sought to examine the independent association of DBP with myocardial damage ( using high-sensitivity cardiac troponin-T [ hs-cTnT ] ) and with coronary heart disease ( CHD ) , stroke , or death over 21 years . METHODS The authors studied 11,565 adults from the ARIC ( Atherosclerosis Risk In Communities ) cohort , analyzing DBP and hs-cTnT associations as well as prospect i ve associations between DBP and events . RESULTS Mean baseline age was 57 years , 57 % of patients were female , and 25 % were black . Compared with persons who had DBP between 80 to 89 mm Hg at baseline ( ARIC visit 2 ) , the adjusted odds ratio of having hs-cTnT ≥14 ng/l at that visit was 2.2 and 1.5 in those with DBP < 60 mm Hg and 60 to 69 mm Hg , respectively . Low DBP at baseline was also independently associated with progressive myocardial damage on the basis of estimated annual change in hs-cTnT over the 6 years between ARIC visits 2 and 4 . In addition , compared with a DBP of 80 to 89 mm Hg , a DBP < 60 mm Hg was associated with incident CHD and mortality , but not with stroke . The DBP and incident CHD association was strongest with baseline hs-cTnT ≥14 ng/l ( p value for interaction < 0.001 ) . Associations of low DBP with prevalent hs-cTnT and incident CHD were most pronounced among patients with baseline SBP ≥120 mm Hg . CONCLUSIONS Particularly among adults with an SBP ≥120 mm Hg , and thus elevated pulse pressure , low DBP was associated with sub clinical myocardial damage and CHD events . When titrating treatment to SBP < 140 mm Hg , it may be prudent to ensure that DBP levels do not fall below 70 mm Hg , and particularly not below 60 mm Hg To appreciate the importance of the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial,1 one needs to remember that the systolic blood pressure ( BP ) target currently recommended by major guidelines for diabetic patients , that is , 130 mm Hg , except in the Appropriate Blood Pressure Control in Diabetes Study ( ABCD ) normotensive trial,7 which consisted of only a few hundred patients and had changes in creatinine clearance as the primary end point . Thus , ACCORD represents the only large-scale r and omized trial that provides information on what happens to the cardiovascular risk of diabetic patients  when SBP is reduced to 130 mm Hg as a result of r and omization to the usual ( rather than the tight ) BP control treatment strategy . Thus , the message from ACCORD to guidelines and clinical practice is that in diabetic patients it is not necessary to adopt
target: CONCLUSIONS Antihypertensive treatment reduces the risk of mortality and cardiovascular morbidity in people with diabetes mellitus and a systolic blood pressure more than 140 mm Hg .
  If systolic blood pressure is less than 140 mm Hg , however , further treatment is associated with an increased risk of cardiovascular death , with no observed benefit
background: OBJECTIVE To assess the effect of antihypertensive treatment on mortality and cardiovascular morbidity in people with diabetes mellitus , at different blood pressure levels .