title: Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) Metoprolol Versus Thiazide Diuretics in Hypertension Morbidity Results From the MAPHY Study Effects of the direct renin inhibitor aliskiren and atenolol alone or in combination in patients with hypertension1 Design and baseline characteristics of participants in the African American Study of Kidney Disease and Hypertension (AASK) Pilot Study. Rationale and design of the International Verapamil SR/Trandolapril Study (INVEST): an Internet-based randomized trial in coronary artery disease patients with hypertension. First-line antihypertensive treatment in patients with pre-diabetes: Rationale, design and baseline results of the ADaPT investigation Baseline predictors of resistant hypertension in the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT): a risk score to identify those at high-risk GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). 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abstract: CONTEXT Incidence of end-stage renal disease due to hypertension has increased in recent decades , but the optimal strategy for treatment of hypertension to prevent renal failure is unknown , especially among African Americans . OBJECTIVE To compare the effects of an angiotensin-converting enzyme ( ACE ) inhibitor ( ramipril ) , a dihydropyridine calcium channel blocker ( amlodipine ) , and a beta-blocker ( metoprolol ) on hypertensive renal disease progression . DESIGN , SETTING , AND PARTICIPANTS Interim analysis of a r and omized , double-blind , 3 x 2 factorial trial conducted in 1094 African Americans aged 18 to 70 years with hypertensive renal disease ( glomerular filtration rate [ GFR ] of 20 - 65 mL/min per 1.73 m(2 ) ) enrolled between February 1995 and September 1998 . This report compares the ramipril and amlodipine groups following discontinuation of the amlodipine intervention in September 2000 . INTERVENTIONS Participants were r and omly assigned to receive amlodipine , 5 to 10 mg/d ( n = 217 ) , ramipril , 2.5 to 10 mg/d ( n = 436 ) , or metoprolol , 50 to 200 mg/d ( n = 441 ) , with other agents added to achieve 1 of 2 blood pressure goals . MAIN OUTCOME MEASURES The primary outcome measure was the rate of change in GFR ; the main secondary outcome was a composite index of the clinical end points of reduction in GFR of more than 50 % or 25 mL/min per 1.73 m(2 ) , end-stage renal disease , or death . RESULTS Among participants with a urinary protein to creatinine ratio of > 0.22 ( corresponding approximately to proteinuria of more than 300 mg/d ) , the ramipril group had a 36 % ( 2.02 [ SE , 0.74 ] mL/min per 1.73 m(2)/y ) slower mean decline in GFR over 3 years ( P = .006 ) and a 48 % reduced risk of the clinical end points vs the amlodipine group ( 95 % confidence interval [ CI ] , 20%-66 % ) . In the entire cohort , there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups ( P = .38 ) . However , compared with the amlodipine group , after adjustment for baseline covariates the ramipril group had a 38 % reduced risk of clinical end points ( 95 % CI , 13%-56 % ) , a 36 % slower mean decline in GFR after 3 months ( P = .002 ) , and less proteinuria ( P<.001 ) . CONCLUSION Ramipril , compared with amlodipine , retards renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria BACKGROUND The most suitable antihypertensive drug to reduce the risk of cardiovascular disease in patients with hypertension and diabetes is unclear . In prespecified analyses , we compared the effects of losartan and atenolol on cardiovascular morbidity and mortality in diabetic patients . METHODS As part of the LIFE study , in a double-masked , r and omised , parallel-group trial , we assigned a group of 1195 patients with diabetes , hypertension , and signs of left-ventricular hypertrophy ( LVH ) on electrocardiograms losartan-based or atenolol-based treatment . Mean age of patients was 67 years ( SD 7 ) and mean blood pressure 177/96 mm Hg ( 14/10 ) after placebo run-in . We followed up patients for at least 4 years ( mean 4.7 years [ 1.1 ] ) . We used Cox regression analysis with baseline Framingham risk score and electrocardiogram-LVH as covariates to compare the effects of the drugs on the primary composite endpoint of cardiovascular morbidity and mortality ( cardiovascular death , stroke , or myocardial infa rct ion ) . FINDINGS Mean blood pressure fell to 146/79 mm Hg ( 17/11 ) in losartan patients and 148/79 mm Hg ( 19/11 ) in atenolol patients . The primary endpoint occurred in 103 patients assigned losartan ( n=586 ) and 139 assigned atenolol ( n=609 ) ; relative risk 0.76 ( 95 % CI 0.58-.98 ) , p=0.031 . 38 and 61 patients in the losartan and atenolol groups , respectively , died from cardiovascular disease ; 0.63 ( 0.42 - 0.95 ) , p=0.028 . Mortality from all causes was 63 and 104 in losartan and atenolol groups , respectively ; 0.61 ( 0.45 - 0.84 ) , p=0.002 . INTERPRETATION Losartan was more effective than atenolol in reducing cardiovascular morbidity and mortality as well as mortality from all causes in patients with hypertension , diabetes , and LVH . Losartan seems to have benefits beyond blood pressure reduction CONTEXT Despite evidence of efficacy of antihypertensive agents in treating hypertensive patients , safety and efficacy of antihypertensive agents for coronary artery disease ( CAD ) have been discerned only from subgroup analyses in large trials . OBJECTIVE To compare mortality and morbidity outcomes in patients with hypertension and CAD treated with a calcium antagonist strategy ( CAS ) or a non-calcium antagonist strategy ( NCAS ) .  DESIGN , SETTING , AND PARTICIPANTS R and omized , open label , blinded end point study of 22 576 hypertensive CAD patients aged 50 years or older , which was conducted September 1997 to February 2003 at 862 sites in 14 countries . INTERVENTIONS Patients were r and omly assigned to either CAS ( verapamil sustained release ) or NCAS ( atenolol ) . Strategies specified dose and additional drug regimens . Tr and olapril and /or hydrochlorothiazide was administered to achieve blood pressure goals according to guidelines from the sixth report of the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure ( JNC VI ) of less than 140 mm Hg ( systolic ) and less than 90 mm Hg ( diastolic ) ; and less than 130 mm Hg ( systolic ) and less than 85 mm Hg ( diastolic ) if diabetes or renal impairment was present . Tr and olapril was also recommended for patients with heart failure , diabetes , or renal impairment . MAIN OUTCOME MEASURES Primary : first occurrence of death ( all cause ) , nonfatal myocardial infa rct ion , or nonfatal stroke ; other : cardiovascular death , angina , adverse experiences , hospitalizations , and blood pressure control at 24 months . RESULTS At 24 months , in the CAS group , 6391 patients ( 81.5 % ) were taking verapamil sustained release ; 4934 ( 62.9 % ) were taking tr and olapril ; and 3430 ( 43.7 % ) were taking hydrochlorothiazide . In the NCAS group , 6083 patients ( 77.5 % ) were taking atenolol ; 4733 ( 60.3 % ) were taking hydrochlorothiazide ; and 4113 ( 52.4 % ) were taking tr and olapril . After a follow-up of 61 835 patient-years ( mean , 2.7 years per patient ) , 2269 patients had a primary outcome event with no statistically significant difference between treatment strategies ( 9.93 % in CAS and 10.17 % in NCAS ; relative risk [ RR ] , 0.98 ; 95 % confidence interval [ CI ] , 0.90 - 1.06 ) . Two-year blood pressure control was similar between groups . The JNC VI blood pressure goals were achieved by 65.0 % ( systolic ) and 88.5 % ( diastolic ) of CAS and 64.0 % ( systolic ) and 88.1 % ( diastolic ) of NCAS patients . A total of 71.7 % of CAS and 70.7 % of NCAS patients achieved a systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg . CONCLUSION The verapamil-tr and olapril-based strategy was as clinical ly effective as the atenolol-hydrochlorothiazide-based strategy in hypertensive CAD patients 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 The present study in hypertensive men ( 40 - 64 years old ) with untreated diastolic blood pressure above 100 mm Hg was aim ed at investigating whether metoprolol ( n = 1,609 ) given as initial treatment would lower the risk for coronary events ( sudden death and myocardial infa rct ion ) more effectively than thiazide diuretics ( n=1,625 ) . A substantial part of this study was the metoprolol arm of the Heart Attack Primary Prevention in Hypertension ( HAPPHY ) study . The HAPPHY study was a pooling of the effect of different /J-blockers , mainly metoprolol and atenolol , in which no favorable effect in relative risk was observed for atenolol as compared with diuretics . In the present study , 255 patients suffered definite coronary events during follow-up ; 25 % of these events were fatal , 39 % were acute myocardial infa rct ions , and 36 % were silent myocardial infa rct ions . The risk for coronary events was significantly lower in patients on metoprolol  than in patients on diuretics  ( 111 versus 144 cases , p=0.001 , corresponding to 143 versus 18.8 cases/1,000 patient years and a relative risk of 0.76 at the end of the trial ; 95 % confidence interval 0.58 - 0.98 ) . This difference in risk has potentially important implication s for clinical practice because of the large number of hypertensive patients who are at increased risk for coronary events . Because a placebo group , for ethical reasons , could not be included , relative risk can only be expressed in relation to diuretics . There was no difference between the two treatment groups in baseline characteristics , blood pressure during follow-up , or stroke rates . Thus , the difference in risk for coronary events is probably mediated via mechanisms other than blood pressure control . However , present data might suggest that different /3-blockers may have different efficacy in preventing coronary events . The reasons for this possibility are as yet unknown . ( Hypertension 1991:17 : Introduction . Aliskiren is the first in a new class of direct renin inhibitors to be approved for the treatment of hypertension . Patients and methods . In this double-blind , multicentre trial , 694 patients with hypertension ( mean sitting diastolic blood pressure [ BP ] ≥ 95 and < 110 mmHg ) were r and omised to once-daily aliskiren 150 mg ( n=231 ) , atenolol 50 mg ( n=231 ) or the combination ( 150/50 mg ; n=232 ) for six weeks , followed by a further six weeks on double the initial doses of aliskiren and atenolol . Efficacy ( reduction from baseline in mean sitting systolic and diastolic BP ) and tolerability of study treatments were assessed ; plasma renin activity ( PRA ) was measured in a subset of patients . Results . At Week 12 endpoint , aliskiren , atenolol and aliskiren/atenolol  lowered systolic and diastolic BP from baseline by 14.3/11.3 , 14.3/13.7 and 17.3/14.1 mmHg , respectively . Systolic BP reductions with aliskiren/atenolol were significantly greater than those with aliskiren ( p=0.039 ) or atenolol ( p=0.034 ) alone , and diastolic BP reductions were greater than with aliskiren alone ( p<0.001 ) . Diastolic BP changes were larger with atenolol than with aliskiren ( p=0.003 , correlating with the large reductions in pulse rate ( > 10 bpm ) observed with atenolol . Aliskiren , atenolol and aliskiren/atenolol  reduced geometric mean PRA from baseline by 65 % , 52 % and 61 % , respectively . In patients with moderate or high baseline PRA ( ≥ 0.65 ng/ml/hour ) , PRA was reduced to low levels ( < 0.65 ng/ml/hour ) at Week 12 endpoint in a greater proportion of patients receiving aliskiren ( 11/15 patients , 73.3 % ) or aliskiren/atenolol ( 18/23 , 78.3 % ) than with atenolol ( 10/21 , 47.6 % ) . Aliskiren treatment was associated with numerically lower rates of adverse events and discontinuations due to adverse events  compared with atenolol or combination treatment , and unlike atenolol was not associated with bradycardia . Conclusions . Direct renin inhibition with aliskiren may be an appropriate substitute for beta-blocker treatment in patients with uncomplicated hypertension .  Aliskiren also represents an attractive option for dual therapy with atenolol to improve systolic BP/pulse pressure reductions and BP control with maintained tolerability compared with atenolol alone Hypertension and end-stage renal disease ( ESRD ) are major causes of morbidity and mortality in the United States , especially among African Americans . The African American Study of Kidney Disease and Hypertension ( AASK ) Pilot Study evaluated the feasibility of conducting a long-term clinical trial to compare the effects of two levels of blood pressure control and three different antihypertensive drug regimens on the rate of decline in glomerular filtration rate ( GFR ) in African Americans with clinical ly diagnosed hypertensive renal disease . African American men and women aged 18 - 70 years with a GFR of 25 - 70 ml/min/ 1.73m2 and hypertension were r and omized in a 3 x 2 factorial design to initial treatment with either an angiotensin-converting enzyme inhibitor ( enalapril ) , a calcium channel blocker ( amlodipine ) , or a beta blocker ( atenolol ) and to a mean arterial blood pressure ( goal MAP ) of either 102 - 107 mm Hg or < or = 92 mm Hg . Furosemide , doxazosin , clonidine , hydralazine , and minoxidil were added sequentially until goal MAP was achieved . To compare the pathologic diagnosis with the clinical diagnosis of renal disease , study participants without contraindication were also asked to undergo a renal biopsy . The goals of the AASK Pilot Study were to evaluate recruitment techniques , adherence to prescribed antihypertensive drug regimens , ability of the antihypertensive regimens to achieve blood pressure goals , rates of participation in scheduled clinic visits and procedures , and variability of GFR measurements . A further goal was to obtain renal biopsy data in at least 75 % of the r and omized study participants . Compared to the ESRD patient population whose renal disease is caused by hypertension , women were underrepresented in the AASK Pilot Study . AASK Pilot Study participants had higher  unemployment rates and lower income levels than African Americans in the general U.S. population OBJECTIVES The primary objective of the International Verapamil SR/Tr and olapril Study ( INVEST ) is to compare the risk for adverse outcomes ( all-cause mortality , nonfatal myocardial infa rct ion [ MI ] or nonfatal stroke ) in hypertensive patients with coronary artery disease ( CAD ) treated with either a calcium antagonist-based or a noncalcium antagonist-based strategy .  BACKGROUND Treatment recommendations for hypertension include initial therapy with a diuretic or beta-adrenergic blocking agent , for which reductions in morbidity and mortality are documented from r and omized trials but are less than expected from epidemiologic data . For this reason , recent attention has focused on calcium antagonists or angiotensin-converting enzyme inhibitors . While these agents reduce blood pressure , outcome data from large r and omized trials are lacking , but some case-control data , dominated by short-acting dihydropyridines , suggest an increased risk of cardiovascular events . These studies had method ologic limitations and did not differentiate among calcium antagonist types and formulations . Several studies differentiating among calcium antagonist types and an overview of published r and omized trials show no increased risk with verapamil and suggestion for benefit in CAD patients . METHODS A total of 27,000 CAD patients with hypertension will be r and omized at 1,500 primary care sites to receive either a calcium antagonist-based ( verapamil ) or beta-blocker/diuretic-based ( atenolol/hydrochlorothiazide ) antihypertensive care strategy . The study uses a novel , electronic " paper-less " system for direct on-screen data entry , r and omization and drug distribution from a mail pharmacy linked to the coordination center via the Internet . RESULTS Contract negotiations with the United States and international sites are ongoing . Patients being enrolled are predominantly elderly ( 72 % aged 60 years or older ) men ( 54 % ) , with either an abnormal coronary angiogram or prior MI ( 71 % ) . In addition to hypertension , CAD and elderly age , most patients ( 89 % ) have one or more associated conditions ( diabetes , dyslipidemia , smoking , cerebral or peripheral vascular disease , etc . ) contributing to increased risk for adverse outcome . While 26 % have diabetes , most of these are noninsulin dependent . Using the protocol strategies , target blood pressures ( according to JNC VI ) have been reached in 58 % at the fourth visit , and as expected most ( 89 % ) are requiring multiple antihypertensive drugs . CONCLUSION The design and baseline characteristics of the initial patients recruited for a prospect i ve , r and omized , international , multicenter study comparing two therapeutic strategies to control hypertension in CAD patients are described Background Recent clinical trials reported conflicting results on the reduction of new-onset diabetes using RAS blocking agents . Therefore the role of these agents in preventing diabetes is still not well defined . Ramipril is an ACE inhibitor ( ACEi ) , that has been shown to reduce cardiovascular events in high risk patients and post-hoc analyses of the HOPE trial have provided evidence for its beneficial action in the prevention of diabetes . Methods The ADaPT investigation ( " ACE inhibitor-based versus diuretic-based antihypertensive primary treatment in patients with pre-diabetes " ) is a 4-year open , prospect i ve , parallel group phase IV study . It compares an antihypertensive treatment regimen based on ramipril versus a treatment based on diuretics or betablockers . The primary evaluation criterion is the first manifestation of type 2 diabetes . The study is conducted in primary care to allow the broadest possible application of its results . The present article provides an outline of the rationale , the design and baseline characteristics of AdaPT and compares these to previous studies including ASCOT-BLPA , VALUE and DREAM . Results Until March 2006 a total of 2,015 patients in 150 general practice s ( general physicians and internists ) throughout Germany were enrolled . The average age of patients enrolled was 67.1 ± 10.3 years , with 47 % being male and a BMI of 29.9 ± 5.0 kg/m2 . Dyslipidemia was present in 56.5 % . 37.8 % reported a family history of diabetes  , 57.8 % were previously diagnosed with hypertension  ( usually long st and ing ) . The HbA1c value at baseline was 5.6 % . Compared to the DREAM study patients were older , had more frequently hypertension and patients with cardiovascular disease were not excluded . Conclusion Comparing the ADaPT design and baseline data to previous r and omized controlled trial it can be acknowledged that AdaPT included patients with a high risk for diabetes development . Results are expected to be available in 2010 . Data will be highly valuable for clinical practice due to the observational study design Background Resistant hypertension is a well recognized clinical entity , which has been inadequately research ed to date . Methods A multivariable Cox model was developed to identify baseline predictors of developing resistant hypertension among 3666 previously untreated Anglo-Sc and inavian Cardiac Outcome Trial ( ASCOT ) patients and construct a risk score to identify those at high risk . Secondary analyses included evaluations among all 19 257 r and omized patients . Results One-third ( 1258 ) of previously untreated , and one-half ( 9333 ) of all r and omized patients ( incidence rates 75.2 and 129.7 per 1000 person-years , respectively ) developed resistant hypertension during a median follow-up of 5.3 and 4.8 years , respectively . Increasing strata of baseline SBP ( 151–160 , 161–170 , 171–180 , and > 180 mmHg ) were associated with increased risk of developing resistant hypertension [ hazard ratio 1.24 ( 95 % confidence interval , CI 0.81–1.88 ) , 1.50 ( 1.03–2.20 ) , 2.15 ( 1.47–3.16 ) , and 4.43 ( 3.04–6.45 ) , respectively ] . Diabetes , left ventricular hypertrophy , male sex , and raised BMI , fasting glucose , and alcohol intake were other significant determinants of resistant hypertension . R and omization to amlodipine ± perindopril vs. atenolol ± thiazide [ 0.57 ( 0.50–0.60 ) ] , previous use  of aspirin  [ 0.78 ( 0.62–0.98 ) ] , and r and omization to atorvastatin vs. placebo [ 0.87 ( 0.76–1.00 ) ] significantly reduced the risk of resistant hypertension . Secondary analysis results were similar . The risk score developed allows accurate risk allocation ( Harrell 's C-statistic 0.71 ) , with excellent calibration ( Hosmer – Lemeshow & khgr;2 statistics , P = 0.99 ) . A 12-fold ( 8.4–17.4 ) increased risk among those in the highest vs. lowest risk deciles was apparent . Conclusion Baseline SBP and choice of subsequent antihypertensive therapy were the two most important determinants of resistant hypertension in the ASCOT population . Individuals at high risk of developing resistant hypertension can be easily identified using an integer-based risk score In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias BACKGROUND The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome . No study , however , has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease ( CHD ) in hypertensive patients who are not conventionally deemed dyslipidaemic . METHODS Of 19342 hypertensive patients ( aged 40 - 79 years with at least three other cardiovascular risk factors ) r and omised to one of two antihypertensive regimens in the Anglo-Sc and inavian Cardiac Outcomes Trial , 10305 with non-fasting total cholesterol concentrations 6.5 mmol/L or less were r and omly assigned additional atorvastatin 10 mg or placebo .  These patients formed the lipid-lowering arm of the study . We planned follow-up for an average of 5 years , the primary endpoint being non-fatal myocardial infa rct ion and fatal CHD . Data were analysed by intention to treat . FINDINGS Treatment was stopped after a median follow-up of 3.3 years . By that time , 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group ( hazard ratio 0.64 [ 95 % CI 0.50 - 0.83 ] , p=0.0005 ) . This benefit emerged in the first year of follow-up . There was no significant heterogeneity among prespecified subgroups . Fatal and non-fatal stroke ( 89 atorvastatin vs 121 placebo , 0.73 [ 0.56 - 0.96 ] , p=0.024 ) , total cardiovascular events ( 389 vs 486 , 0.79 [ 0.69 - 0.90 ] , p=0.0005 ) , and total coronary events ( 178 vs 247 , 0.71 [ 0.59 - 0.86 ] , p=0.0005 ) were also significantly lowered . There were 185 deaths in the atorvastatin group and 212 in the placebo group ( 0.87 [ 0.71 - 1.06 ] , p=0.16 ) . Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months , and by 1.1 mmol/L after 3 years of follow-up . INTERPRETATION The reductions in major cardiovascular events with atorvastatin are large , given the short follow-up time . These findings may have implication s for future lipid-lowering guidelines BACKGROUND Calcium antagonists are a first-line treatment for hypertension . The effectiveness of diltiazem , a non-dihydropyridine calcium antagonist , in reducing cardiovascular morbidity or mortality is unclear . We compared the effects of diltiazem with that of diuretics , beta-blockers , or both on cardiovascular morbidity and mortality  in hypertensive patients . METHODS In a prospect i ve , r and omised , open , blinded endpoint study , we enrolled 10,881 patients , aged 50 - 74 years , at health centres in Norway and Sweden , who had diastolic blood pressure of 100 mm Hg or more . We r and omly assigned patients diltiazem , or diuretics , beta-blockers , or both . The combined primary endpoint was fatal and non-fatal stroke , myocardial infa rct ion , and other cardiovascular death . Analysis was done by intention to treat . FINDINGS Systolic and diastolic blood pressure were lowered effectively in the diltiazem and diuretic and beta-blocker groups ( reduction 20.3/18.7 vs 23.3/18.7 mm Hg ; difference in systolic reduction p<0.001 ) . A primary endpoint occurred in 403 patients in the diltiazem group and in 400 in the diuretic and beta-blocker group ( 16.6 vs 16.2 events per 1000 patient-years ; relative risk 1.00 [ 95 % CI 0.87 - 1.15 ] , p=0.97 ) . Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 in the diuretic and beta-blocker group ( 6.4 vs 7.9 events per 1000 patient-years ; 0.80 [ 0.65 - 0.99 ] , p=0.04 ) and fatal and non-fatal myocardial infa rct ion in 183 and 157 patients ( 7.4 vs 6.3 events per 1000 patient-years ; 1.16 [ 0.94 - 1.44 ] , p=0.17 ) . INTERPRETATION Diltiazem was as effective as treatment based on diuretics , beta-blockers , or both in preventing the combined primary endpoint of all stroke , myocardial infa rct ion , and other cardiovascular death OBJECTIVES The Initiation Management Predischarge : Process for Assessment of Carvedilol Therapy in Heart Failure ( IMPACT-HF ) trial was an investigator-initiated study to evaluate if predischarge carvedilol initiation in stabilized patients hospitalized for heart failure ( HF ) increased the number of patients treated with beta-blockade at 60 days after r and omization without increasing side effects or length of hospital stay . BACKGROUND Beta-blockers are underused in HF . Predischarge initiation may improve the use of evidence -based beta-blockade . METHODS The IMPACT-HF was a prospect i ve , r and omized open-label trial conducted in 363 patients hospitalized for HF . Patients were r and omized to carvedilol initiation pre-hospital discharge or to postdischarge initiation ( > 2 weeks ) of beta-blockade at the physicians ' discretion . The primary end point of the study was the number of patients treated with beta-blockade at 60 days after r and omization . Secondary end points included the number of patients discontinuing beta-blockade , median dose achieved , and a composite of death , rehospitalization , unscheduled visit for HF , or > or = 50 % increase in oral diuretic , new oral diuretic , or any intravenous therapy with diuretics , inotropes , or other vasoactive agents . RESULTS At 60 days 165 patients ( 91.2 % ) r and omized to predischarge carvedilol initiation were treated with a beta-blocker , compared with 130 patients ( 73.4 % ) r and omized to initiation postdischarge ( p < 0.0001 ) . Predischarge initiation was not associated with an increased risk of serious adverse events . The median length of stay was five days in both groups . CONCLUSIONS Predischarge initiation of carvedilol in stabilized patients hospitalized for HF improved the use of beta-blockade at 60 days without increasing side effects or length of stay . Predischarge initiation may be one approach to improve beta-blocker use in this population BACKGROUND In patients with heart failure , beta-blockade has improved morbidity and left-ventricular function , but the impact on survival is uncertain . We investigated the efficacy of bisoprolol , a beta1 selective adrenoceptor blocker in decreasing all-cause mortality in chronic heart failure . METHODS In a multicentre double-blind r and omised placebo-controlled trial in Europe , we enrolled 2647 symptomatic patients in New York Heart Association class III or IV , with left-ventricular ejection fraction of 35 % or less receiving st and ard therapy with diuretics and inhibitors of angiotensin-converting enzyme .  We r and omly assigned patients bisoprolol 1.25 mg ( n=1327 ) or placebo ( n=1320 ) daily , the drug being progressively increased to a maximum of 10 mg per day . Patients were followed up for a mean of 1.3 years . Analysis was by intention to treat . FINDINGS CIBIS-II was stopped early , after the second interim analysis , because bisoprolol showed a significant mortality benefit . All-cause mortality was significantly lower with bisoprolol than on placebo ( 156 [ 11.8 % ] vs 228 [ 17.3 % ] deaths with a hazard ratio of 0.66 ( 95 % CI 0.54 - 0.81 , p<0.0001 ) . There were significantly fewer sudden deaths among patients on bisoprolol than in those on placebo ( 48 [ 3.6 % ] vs 83 [ 6.3 % ] deaths ) , with a hazard ratio of 0.56 ( 0.39 - 0.80 , p=0.0011 ) . Treatment effects were independent of the severity or cause of heart failure . INTERPRETATION Beta-blocker therapy had benefits for survival in stable heart-failure patients . Results should not , however , be extrapolated to patients with severe class IV symptoms and recent instability because safety and efficacy has not been established in these patients The present primary prevention study aim ed at investigating whether metoprolol given as initial antihypertensive treatment would lower cardiovascular complications of high blood pressure to a greater extent than thiazide diuretics .  Patients were r and omized to metoprolol ( n = 1,609 , 8,110 patient-years ) or a thiazide diuretic ( n = 1,625 , 8,070 patient-years ) . At r and omization , 535 patients in the metoprolol group and 524 patients in the diuretic group were classified as smokers . Blood pressure control during follow-up was equally effective regardless of smoking habits at r and omization . Cardiovascular and coronary heart disease mortality was three to four times higher in smokers than in nonsmokers , underlining the importance of smoking as a risk factor . Total and cardiovascular mortality were significantly lower for the metoprolol group than for the thiazide diuretic group in the whole study population ( p = 0.028 and p = 0.012 ) , as well as in smokers ( p = 0.013 and p = 0.016 ) . Coronary heart disease mortality was significantly lower for patients on metoprolol  than for patients on diuretics  in the whole study population ( p = 0.048 ) as well as in smokers ( p = 0.02l ) . The results suggest that initial antihypertensive therapy with metoprolol is associated with a lesser incidence of total , cardiovascular , and coronary heart disease mortality as compared with initial diuretic treatment , both in the whole study population and in smokers . The favorable effect of metoprolol must be mediated via mechanisms other than the blood pressure-lowering effect of metoprolol because equal blood pressure control was achieved with both types of medication , irrespective of smoking habits at r and omization OBJECTIVES We sought to evaluate the role of arterial stiffness on  blood pressure ( BP ) response to drug treatment . BACKGROUND Increased arterial stiffness ( pulse wave velocity [ PWV ] ) is associated with increased systolic blood pressure ( SBP ) . Antihypertensive drug therapy achieves better control of diastolic blood pressure ( DBP ) than SBP does , implying that increased PWV might be a predictor of the SBP response to treatment . METHODS The REASON ( Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind ) study is a r and omized , double-blind trial comparing atenolol versus perindopril/indapamide ;  375 patients with hypertension , with BP and PWV measurements at baseline and after 12 months of treatment , were divided into 3 tertiles according to baseline PWV and included in a post-hoc analysis . RESULTS After 12 months of treatment , BP differed significantly between PWV tertiles ( the third having the lowest response , p < 0.05 ) . Factors related to smaller BP decline were low baseline BP , high baseline PWV , need for a double dose of treatment , use of atenolol ( only for SBP response ) , and age ( only for DBP ) . Although DBP control did not differ in the PWV tertiles , SBP control was significantly associated with PWV level ( p = 0.001 ) as well as with the use of perindopril/indapamide ( p < 0.001 ) . The predictive value of PWV on BP response was independent of age , sex , mean BP , and cardiovascular risk factors . CONCLUSIONS Baseline PWV is a significant predictor of BP response to antihypertensive treatment , independent from age , the need for increasing drug dosage , and the presence of cardiovascular risk factors . Achievement of SBP control appears to be influenced by aortic stiffness as well as by angiotensin-converting enzyme inhibition Background —Most cardiovascular events associated with hypertension are complications of atherosclerosis . Some antihypertensive agents influence experimental models of atherosclerosis through mechanisms independent of blood pressure lowering . Methods and Results —The European Lacidipine Study on Atherosclerosis ( ELSA ) was a r and omized , double-blind trial in 2334 patients with hypertension that compared the effects of a 4-year treatment based on either lacidipine or atenolol on an index of carotid atherosclerosis , the mean of the maximum intima-media thicknesses ( IMT ) in far walls of common carotids and bifurcations ( CBMmax ) . This index has been shown by epidemiological studies to be predictive of cardiovascular events . A significant ( P < 0.0001 ) effect of lacidipine was found compared with atenolol , with a treatment difference in 4-year CBMmax progression of −0.0227 mm ( intention-to-treat population ) and −0.0281 mm ( completers ) . The yearly IMT progression rate was 0.0145 mm/y in atenolol-treated and 0.0087 mm/y in lacidipine-treated patients ( completers , 40 % reduction;P = 0.0073 ) . Patients with plaque progression were significantly less common , and patients with plaque regression were significantly more common in the lacidipine group . Clinic blood pressure reductions were identical with both treatments , but 24-hour ambulatory systolic/diastolic blood pressure changes were greater with atenolol ( −10/−9 mm Hg ) than with lacidipine ( −7/−5 mm Hg ) . No significant difference between treatments was found in any cardiovascular events , although the relative risk for stroke , major cardiovascular events , and mortality showed a trend favoring lacidipine . Conclusion —The greater efficacy of lacidipine  on carotid IMT progression and number of plaques per patient , despite a smaller ambulatory blood pressure reduction , indicates an antiatherosclerotic action of lacidipine independent of its antihypertensive action 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 BACKGROUND Raised blood pressure is common after acute stroke and is associated with an adverse prognosis . We sought to assess the feasibility , safety , and effects of two regimens for lowering blood pressure in patients who have had a stroke . METHODS Patients who had cerebral infa rct ion or cerebral haemorrhage and were hypertensive ( systolic blood pressure [ SBP ] > 160 mm Hg ) were r and omly assigned by secure internet central r and omisation to receive oral labetalol , lisinopril , or placebo if they were non-dysphagic , or intravenous labetalol , sublingual lisinopril , or placebo if they had dysphagia , within 36 h of symptom onset in this double-blind pilot trial . The doses were titrated up if target blood pressure was not reached . Analysis was by intention to treat . This trial is registered with the National Research Register , number N0484128008 . FINDINGS 179 patients ( mean age 74 [ SD 11 ] years ; SBP 181 [ SD 16 ] mm Hg ; diastolic blood pressure [ DBP ] 95 [ SD 13 ] mm Hg ; median National Institutes of Health stroke scale [ NIHSS ] score 9 [ IQR 5 - 16 ] points ) were r and omly assigned to receive labetolol ( n=58 ) , lisinopril ( n=58 ) , or placebo ( n=63 ) between January , 2005 , and December , 2007 . The primary outcome --death or dependency at 2 weeks -- occurred in 61 % ( 69 ) of the active and 59 % ( 35 ) of the placebo group ( relative risk [ RR ] 1.03 , 95 % CI 0.80 - 1.33 ; p=0.82 ) . There was no evidence of early neurological deterioration with active treatment ( RR 1.22 , 0.33 - 4.54 ; p=0.76 ) despite the significantly greater fall in SBP within the first 24 h in this group compared with placebo ( 21 [ 17 - 25 ] mm Hg vs 11 [ 5 - 17 ] mm Hg ; p=0.004 ) . No increase in serious adverse events was reported with active treatment ( RR 0.91 , 0.69 - 1.12 ; p=0.50 ) but 3-month mortality was halved ( 9.7%vs 20.3 % , hazard ratio [ HR ] 0.40 , 95 % CI 0.2 - 1.0 ; p=0.05 ) . INTERPRETATION Labetalol and lisinopril are effective antihypertensive drugs in acute stroke that do not increase serious adverse events . Early lowering of blood pressure with lisinopril and labetalol after acute stroke seems to be a promising approach to reduce mortality and potential disability . However , in view of the small sample size , care must be taken when these results are interpreted and further evaluation in larger trials is needed BACKGROUND Angiotensin-converting-enzyme ( ACE ) inhibitors have been used for more than a decade to treat high blood pressure  , despite the lack of data from r and omised intervention trials to show that such treatment affects cardiovascular morbidity and mortality . The Captopril Prevention Project ( CAPPP ) is a r and omised intervention trial to compare the effects of ACE inhibition and conventional therapy on cardiovascular morbidity and mortality in patients with hypertension . METHODS CAPPP was a prospect i ve , r and omised , open trial with blinded endpoint evaluation . 10,985 patients were enrolled at 536 health centres in Sweden and Finl and . Patients aged 25 - 66 years with a measured diastolic blood pressure of 100 mm Hg or more on two occasions were r and omly assigned captopril or conventional antihypertensive treatment ( diuretics , beta-blockers ) . Analysis was by intention-to-treat . The primary endpoint was a composite of fatal and non-fatal myocardial infa rct ion , stroke , and other cardiovascular deaths . FINDINGS Of 5492 patients assigned captopril and 5493 assigned conventional therapy , 14 and 13 , respectively , were lost to follow-up . Primary endpoint events occurred in 363 patients in the captopril group ( 11.1 per 1000 patient-years ) and 335 in the conventional-treatment group ( 10.2 per 1000 patient-years ; relative risk 1.05 [ 95 % CI 0.90 - 1.22 ] , p=0 - 52 ) . Cardiovascular mortality was lower with captopril than with conventional treatment ( 76 vs 95 events ; relative risk 0.77 [ 0.57 - 1 - 04 ] , p=0.092 ) , the rate of fatal and non-fatal myocardial infa rct ion was similar ( 162 vs 161 ) , but fatal and non-fatal stroke was more common with captopril ( 189 vs 148 ; 1.25 [ 1 - 01 - 1 - 55 ] . p=0.044 ) . INTERPRETATION Captopril and conventional treatment did not differ in efficacy in preventing cardiovascular morbidity and mortality . The difference in stroke risk is probably due to the lower levels of blood pressure obtained initially in previously treated patients r and omised to conventional therapy BACKGROUND Blood pressure reduction achieved with beta-blockers and diuretics is the best recorded intervention to date for prevention of cardiovascular morbidity and death in patients with hypertension . Left ventricular hypertrophy ( LVH ) is a strong independent indicator of risk of cardiovascular morbidity and death . We aim ed to establish whether selective blocking of angiotensin II improves LVH beyond reducing blood pressure and , consequently , reduces cardiovascular morbidity and death . METHODS We did a double-masked , r and omised , parallel-group trial in 9193 participants aged 55 - 80 years with essential hypertension ( sitting blood pressure 160 - 200/95 - 115 mm Hg ) and LVH ascertained by electrocardiography ( ECG ) . We assigned participants once daily losartan-based or atenolol-based antihypertensive treatment for at least 4 years and until 1040 patients had a primary cardiovascular event ( death , myocardial infa rct ion , or stroke ) . We used Cox regression analysis to compare regimens . FINDINGS Blood pressure fell by 30.2/16.6 ( SD 18.5/10.1 ) and 29.1/16.8 mm Hg ( 19.2/10.1 ) in the losartan and atenolol groups , respectively . The primary composite endpoint occurred in 508 losartan ( 23.8 per 1000 patient-years ) and 588 atenolol patients ( 27.9 per 1000 patient-years ; relative risk 0.87 , 95 % CI 0.77 - 0.98 , p=0.021 ) . 204 losartan and 234 atenolol patients died from cardiovascular disease ( 0.89 , 0.73 - 1.07 , p=0.206 ) ; 232 and 309 , respectively , had fatal or non-fatal stroke ( 0.75 , 0.63 - 0.89 , p=0.001 ) ; and myocardial infa rct ion ( non-fatal and fatal ) occurred in 198 and 188 , respectively ( 1.07 , 0.88 - 1.31 , p=0.491 ) . New-onset diabetes was less frequent with losartan . Interpretation Losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure and is better tolerated . Losartan seems to confer benefits beyond reduction in blood pressure AIMS Large r and omized trials have shown that beta-blockers reduce mortality and hospital admissions in patients with heart failure . The effects of beta-blockers in elderly patients with a broad range of left ventricular ejection fraction are uncertain . The SENIORS study was performed to assess effects of the beta-blocker , nebivolol , in patients > /=70 years , regardless of ejection fraction . METHODS AND RESULTS We r and omly assigned 2128 patients aged > /=70 years with a history of heart failure ( hospital admission for heart failure within the previous year or known ejection fraction < /=35 % ) , 1067 to nebivolol  ( titrated from 1.25 mg once daily to 10 mg once daily ) , and 1061 to placebo . The primary outcome was a composite of all cause mortality or cardiovascular hospital admission ( time to first event ) . Analysis was by intention to treat . Mean duration of follow-up was 21 months . Mean age was 76 years ( SD 4.7 ) , 37 % were female , mean ejection fraction was 36 % ( with 35 % having ejection fraction > 35 % ) , and 68 % had a prior history of coronary heart disease . The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mg . The primary outcome occurred in 332 patients ( 31.1 % ) on nebivolol compared with 375 ( 35.3 % ) on placebo [ hazard ratio ( HR ) 0.86 , 95 % CI 0.74 - 0.99 ; P=0.039 ] . There was no significant influence of age , gender , or ejection fraction on the effect of nebivolol on the primary outcome . Death ( all causes ) occurred in 169 ( 15.8 % ) on nebivolol and 192 ( 18.1 % ) on placebo ( HR 0.88 , 95 % CI 0.71 - 1.08 ; P=0.21 ) . CONCLUSION Nebivolol , a beta-blocker with vasodilating properties , is an effective and well-tolerated treatment for heart failure in the elderly BACKGROUND The efficacy of new antihypertensive drugs has been question ed . We compared the effects of conventional and newer antihypertensive drugs on cardiovascular mortality and morbidity in elderly patients . METHODS We did a prospect i ve , r and omised trial in 6614 patients aged 70 - 84 years with hypertension ( blood pressure > or = 180 mm Hg systolic , > or = 105 mm Hg diastolic , or both ) . Patients were r and omly assigned conventional antihypertensive drugs ( atenolol 50 mg , metoprolol 100 mg , pindolol 5 mg , or hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily ) or newer drugs ( enalapril 10 mg or lisinopril 10 mg , or felodipine 2.5 mg or isradipine 2 - 5 mg daily ) . We assessed fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease . Analysis was by intention to treat . FINDINGS Blood pressure was decreased similarly in all treatment groups . The primary combined endpoint of fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease occurred in 221 of 2213 patients in the conventional drugs group ( 19.8 events per 1000 patient-years ) and in 438 of 4401 in the newer drugs group ( 19.8 per 1000 ; relative risk 0.99 [ 95 % CI 0.84 - 1.16 ] , p=0.89 ) . The combined endpoint of fatal and non-fatal stroke , fatal and non-fatal myocardial infa rct ion , and other cardiovascular mortality occurred in 460 patients taking conventional drugs and in 887 taking newer drugs ( 0.96 [ 0.86 - 1.08 ] , p=0.49 ) . INTERPRETATION Old and new antihypertensive drugs were similar in prevention of cardiovascular mortality or major events . Decrease in blood pressure was of major importance for the prevention of cardiovascular events 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 Blood pressure ( BP ) guidelines that set target BP levels often rely on analyses of achieved BP from hypertension treatment trials . The objective of this article was to compare the results of analyses of achieved BP to intention-to-treat analyses on renal disease progression . Participants ( n=1094 ) in the African-American Study of Kidney Disease and Hypertension Trial were r and omly assigned to  either usual BP goal defined by a mean arterial pressure goal of 102 to 107 mm Hg or lower BP goal defined by a mean arterial pressure goal of ⩽92 mm Hg . Median follow-up was 3.7 years . Primary outcomes were rate of decline in measured glomerular filtration rate and a composite of a decrease in glomerular filtration rate by > 50 % or > 25 mL/min per 1.73 m2 , requirement for dialysis , transplantation , or death . Intention-to-treat analyses showed no evidence of a BP effect on either the rate of decline in glomerular filtration rate or the clinical composite outcome . In contrast , the achieved BP analyses showed that each 10-mm Hg increment in mean follow-up achieved mean arterial pressure was associated with a 0.35 mL/min per 1.73 m2 ( 95 % CI : 0.08 to 0.62 mL/min per 1.73 m2 ; P=0.01 ) faster mean glomerular filtration rate decline and a 17 % ( 95 % CI : 5 % to 32 % ; P=0.006 ) increased risk of the clinical composite outcome . Analyses based on achieved BP lead to markedly different inferences than traditional intention-to-treat analyses , attributed in part to confounding of achieved BP with comorbidities , disease severity , and adherence . Clinicians and policy makers should exercise caution when making treatment recommendations based on analyses relating outcomes to achieved BP BACKGROUND Identification of persons with chronic kidney disease ( CKD ) who are at highest risk to progress to end-stage renal disease ( ESRD ) is necessary to reduce the burden of kidney failure . The relative utility of traditional markers of kidney function , including estimated glomerular filtration rate ( eGFR ) and serum creatinine level , and emerging markers of kidney function , including cystatin C and beta-trace protein ( BTP ) levels , to predict ESRD and mortality has yet to be established . STUDY DESIGN R and omized clinical trial followed by an observational cohort study . SETTING & PARTICIPANTS 865 African American individuals with hypertensive CKD enrolled in a clinical trial of 2 levels of blood pressure control and 3 different antihypertensive drugs as initial therapy and subsequently followed by an observational cohort study . PREDICTORS Quintile of measured GFR ( mGFR ) by iothalamate clearance , serum creatinine , serum creatinine-based eGFR , cystatin C , and BTP values . OUTCOMES & MEASUREMENTS Incidence of ESRD and mortality . RESULTS 246 participants reached ESRD during a median follow-up of 102 months . The incidence rate of ESRD was higher with higher quintiles of each marker . The association between higher BTP level and ESRD was stronger than those for the other markers , including mGFR . All markers remained significantly associated with ESRD after adjustment for mGFR and relevant covariates ( all P < 0.05 ) , with BTP level retaining the strongest association ( HR for highest vs lowest quintile , 5.7 ; 95 % CI , 2.2 - 14.9 ) . Associations with the combined end point of ESRD or mortality ( n = 390 ) were weaker , but remained significant for cystatin C ( P = 0.05 ) and BTP levels ( P = 0.004 ) . LIMITATIONS The ability of these markers to predict ESRD and mortality in other racial and ethnic groups and in individuals with CKD due to other causes is unknown . CONCLUSIONS Plasma BTP and cystatin C levels may be useful adjuncts to serum creatinine level and mGFR in evaluating risk of progression of kidney disease Abstract Objective : To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes . Design : R and omised controlled trial comparing tight control of blood pressure aim ing at a blood pressure of < 150/85 mm Hg ( with the use of an angiotensin converting enzyme inhibitor captopril or a β blocker atenolol as main treatment ) with less tight control aim ing at a blood pressure of < 180/105 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 , mean blood pressure at entry 160/94 mm Hg ) ; 758 patients were allocated to tight control of blood pressure  and 390 patients to less tight control  with a median follow up of 8.4 years . Main outcome measures : Predefined clinical end points , fatal and non-fatal , related to diabetes , deaths related to diabetes , and all cause mortality . Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography . Results : Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control ( 144/82 mm Hg ) compared with the group assigned to less tight control ( 154/87 mm Hg ) ( P<0.0001 ) . Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24 % in diabetes related end points ( 95 % confidence interval 8 % to 38 % ) ( P=0.0046 ) , 32 % in deaths related to diabetes ( 6 % to 51 % ) ( P=0.019 ) , 44 % in strokes ( 11 % to 65 % ) ( P=0.013 ) , and 37 % in microvascular end points ( 11 % to 56 % ) ( P=0.0092 ) , predominantly owing to a reduced risk of retinal photocoagulation . There was a non-significant reduction in all cause mortality . After nine years of follow up the group assigned to tight blood pressure control also had a 34 % reduction in risk in the proportion of patients with deterioration of retinopathy by two steps ( 99 % confidence interval 11 % to 50 % ) ( P=0.0004 ) and a 47 % reduced risk ( 7 % to 70 % ) ( P=0.004 ) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study ( ETDRS ) chart . After nine years of follow up 29 % of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures . Conclusion : Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinical ly important reduction in the risk of deaths related to diabetes , complications related to diabetes , progression of diabetic retinopathy , and deterioration in visual acuity The treatment of hypertension mainly with diuretics and beta blockers reduces cardiovascular mortality and morbidity , largely due to a decreased incidence of stroke , whereas the beneficial effects of antihypertensive therapy on the occurrence of coronary events have been less than expected from epidemiological studies . Furthermore , treated hypertensive patients still have a higher cardiovascular complication rate , compared with matched normotensives . This is particularly evident in patients with left ventricular hypertrophy ( LVH ) , a major independent risk indicator for cardiovascular disease . In addition to elevating blood pressure , angiotensin II ( A-II ) exerts an important influence on cardiac structure and function , stimulating cell proliferation and growth . Thus , to further reduce morbidity and mortality when treating hypertensive patients , it may be important to effectively block the effects of A-II . This can be achieved directly at the A-II receptor level by losartan , the first of a new class of antihypertensive agents . It therefore seems pertinent to investigate whether selective A-II receptor blockade with losartan not only lowers blood pressure but also reduces LVH more effectively than current therapy , and thus improves prognosis . The Losartan Intervention For Endpoint reduction ( LIFE ) in Hypertension study is a double-blind , prospect i ve , parallel group study design ed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality in approximately 8,300 hypertensive patients ( initial sitting diastolic blood pressure 95 to 115 mm Hg or systolic blood pressure 160 to 200 mm Hg ) with electrocardiographically documented LVH . The study , which will continue for at least 4 years and until 1,040 patients experience one primary endpoint , has been design ed with a statistical power that will detect a difference of at least 15 % between groups in the incidence of combined cardiovascular morbidity and mortality . It is also the first prospect i ve study with adequate power to link reversal of LVH to reduction in major cardiovascular events . The rationale of the study , which will involve more than 800 clinical centers in Sc and inavia , the United Kingdom , and the United States , is discussed , and the major features of its design and general organization are described . On April 30 , 1997 , when inclusion was stopped , 9,218 patients had been r and omized Two first‐line antihypertensive therapies for initiating treatment in hypertension were compared , the angiotensin‐converting enzyme inhibitor ( ACEI ) zofenopril and the beta‐blocker atenolol . The study was multi‐centre and double‐blind , and included 304 middle‐aged to elderly patients with mild to moderate hypertension who were r and omized to receive either zofenopril 30–60 mg once daily ( od ) or atenolol 50–100 mg od for 4 weeks with the possibility to an up‐titration in non‐responding patients . The higher dose level was then administered until 12 weeks after r and omization . Blood pressures ( BPs ) were substantially reduced by either treatment , but after 4 weeks , the systolic and diastolic BP reductions were significantly greater ( p<0.05 ) with zofenopril ( −15.6/−13.5 mmHg ) compared with atenolol ( −13.1/−11.8 mmHg ) . After 12 weeks and the possibility of dose up‐titration , BP differences between treatments were no longer significant . However , control rates ( sitting diastolic BP < 90 mmHg ) for zofenopril remained significantly higher compared with atenolol .  The number of subjects with adverse drug reactions possibly or probably related to the study medication was 14 ( 9.1 % ) in the zofenopril group and 30 ( 20.8 % ) in the atenolol group ( p = 0.008 ) . It is concluded that zofenopril as well as atenolol induces substantial reductions of diastolic BP in middle‐aged to elderly patients with hypertension . However , the control rate when initiating antihypertensive therapy with zofenopril is higher than that for atenolol Objective : To compare the blood pressure‐lowering efficacy , the frequency of side effects and changes in laboratory values of three & bgr;‐blockers and a potassium‐sparing diuretic combination in elderly hypertensive patients . Design : The Swedish Trial in Old Patients with Hypertension ( STOP‐Hypertension ) was a prospect i ve , r and omized , double‐blind , multicentre trial comparing active antihypertensive treatment with placebo in patients aged 70‐84 years . Methods : The study group consisted of 1627 elderly hypertensive patients ( mean ± SD age 75.7 ± 3.7 years ; 37 % males , 63 % females ) . Supine and st and ing blood pressure , heart rate and side effects were recorded at each visit . Blood was drawn for routine analysis . The mean length of follow‐up was 25 months ( range 6‐65 ) . No patient was lost to follow‐up . Results : After 2‐months ' single‐drug therapy , all four active drugs were found to be equally effective in reducing diastolic blood pressure ( DBP ) . However , there were differences in their efficacy in reducing systolic blood pressure ( SBP ) ; the diuretic was significantly more effective than the & bgr;‐receptor blockers . The results of a series of multiple linear regression analyses showed that the observed differences in effect on SBP could not be explained by the different effects of the drugs on heart rate . More than two‐thirds of the patients were given supplementary treatment , most of them already by the 2‐month visit , after which there was no significant difference in blood pressure among the treatment regimens . The changes in laboratory values and in the prevalence of symptoms were minor for all four regimens . Conclusion : Metoprolol ( controlled release ) , atenolol , pindolol and the combination hydrochlorothiazide + amiloride were equally effective as single drugs in reducing DBP . There were differences in their efficacy in reducing SBP , the diuretic being more effective than the & bgr;‐blockers . After addition of supplementary treatment ( & bgr;‐blocker to diuretic , or vice versa ) there were no significant differences in blood pressure reduction among the groups . The changes in laboratory values and in the prevalence of symptoms were minor for all active treatment regimens . Thus , the satisfactory effect on cardiovascular morbidity and mortality was not impaired by low tolerability of the drugs Background —&bgr;-Blockade improves survival when administered over a long period of time to patients with heart failure . However , the time course of any possible deterioration during the titration phase has not been reported . Methods and Results —We looked at evidence of clinical deterioration in the Metoprolol CR/XL R and omized Intervention Trial in Congestive Heart Failure ( MERIT-HF ) by analyzing events and symptoms during the first 90 days . During titration , the Kaplan-Meier curves for the combined end point of all-cause mortality/all-cause hospitalization were similar in all patients r and omized , with no significant difference in favor of placebo at any visit or in any of the analyzed subgroups ( New York Heart Association class II , III/IV , or III/IV with ejection fraction < 0.25 , heart rate ≤76 bpm , and systolic blood pressure ≤120 mm Hg ) . The curves started to diverge in favor of & bgr;-blockade after 60 days . Low heart rate was the main factor that limited titration . In New York Heart Association class III/IV , 5.9 % of the patients receiving placebo discontinued study medicine during the first 90 days compared with 8.1 % of those receiving metoprolol CR/XL ( P = 0.037 unadjusted , P = NS adjusted ) ; corresponding figures in those with New York Heart Association class III/IV and ejection fraction < 0.25 were 7.1 % and 8.0 % ( P = NS ) . From day 90 until the end of the study , more patients in the placebo group discontinued study medicine in all subgroups . There was no change in diuretic or ACE inhibitor dosing with & bgr;-blocker titration . Most patients reported no change in symptoms of breathlessness or fatigue during the titration phase . Conclusions —When carefully titrated , metoprolol CR/XL can be given safely to the overwhelming majority of patients with stable mild to moderate heart failure  , with minimal side effects or deterioration In the ELSA trial , the effects of lacidipine-based treatment and beta-blocker (atenolol)-based treatment on the development and progression of carotid wall alterations are assessed in hypertensive patients . The primary endpoint of this study is the rate of change in the intima-media thickness of the carotid artery wall , measured with B-mode ultrasound . About 2300 hypertensive patients have been recruited and r and omized to either of the antihypertensive agents . Baseline data for 1965 patients are available , showing a high prevalence of carotid wall lesions : about 82 % of the subjects have an intima-media thickness > or = 1.3 mm , defined as plaque in the ELSA protocol ; 16 % of the subjects have intima-media thickening ( > or = 1.0 mm , < 1.3 mm ) and only about 1 % have normal carotid artery walls . Analysis of demographic data and risk factor prevalence in ELSA patients , and comparison of these preliminary observations with data from other intervention or observational studies indicate that high blood pressure is a very important risk factor for carotid atherosclerosis 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 Blood pressure ( BP ) and metabolic variables were determined initially and after 1 , 2 , 4 , 6 and 10 years ' treatment in two groups of hypertensive men ( n = 53 each ) r and omized to bendroflumethiazide 2.5 - 5 mg/day or propranolol 160 - 320 mg daily . There was no significant differences in BP or metabolic variables between the two groups at entry . BP was reduced to the same degree by both treatments . Five men in the propranolol group and one man in the thiazide group developed clinical ly overt diabetes during follow-up . Fasting blood sugar increased slightly but significantly though equally in both groups . Oral glucose tolerance was initially impaired to the same degree in both groups but improved significantly during treatment with both drugs . Fasting insulin increased slightly but to the same degree . While serum potassium decreased significantly in the thiazide group , the total body potassium was unchanged in this group . In the propranolol group , serum potassium rose , while total body potassium decreased significantly . Serum urate increased in both groups , though slightly more during thiazide treatment . One case of gout was found in each group . There was no difference in serum lipids between the two groups . The finding in this long-term trial indicate that in middle-aged men with mild to moderate hypertension a low-dose thiazide diuretic like bendroflumethiazide is as effective and safe an antihypertensive agent as the beta-blocker propranolol is and that it does not induce diabetes . The total clinical picture favors the retention of thiazide diuretics as a first choice drug in hypertension BACKGROUND Metoprolol provides clinical benefits in patients with congestive heart failure ( CHF ) . In this study , we investigated the effects of controlled-release metoprolol ( metoprolol CR ) on clinical status , on left ventricular ( LV ) volumes and function , and on neurohumoral activation in a large number of patients with CHF of mixed causes . METHODS AND RESULTS Four hundred twenty-six patients with symptomatic CHF were r and omized to receive metoprolol CR or placebo for 24 weeks . Metoprolol CR did not affect 6-minute walk distance , New York Heart Association functional class , or quality of life . However , there was a significant improvement in measures of LV function with an attenuation in the increase in LV end-diastolic ( + 23+/-65 mL [ placebo ] versus + 6+/-61 mL , P=0.01 ) and LV end-systolic ( + 19+/-55 mL [ placebo ] versus -2+/-51 mL , P<0.001 ) volumes after 24 weeks of therapy . LV ejection fraction was unchanged ( -0.05 % or -0.005 ) in the placebo group but increased by 2 . 4 % in the metoprolol CR-treated patients ( P=0.001 ) . Patients receiving metoprolol CR had a greater decrease in angiotensin II ( P=0.036 ) and renin ( P=0.032 ) levels but an increase in N-terminal atrial natriuretic peptide and brain natriuretic peptide levels ( P<0 . 01 ) . There were fewer deaths in the group receiving beta-blockers ( 3 . 4 % versus 8.1 % ) , and there was a similar number of patients experiencing the composite outcomes of death or any hospitalization . CONCLUSIONS When added to ACE inhibitors , angiotensin II receptor antagonists , or both , the use of metoprolol CR improves ventricular function , reduces activation of the renin-angiotensin systems , and results in fewer deaths In a r and omized primary prevention trial including 3,234 men with mild to moderate uncomplicated hypertension , the effect of the beta-blocker metoprolol or a thiazide diuretic as an initial antihypertensive therapy was compared regarding the risk of sudden cardiovascular death during a follow-up ranging from 2.3 to 10.8 years ( median of 4.2 years ) . Only men aged 40 to 64 years were included in the study . The r and omization of patients into the metoprolol ( n = 1,609 ) or diuretic group ( n = 1,625 ) was performed after stratification for age , smoking habits , serum cholesterol , and systolic blood pressure . At baseline the two treatment groups were well matched . Metoprolol was given in a mean dose of 174 mg daily and the mean dose of thiazide diuretic was either 46 mg hydrochlorothiazide daily or 4.4 mg bendroflumethiazide daily . Identical blood pressure control was achieved using the fixed therapeutic schedule . Total and cardiovascular mortality were significantly lower for metoprolol than for diuretics , owing to fewer deaths from coronary heart disease and stroke . Of the cardiovascular deaths , 78 % were classified as sudden cardiovascular deaths ( occurred within 24 h after the onset of symptoms ) . There were significantly fewer sudden cardiovascular deaths in the metoprolol group compared to the diuretic group ( 32 v 45 , P = .017 ) . The present results suggest that initial antihypertensive therapy with metoprolol is associated with a lesser incidence of sudden cardiovascular deaths than initial diuretic treatment in uncomplicated hypertension 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 OBJECTIVES We sought to evaluate the influence of pretreatment systolic blood pressure ( SBP ) on the efficacy and safety of carvedilol in patients with chronic heart failure ( CHF ) . BACKGROUND Although beta-blockers reduce the risk of death in CHF , there is little reported experience with these drugs in patients with a low pretreatment SBP , who may respond poorly to beta-blockade . METHODS We studied 2,289 patients with severe CHF who participated in the Carvedilol Prospect i ve R and omized Cumulative Survival ( COPERNICUS ) trial . RESULTS Compared with placebo , carvedilol improved the clinical status and reduced the risk of death and the combined risk of death or hospitalization for any reason , for a cardiovascular reason , or for worsening heart failure ( p < 0.001 for all ) . The relative magnitude of these benefits did not vary as a function of the pretreatment SBP ( all interaction : p > 0.10 ) . However , because patients with the lowest SBP were at highest risk of an event , they experienced the greatest absolute benefit from treatment with carvedilol . The lower the pretreatment SBP , the more likely that patients would report an adverse event , be intolerant of high doses of the study drug , or require permanent withdrawal of treatment ( p < 0.001 for all ) . However , these risks were primarily related to the severity of the underlying illness and not to treatment with carvedilol . CONCLUSIONS The current study provides little support for concerns about using beta-blockers ( particularly those with vasodilatory actions ) in patients with severe CHF who have a low SBP . Pretreatment blood pressure can identify patients who have the greatest need for risk reduction with carvedilol BACKGROUND The apparent shortfall in prevention of coronary heart disease ( CHD ) noted in early hypertension trials has been attributed to disadvantages of the diuretics and beta blockers used . For a given reduction in blood pressure , some suggested that newer agents would confer advantages over diuretics and beta blockers . Our aim , therefore , was to compare the effect on non-fatal myocardial infa rct ion and fatal CHD of combinations of atenolol with a thiazide versus amlodipine with perindopril . METHODS We did a multicentre , prospect i ve , r and omised controlled trial in 19 257 patients with hypertension who were aged 40 - 79 years and had at least three other cardiovascular risk factors . Patients were assigned either amlodipine 5 - 10 mg adding perindopril 4 - 8 mg as required ( amlodipine-based regimen ; n=9639 ) or atenolol 50 - 100 mg adding bendroflumethiazide 1.25 - 2.5 mg and potassium as required ( atenolol-based regimen ; n=9618 ) . Our primary endpoint was non-fatal myocardial infa rct ion ( including silent myocardial infa rct ion ) and fatal CHD . Analysis was by intention to treat . FINDINGS The study was stopped prematurely after 5.5 years ' median follow-up and accumulated in total 106 153 patient-years of observation . Though not significant , compared with the atenolol-based regimen , fewer individuals on the amlodipine-based regimen had a primary endpoint ( 429 vs 474 ; unadjusted HR 0.90 , 95 % CI 0.79 - 1.02 , p=0.1052 ) , fatal and non-fatal stroke ( 327 vs 422 ; 0.77 , 0.66 - 0.89 , p=0.0003 ) , total cardiovascular events and procedures ( 1362 vs 1602 ; 0.84 , 0.78 - 0.90 , p<0.0001 ) , and all-cause mortality ( 738 vs 820 ; 0.89 , 0.81 - 0.99 , p=0.025 ) . The incidence of developing diabetes was less on the amlodipine-based regimen ( 567 vs 799 ; 0.70 , 0.63 - 0.78 , p<0.0001 ) . INTERPRETATION The amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen . On the basis of previous trial evidence , these effects might not be entirely explained by better control of blood pressure , and this issue is addressed in the accompanying article . Nevertheless , the results have implication s with respect to optimum combinations of antihypertensive agents The Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints ( CONVINCE ) Trial is a r and omized , prospect i ve , double-blind , parallel-group , two-arm , actively controlled , multicenter , international 5-year clinical trial involving 15,000 patients . CONVINCE will compare the incidence of fatal or nonfatal myocardial infa rct ion ( MI ) , fatal or nonfatal stroke , or cardiovascular-disease-related death in two antihypertensive treatment regimens . One treatment arm begins with controlled onset-extended release (COER)-verapamil , which has its major antihypertensive effect 6 - 12 hours after administration . The other arm ( st and ard of care ( SOC ) ) begins with either hydrochlorothiazide ( HCTZ ) or atenolol , one of which is preselected by the investigator for an individual patient prior to r and omization . Secondary objectives include comparisons of the regimens for each of the components of the primary endpoint ( separately ) , death or hospitalization related to cardiovascular disease , efficacy in lowering blood pressure to goal , primary events occurring between 6 am and noon , all-cause mortality , withdrawals from blinded therapy , cancer , and hospitalizations due to bleeding .  Patients may be enrolled if they are hypertensive and at least 55 years of age and have an established second risk factor for cardiovascular disease . Initial medications include COER-verapamil ( 180 mg/d ) , HCTZ ( 12.5 mg/d ) , or atenolol ( 50 mg/d ) . Initial doses are doubled if blood pressure ( BP ) does not reach goal ( systolic BP < 140 mm and diastolic BP < 90 mm Hg ) . If BP is not controlled by the higher dose of the initial medication , HCTZ is added to COER-verapamil , or the SOC choice not initially selected is added in the SOC arm . An ACE-inhibitor is recommended ( although nearly any open-label medication is allowed ) as the third step for patients whose BP is not adequately controlled or who have a contraindication to one of the two SOC medications . Patients take two sets of tablets daily , one in the morning and one in the evening . Although most patients switch from an established antihypertensive medication to r and omized treatment , untreated patients with stages I-III hypertension ( SBP between 140 and 190 or DBP between 90 and 110 mm Hg ) are eligible . Outcomes are monitored by an independent Data and Safety Monitoring Board . Enrollment began during the third quarter of 1996 , and follow-up is to be completed in the third quarter of 2002 BACKGROUND Beta blockers reduce mortality in patients who have chronic heart failure , systolic dysfunction , and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors .  We aim ed to compare the effects of carvedilol and metoprolol on clinical outcome . METHODS In a multicentre , double-blind , and r and omised parallel group trial , we assigned 1511 patients with chronic heart failure to treatment with carvedilol ( target dose 25 mg twice daily ) and 1518 to metoprolol ( metoprolol tartrate , target dose 50 mg twice daily ) . Patients were required to have chronic heart failure ( NYHA II-IV ) , previous admission for a cardiovascular reason , an ejection fraction of less than 0.35 , and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated . The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission . Analysis was done by intention to treat . FINDINGS The mean study duration was 58 months ( SD 6 ) . The mean ejection fraction was 0.26 ( 0.07 ) and the mean age 62 years ( 11 ) . The all-cause mortality was 34 % ( 512 of 1511 ) for carvedilol and 40 % ( 600 of 1518 ) for metoprolol ( hazard ratio 0.83 [ 95 % CI 0.74 - 0.93 ] , p=0.0017 ) . The reduction of all-cause mortality was consistent across predefined subgroups . The composite endpoint of mortality or all-cause admission occurred in 1116 ( 74 % ) of 1511 on carvedilol and in 1160 ( 76 % ) of 1518 on metoprolol ( 0.94 [ 0.86 - 1.02 ] , p=0.122 ) . Incidence of side-effects and drug withdrawals did not differ by much between the two study groups . INTERPRETATION Our results suggest that carvedilol extends survival compared with metoprolol Summary The International Prospect i ve Primary Prevention Study in Hypertension ( IPPPSH ) , an international multicentre r and omised double-blind trial , compares antihypertensive regimens containing a beta-blocker ( oxprenolol ) with regimens not containing a beta-blocker . The protocol was developed and the study started in 1977 . 6,357 patients fulfilled the inclusion criteria and were enrolled by the end of 1980 . Patients have been treated in 6 countries for 3 to 5 years by 288 general practitioner and hospital out-patient centres . Follow-up was finished at the end of 1983 when 25,651 years of patient treatment had been completed . At entry patients had a diastolic pressure of 100–125 mmHg with no clinical evidence of cerebrovascular or ischaemic heart disease ( W.H.O. Stages I and II hypertension ) . The study was design ed to examine three main objectives : any influence of oxprenolol on the incidence of myocardial infa rct ion and sudden death compared with antihypertensive therapy not containing a beta-blocker ; the influence of cerebrovascular accidents in the same two groups ; a comparison of the antihypertensive effectiveness , and the subjective and objective tolerability of the regimens . This paper summarises the objectives and methodology , and examines r and omisation between the two treatment groups at entry into the IPPPSH -Losartan was the first available orally administered selective antagonist of the angiotensin II type 1 receptor developed for the treatment of hypertension . The Losartan Intervention For Endpoint ( LIFE ) Reduction in Hypertension Study is a double-blind , prospect i ve , parallel group study design ed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality .  Patients with essential hypertension , aged between 55 and 80 years , and ECG-documented left ventricular hypertrophy ( LVH ) were included . Altogether , 9223 patients in Sc and inavia , the United Kingdom , and the United States were r and omized from June 1995 through April 1997 , and 9194 remain after exclusion of a study center at which irregularities were discovered . This population of hypertensives ( mean systolic/diastolic blood pressure , 174.4/97.8 mm Hg ) with LVH comprises women ( 54.1 % ) and men , mostly retired from active work ( mean age , 66.9 years ) , with a high prevalence of overweight ( mean body mass index , 28.0 kg/m2 ) , diabetes mellitus ( 12.3 % ) , lipid disorders ( 18.0 % ) , and symptoms or signs of coronary heart disease ( 15.1 % ) . There were fewer current smokers  ( < 17 % ) than in the general population , and approximately 7 % were nonwhite . Almost 30 % of participants had been untreated for at least 6 months when screened for the study . Only 1557 persons who entered the placebo run-in period of 14 days were excluded , predominantly because of sitting blood pressures above or below the predetermined range of 160 - 200/95 - 115 mm Hg and ECG-LVH criteria not met . By application of simple 12-lead ECG criteria for LVH ( Cornell voltage QRS duration product formula plus Sokolow-Lyon voltage read by a core laboratory ) , hypertensive patients with LVH with an average 5-year coronary heart disease risk of 22.3 % according to the Framingham score were identified . This population is now being treated ( goal , < 140/90 mm Hg ) in adherence with the protocol for at least 4 years after final enrollment ( ie , through April 2001 ) and until at least 1040 patients suffer myocardial infa rct ion , stroke , or cardiovascular death A r and omised trial of the treatment of hypertension in 884 patients aged 60 to 79 years at the onset showed a reduction of 18/11 mm Hg in blood pressure over a mean follow up period of 4.4 years . The principal antihypertensive agents were atenolol and bendrofluazide . There was a reduction in the rate of fatal stroke in the treatment group to 30 % of that in the control group ( 95 % confidence interval 11 - 84 % , p less than 0.025 ) . The rate of all strokes ( fatal and non-fatal ) in the treatment group was 58 % of that in the control group ( 95 % confidence interval 35 - 96 % , p less than 0.03 ) . The incidence of myocardial infa rct ion and total mortality was unaffected by treatment . Question naires completed by the patients and their relatives failed to identify any differences in symptoms that were likely to be due to treatment BACKGROUND Characteristics such as age and race are often cited as determinants of the response of blood pressure to specific antihypertensive agents , but this clinical ly important issue has not been examined in sufficiently large trials , involving all st and ard treatments , to determine the effect of such factors . METHODS In a r and omized , double-blind study at 15 clinics , we assigned 1292 men with diastolic blood pressures of 95 to 109 mm Hg , after a placebo washout period , to receive  placebo or one of six drugs : hydrochlorothiazide ( 12.5 to 50 mg per day ) , atenolol ( 25 to 100 mg per day ) , captopril ( 25 to 100 mg per day ) , clonidine ( 0.2 to 0.6 mg per day ) , a sustained-release preparation of diltiazem ( 120 to 360 mg per day ) , or prazosin ( 4 to 20 mg per day ) . The drug doses were titrated to a goal of less than 90 mm Hg for maximal diastolic pressure , and the patients continued to receive therapy for at least one year . RESULTS The mean ( + /- SD ) age of the r and omized patients was 59 + /- 10 years , and 48 percent were black . The average blood pressure at base line was 152 + /- 14/99 + /- 3 mm Hg . Diltiazem therapy  had the highest rate of success : 59 percent of the treated patients had reached the blood-pressure goal at the end of the titration phase and had a diastolic blood pressure of less than 95 mm Hg at one year .  Atenolol  was successful by this definition in 51 percent of the patients , clonidine in 50 percent , hydrochlorothiazide in 46 percent , captopril in 42 percent , and prazosin in 42 percent ; all these agents were superior to placebo ( success rate , 25 percent ) . Diltiazem ranked first for younger blacks ( < 60 years ) and older blacks ( > or = 60 years ) , among whom the success rate was 64 percent , captopril for younger whites ( success rate , 55 percent ) , and atenolol for older whites ( 68 percent ) . Drug intolerance was more frequent with clonidine ( 14 percent ) and prazosin ( 12 percent ) than with the other drugs . CONCLUSIONS Among men , race and age have an important effect on the response to single-drug therapy for hypertension . In addition to cost and quality of life , these factors should be considered in the initial choice of a drug Hypertension treatment commonly requires multiple agents to achieve target blood pressure ( BP ) .  β-blockers and angiotensin-converting enzyme inhibitors ( ACEIs ) are commonly co-prescribed in clinical practice although few data are available that test their additivity on BP lowering . The efficacy and safety of once-daily extended-release carvedilol ( carvedilol CR ) combined with the ACEI lisinopril in a double-blind , r and omized , factorial design study were studied . Patients ( N=656 ) with stage 1 or 2 hypertension were r and omized evenly to 1 of 15 groups for 6 weeks : carvedilol CR monotherapy 20 mg , 40 mg , or 80 mg/d ; lisinopril monotherapy 10 mg , 20 mg , or 40 mg/d ; or 1 of 9 combinations of carvedilol CR plus lisinopril initiated simultaneously . Primary efficacy measures ( assessed by ambulatory BP monitoring [ ABPM ] ) were change from baseline in 24-hour mean diastolic BP ( DBP ) and in trough ( 20 - 24 hours ) DBP . Continuous efficacy variables were assessed using analysis of covariance . Whether any combination dose was superior to its monotherapy components was assessed using the Hung AVE procedure . Despite the presence of additional BP lowering observed with most of the combinations compared with their monotherapy components , the Hung AVE test was not significant for either primary efficacy measures . Post hoc analyses of the high-dose combination groups ( carvedilol CR/lisinopril regimens of 80/10 mg , 80/20 mg , 80/40 mg , 20/40 mg , and 40/40 mg ) showed a significant treatment difference compared with both carvedilol CR 80 mg and lisinopril  40 mg for 24-hour mean DBP but not for trough DBP . With the exception of dizziness , individual adverse events did not increase with ascending doses or combinations . The superiority of initiating combination treatment with carvedilol CR and lisinopril compared with the monotherapy components was not demonstrated with the ABPM measurements . Nonetheless , the post hoc assessment combining all high-dose groups did produce significant 24-hour mean BP reduction when compared with the high-dose monotherapy groups . The tolerability profile of initiating combination therapy was generally comparable to the initiation of treatment with monotherapy Abstract Objective : To compare the effectiveness and tolerability of hydrochlorothiazide , atenolol , nitrendipine , and enalapril in patients with mild to moderate hypertension . Design : R and omised multicentre trial over 48 weeks with double blind comparison of treatments . Setting : 48 centres in four countries . Patients : 868 patients with essential hypertension ( diastolic blood pressure 95 - 120 mm Hg ) Interventions : Initial treatment ( step 1 ) consisted of 12.5 mg hydrochlorothiazide ( n=215 ) , 25 mg atenolol ( n=215 ) , 10 mg nitrendipine ( n=218 ) , or 5 mg enalapril ( n=220 ) once daily . If diastolic blood pressure was not reduced to < 90 mm Hg within four weeks , doses were increased to 25 mg , 50 mg , 20 mg , 10 mg , respectively , once daily ( step 2 ) and after two more weeks to twice daily ( step 3 ) . The eight week titration phase was followed by an additional 40 weeks for patients who had reached the target diastolic pressure . Main outcome measure : Blood pressure by means of an automatic device with repeated measurements . Results : After eight weeks the response rate for  atenolol  ( 63.7 % ) was significantly higher than for enalapril ( 50.0 % ) , hydrochlorothiazide ( 44.7 % ) , or nitrendipine ( 44.5 % ) . After one year atenolol was still more effective ( 48.0 % ) than hydrochlorothiazide ( 35.4 % ) and nitrendipine ( 32.9 % ) , but not significantly better than enalapril ( 42.7 % ) . The treatment related dropout rate was higher ( P<0.001 ) in the nitrendipine group ( n=28 ) . Conclusions : There is no evidence of superiority for antihypertensive effectiveness or tolerability of the “ new ” classes of antihypertensives ( calcium channel blockers and angiotensin converting enzyme inhibitors ) . As these drugs are now widely used as treatment of first choice , our results further emphasise the need for studies confirming that they also reduce morbidity and mortality , as has been shown for diuretics and ß blockers . Key messages Calcium channel blockers and angiotensin converting enzyme inhibitors as initial monotherapy in the treatment of hypertension Reduction in mortality has been shown only with established ß blockers and diuretics Comparison of treatment with hydrochlorothiazide , atenolol , nitrendipine , and enalapril showed no superiority of the new drug classes Atenolol was the most effective drug , while nitrendipine showed the highest drop out rat  Elderly patients  respond better to hydrochlorothiazide and nitrendipine , and women better to enalapril , although in both subgroups the highest rate of response was with Objective To test the primary hypothesis that a newer antihypertensive treatment regimen ( calcium channel blocker ± an angiotensin converting enzyme inhibitor ) is more effective than an older regimen ( β-blocker ± a diuretic ) in the primary prevention of coronary heart disease ( CHD ) . To test a second primary hypothesis that a statin compared with placebo will further protect against CHD endpoints in hypertensive subjects with a total cholesterol ⩽ 6.5 mmol/l . Design Prospect i ve , r and omized , open , blinded endpoint trial with a double-blinded 2 × 2 factorial component . Setting Patients were recruited mainly from general practice s. Patients Men and women aged 40–79 were eligible if their blood pressure was ⩾160 mmHg systolic or ⩾ 100 mmHg diastolic ( untreated ) or ⩾140 mmHg systolic or ⩾ 90 mmHg diastolic ( treated ) at r and omization . Interventions Patients received either amlodipine ( 5/10 mg ) ± perindopril ( 4/8 mg ) or atenolol ( 50/100 mg ) ± bendroflumethiazide ( 1.25/2.5 mg ) + K+ with further therapy as required to reach a blood pressure of ⩽140 mmHg systolic and 90 mmHg diastolic . Patients with a total cholesterol of ⩽ 6.5 mmol/l were further r and omized to receive either atorvastatin 10 mg or placebo daily . Main outcome measure Non-fatal myocardial infa rct ion ( MI ) and fatal coronary heart disease ( CHD ) . Results 19 342 men and women were initially r and omized , of these 10 297 were also r and omized into the lipid-lowering limb . All patients had three or more additional cardiovascular risk factors . Conclusions The study has 80 % power ( at the 5 % level ) to detect a relative difference of 20 % in CHD endpoints between the calcium channel blocker-based regimen and the β-blocker-based regimen . The lipid-lowering limb of the study has 90 % power at the 1 % level to detect a relative difference of 30 % in CHD endpoints between groups Background and Purpose : & bgr;‐Blockers prevent vascular events in patients after myocardial infa rct ion and lower blood pressure , the main risk factor for stroke . Hence , we assessed the effects of atenolol on the occurrence of death from vascular causes , stroke , or myocardial infa rct ion and on blood pressure in patients after a transient ischemic attack or nondisabling ischemic stroke . Methods : In a double‐blind , placebo‐controlled r and omized clinical trial we studied the occurrence of the outcome event death from vascular causes , nonfatal stroke , or nonfatal myocardial infa rct ion and the outcome event fatal or nonfatal stroke as well as blood pressure on follow‐up . A total of 1,473 aspirin‐treated patients with transient ischemic attack or nondisabling ischemic stroke were r and omized to 50 mg atenolol daily or placebo . The mean follow‐up was 2.6 years . Results : Patients on atenolol had a risk of 97/732 ( 13.3 % ) for the combined outcome event versus a risk of 95/741 ( 12.8 % ) for those on placebo ( adjusted hazard ratio , 1.00 ; 95 % confidence interval , 0.76‐1.33 ) . The adjusted hazard ratio for fatal or nonfatal stroke was 0.82 ( 95 % confidence interval , 0.57‐1.19 ) . More patients on & bgr;‐blocker ( 153 ) reported adverse effects than on placebo ( 103 ) . At the first follow‐up visit after r and omization ( median at 4 months ) systolic blood pressure in the atenolol group had dropped by 8.0 mm Hg compared with 2.2 mm Hg in the placebo group ( difference , 5.8 mm Hg ; 95 % confidence interval , 2.9‐8.6 mm Hg ) . For diastolic blood pressure this difference was 2.9 mm Hg ( 95 % confidence interval , 1.5‐4.4 mm Hg ) . Conclusions : Our data neither confirm nor rule out that atenolol prevents important vascular events in patients after transient ischemic attack or nondisabling ischemic stroke , given the modest effect on blood pressure , the restrictions in patient selection , and the limited number of patient‐years . ( Stroke 1993;24:543‐548 BACKGROUND Beta-blockers improve left ventricular ( LV ) systolic function and prognosis in patients with chronic heart failure ( CHF ) , but their different pleiotropic properties may influence their cardiovascular effects . This open-label study compared the effects of long-term treatment with nebivolol versus carvedilol on LV ejection fraction ( LVEF ) , in hypertensive CHF patients . Secondary end points were to assess the effect of the 2 beta-blockers on exercise capacity and clinical outcome . METHODS AND RESULTS A total of 160 hypertensive CHF patients , with LVEF < 40 % and in New York Heart Association ( NYHA ) functional class I , II , or III , were r and omly assigned to receive nebivolol or carvedilol for 24 months . At baseline and at the end of treatment , all patients underwent clinical evaluation , echocardiography , and 6-minute walking test . The target doses were 10 mg/d for nebivolol and 50 mg/d for carvedilol . Compared with baseline values , LVEF increased by a similar extent in the carvedilol ( C ) and nebivolol ( N ) groups ( C from 36.1 % ( SD 1.5 % ) to 40.9 % ( SD 1.9 % ) , P < .001 ; N from 34.1 % ( SD 1.8 % ) to 38.5 % ( SF 2.2 % ) , P < .001 ) . Heart rate and NYHA functional class decreased significantly in both groups , and the 6-minute walking distance increased ( C from 420 m ( SD 104 m ) to 490 m ( SD 115 m ) , P < .001 ; N from 421 m ( SD 118 m ) to 487 m ( SD 138 m ) , P < .001 ) . During 24 months , 21 carvedilol recipients ( 26 % ) and 18 nebivolol recipients ( 22 % ) had cardiac events , including 3 and 4 deaths , respectively . CONCLUSION In the long term , nebivolol and carvedilol appear to be similarly effective in the treatment of hypertensive patients with CHF The present study of primary prevention in white men aged 40 to 64 years attempts to investigate whether a beta-blocker given as initial antihypertensive treatment would lower total mortality to a greater extent than thiazide diuretics .  Patients were r and omized to metoprolol ( n = 1609 , 8110 patient-years ) or a thiazide diuretic ( n = 1625 , 8070 patient-years ) . The median follow-up time was 4.2 years . The mean dose of metoprolol was 174 mg/d , and of thiazide diuretics , 46 mg/d of hydrochlorothiazide or 4.4 mg/d of bendroflumethiazide . Identical control of blood pressure was achieved using a fixed therapeutic schedule . Total mortality was significantly lower for metoprolol than for thiazide diuretics because of fewer deaths from coronary heart disease and stroke . Total mortality was also significantly lower in smokers r and omized to metoprolol .  The benefit demonstrated in patients treated with metoprolol seems to have important implication s for clinical practice 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 . Abstract Beta-blocking drugs may be more effective than saluretic diuretics in reducing the total mortality and incidence of myocardial infa rct ion , sudden death and stroke in middle-aged men with mild to moderate hypertension . To test this hypothesis , an international multicenter , r and omized study is in progress , and its design and some early results are presented here . It is probable that 4,000–5,000 men will need to be enrolled for five years to show a statistically significant difference between treatments . Identical control of blood pressure in the two treatment groups is m and atory , and has been achieved using a fixed therapeutic schedule . The ongoing study will be completed during 1985–1990 Tobacco smoking is a powerful risk predictor for coronary disease . In the recent Medical Research Council ( MRC ) Hypertension Trial , which this article discusses , it also proved to be an important predictor of stroke . The MRC trial had two active treatment groups , one of which received bendrofluazide and the other propranolol . The main positive result of the trial was a 45 % reduction in stroke events in the actively treated groups . Propranolol appeared to be much less effective than bendrofluazide in the prevention of stroke in smokers , although both active drugs were equally effective in nonsmokers . Possible explanations for this lack of efficacy in smokers are discussed . Coronary events were not reduced by treatment , although there was a trend toward their reduction in nonsmoking men treated with propranolol . The lack of effect of propranolol in reducing coronary morbidity and mortality rates was a surprise in view of the positive results from trials with both short-term and long-term treatment with beta-adrenergic blockade after myocardial infa rct ion OBJECTIVE The CARDHIAC ( CARduran en pacientes Diabéticos con HIpertensi'on Arterial no Controlada ) trial examined the effects of doxazosin gastrointestinal therapeutic system ( GITS ) and atenolol on 3 separate measures of target-organ damage -- left ventricular mass index ( LVMI ) , carotid intima media thickness ( IMT ) , and urinary albumin excretion (UAE)--in  patients with type 2 diabetes mellitus and hypertension . METHOD This trial had a prospect i ve , open-label , blinded-evaluation design and a duration of 9 months . Patients whose blood pressure ( BP ) was uncontrolled ( systolic BP > or = 130 mm Hg and /or diastolic BP > or = 80 mm Hg ) despite at least 1 month of treatment with a renin-angiotensin blocker and diuretic  were r and omly allocated to receive doxazosin GITS 4 mg or atenolol 50 mg once daily in addition to their existing treatment . Seated BP was measured at study visits at 1 , 3 , 6 and 9 months ; if the BP goal was not achieved at any visit , the dose of doxazosin or atenolol was titrated upward to 8 or 100 mg , respectively . Treatment compliance ( pill count ) and adverse reactions were monitored at each visit . Each patient underwent echocardiography and Doppler ultrasonography at baseline and at the end of the study for evaluation of the change in LVMI . The change in carotid IMT was evaluated by carotid ultrasound examination at the same time points . UAE also was measured at baseline and the end of the study . RESULTS Sixty patients ( 100 % white ; 51 % female ; mean [ SD ] age , 63.4 [ 7.5 ] years ; body mass index , 28.2 [ 3.4 ] kg/m(2 ) ) were r and omized to receive doxazosin GITS ( n=32 ) or atenolol ( n=28 ) . At baseline , mean BP was 150.2 (10.6)/90.1 ( 7.3 ) mm Hg in the doxazosin group and 153.1 (13.8)/92.3 ( 6.1 ) mm Hg in the atenolol group ( P = NS ) . At the end of the study , BP had decreased by 10.1 (3.2)/5.2 ( 1.3 ) mm Hg in the doxazosin group and 12.2 (4.2)/6.3 ( 2.1 ) mm Hg in the atenolol group ( both , P<0.001 vs baseline ; P = NS between groups ) . Heart rate at the end of the study was 78(6 ) beats/min in the doxazosin group ( P = NS vs baseline ) and 66(7 ) beats/min in the atenolol group ( P<0.01 vs baseline and between groups ) . LVMI decreased by 10.8 in the doxazosin group ( P=0.001 vs baseline ) and 4.2 % in the atenolol group ( P = NS vs baseline ; P=0.03 between groups ) . The changes in carotid IMT and UAE were not statistically significant between groups . CONCLUSIONS In this study in hypertensive patients with type 2 diabetes , LVMI was significantly decreased in doxazosin-treated patients relative to baseline and compared with atenolol-treated patients . The differences in carotid IMT and UAE were not statistically significant between groups BACKGROUND Patients with chronic kidney disease are at increased risk for cardiovascular ( CV ) events . METHODS We r and omly assigned 1,094 African Americans with hypertensive nephrosclerosis ( glomerular filtration rate [ GFR ] , 20 to 65 mL/min/1.73 m(2 ) [ 0.33 to 1.08 mL/s ] ) to initial antihypertensive treatment with either : ( 1 ) a beta-blocker , metoprolol ; ( 2 ) an angiotensin-converting enzyme inhibitor , ramipril ; or ( 3 ) a dihydropyridine calcium channel blocker , amlodipine , and either a usual-blood pressure ( BP ) or low-BP treatment goal . Using a design powered to detect renal outcome differences , we compared the effect of treatment on the CV event rate ( cardiac death , myocardial infa rct ion , stroke , and heart failure ) during a mean follow-up period of 4.1 years and determined baseline factors that predict CV outcomes . RESULTS Thirty-one patients died of CV disease ( 0.7%/patient-year ) , and 149 patients experienced at least 1 CV outcome ( 3.3%/patient-year ) . Overall , 202 CV events ( 4.5%/patient-year ) occurred . The CV outcome rate was not related significantly to r and omized interventions . In multivariable analyses , 7 baseline risk factors remained independently associated with increased risk for the CV composite outcome after controlling for age , sex , baseline GFR , and baseline proteinuria group : pulse pressure , duration of hypertension , abnormal electrocardiogram result , non-high-density lipoprotein cholesterol level , serum urea nitrogen level , urine protein-creatinine ratio , urine sodium-potassium ratio , and annual income less than 15,000 dollars . CONCLUSION Neither r and omized class of antihypertensive therapy nor BP level had a significant effect on the occurrence of CV events , possibly because of limited power . However , this analysis identifies unique and potentially modifiable CV risk factors in this high-risk cohort The Swedish trial in old patients with hypertension ( STOP-Hypertension ) is a multicentre , r and omized , double-blind study of beta-blockers/diuretics versus placebo in old hypertensives . Primary end-points are stroke and myocardial infa rct ion ( fatal and non-fatal ) as well as other cardiovascular mortality . To evaluate the logistics of STOP-Hypertension , a pilot study was carried out . All patients aged 70 - 84 years in 31 centres were consecutively registered in a log-book . Altogether 4668 patients were screened : 41.5 % had previously been treated for hypertension and 13.5 % had blood pressures greater than or equal to 180/105 mmHg . Thus , 55 % were ' hypertensive ' . In all , 465 patients ( 18 % of the ' hypertensive ' patients ) started a 3-month washout period ( previously treated , n = 396 ) or a 4-week run-in period ( previously untreated , n = 69 ) period . The most frequent reasons for not starting the run-in/washout were other indications for treatment with beta-blockers/diuretics ( 13 % ) , unwillingness to participate ( 8 % ) or isolated systolic hypertension ( 4 % ) . The pilot study was evaluated after 1 year : 89 patients ( 1.9 % ) had been r and omized , 66 patients ( 1.4 % ) were still in the run-in/washout period and the majority of the remaining patients were not r and omized because they had not reached the inclusion blood pressure ( greater than or equal to 180 mmHg systolic and /or greater than or equal to 105 mmHg diastolic ) following withdrawal of their antihypertensive medication . During the run-in/washout period there were few serious clinical events : one case of myocardial infa rct ion , three patients had strokes ( two fatal ) , 10 developed congestive heart failure , three tachyarrhythmia and two pneumonia ( one fatal ) . ( ABSTRACT TRUNCATED AT 250 WORDS Background The possibility that calcium antagonists exert an anti-atherosclerotic action at least partly independently of the blood-pressure-lowering effect is supported by results of a large number of experimental studies and can now be investigated by quantitative β-mode ultrasound imagining of the carotid artery walls . Design The European Lacidipine Study on Atherosclerosis ( ELSA ) is a prospect i ve , r and omized , double-blind , multinational trial comparing effects of 4-year treatment based on the long-acting , highly lipophilic calcium antagonist lacidipine with those of treatment based on the β-blocker atenolol on the development of carotid artery wall alterations in patients ( aged 45–75 years ) with mild-to-moderate hypertension ( systolic blood pressure 150–210 mmHg and diastolic blood pressure 95–115 mmHg ) . While the intervention study is progressing , this article summarizes baseline data obtained from the whole cohort of 2259 patients r and omly allocated to treatment . Methods Baseline ultrasound data were obtained from two replicate examinations performed shortly before r and om allocation to treatment by certified sonographers at 23 referral centres and read at the ultrasound coordinating centre at the Wake Forest University School of Medicine  . Intima — media thickness was measured at up to 12 different sites in the carotid artery tree and expressed as the mean of the maxima at these sites ( Mmax ) , the mean of the maxima at four sites in the distal common carotid artery and bifurcation ( CBMmax ) and the maximum intima — media thickness ( Tmax ) . Baseline demographic and clinical measurements were performed by investigators in 410 peripheral clinical units and 24 h ambulatory blood pressure monitorings read and vali date d by members of a central ized unit at the University of Milan . The statistical analysis centre at the Technische Universität Mächen received and analysed all baseline data , by calculating means ± SD , medians and ranges and performing correlation ( Spearman correlation coefficients ) and multiple regression analyses . Results Prevalence of carotid artery wall alterations among the hypertensive patients r and omly allocated to treatment in the ELSA was very high : 82 % had Tmax > 1.3 mm ( ‘ plaques ’ according to protocol ) and 17 % had Tmax > 1.0 and < 1.3 mm ( ‘ thickening ’ ) , with a median of two plaques per patient . We found significant correlations between ultrasound measurements and the following demographic and clinical variables : age , sex , systolic blood pressure and pulse pressure ( both clinic and ambulatory ) , concentrations of total , high-density lipoprotein and low-density lipoprotein cholesterol and triglycerides , smoking habit and duration of hypertension . We found no significant correlation to diastolic blood pressure and glucose concentration . A multiple regression analysis indicated significant variables in the following rank order : age , 24 h ambulatory pulse pressure , sex , low-density lipoprotein cholesterol concentration , triglyceride concentration , smoking and clinic systolic blood pressure . Conclusions Analysis of baseline data from the ELSA has shown that there is an extremely marked prevalence of carotid artery wall alterations among mild-to-moderate , middle-aged hypertensive patients . In addition to age , systolic blood pressure and pulse pressure , particularly if they are accurately measured by ambulatory monitoring , play a major role , somewhat greater than those of sex , low-density lipoprotein cholesterol concentration and smoking , in influencing intima — media thickness Men aged 40 - 64 years with mild to moderate hypertension [ diastolic blood pressure ( DBP ) 100 - 130 mmHg ] were r and omized to treatment with a  diuretic ( n = 3272 ) or a  beta-blocker ( n = 3297 ) , with additional drugs if necessary , to determine whether a beta-blocker based treatment differs from thiazide diuretic based treatment with regard to the prevention of coronary heart disease ( CHD ) events and death .  Patients with previous CHD , stroke or other serious diseases , or with contraindications to diuretics or beta-blockers were excluded . If normotension ( DBP less than 95 mmHg ) was not achieved by monotherapy , other antihypertensive drugs were added , but the two basic drugs were not crossed over . Patients were assessed at 6-monthly intervals . The mean follow-up for end-points was 45.1 months . Blood pressure ( BP ) side effects and end-points were recorded in a st and ardized manner . Entry characteristics and the BP reduction achieved were very similar in both treatment groups . All analyses were made on an intention-to-treat basis . The incidence of CHD did not differ between the two treatment groups . The incidence of fatal stroke tended to be lower in the beta-blocker treated group than in the diuretic treated group . Total mortality and the total number of end-points were similar in both groups . The percentage of patients withdrawn due to side effects was similar , whereas the number of reported symptoms , according to a question naire , was higher for patients on beta-blockers . The incidence of diabetes did not differ between the two groups . Subgroup analyses did not detect a difference in the effect of beta-blockers compared with diuretics in smokers as opposed to non-smokers , and beta-blockers also had the same effects as diuretics in the quartile with the highest predicted risk for CHD . Beta-blockers and thiazide diuretics were approximately equally well tolerated . The two drugs had a similar BP reducing effect although additional drugs had to be given more often in the diuretic group . Antihypertensive treatment based on a beta-blocker or on a thiazide diuretic could not be shown to affect the prevention of hypertensive complications , including CHD , to a different extent 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
target: Atenolol  was the beta‐blocker most used .
  Current evidence suggests that initiating treatment of hypertension with beta‐blockers leads to modest CVD reductions and little or no effects on mortality .
  These beta‐blocker effects are inferior to those of other antihypertensive drugs .
background: Abstract Background Beta‐blockers refer to a mixed group of drugs with diverse pharmacodynamic and pharmacokinetic properties .
  They have shown long‐term beneficial effects on mortality and cardiovascular disease ( CVD ) when used in people with heart failure or acute myocardial infa rct ion .
  Beta‐blockers were thought to have similar beneficial effects when used as first‐line therapy for hypertension .
  However , the benefit of beta‐blockers as first‐line therapy for hypertension without compelling indications is controversial .
  This review is an up date of a Cochrane Review initially published in 2007 and up date d in 2012 .
  Objectives To assess the effects of beta‐blockers on morbidity and mortality endpoints in adults with hypertension .