title: Effect of Irbesartan Versus Atenolol on Left Ventricular Mass and Voltage: Results of the CardioVascular Irbesartan Project Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack 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 The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial: Outcomes in Patients Receiving Monotherapy Myocardial Perfusion During Long-Term Angiotensin-Converting Enzyme Inhibition or &bgr;-Blockade in Patients With Essential Hypertension Stroke Reduction in Hypertensive Adults With Cardiac Hypertrophy Randomized to Losartan Versus Atenolol: The Losartan Intervention For Endpoint Reduction in Hypertension Study A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly. 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Long-Term Antihypertensive Efficacy and Safety of the Oral Direct Renin Inhibitor Aliskiren: A 12-Month Randomized, Double-Blind Comparator Trial With Hydrochlorothiazide Differential effects of angiotensin converting enzyme inhibition and diuretic therapy on reductions in ambulatory blood pressure, left ventricular mass, and vascular hypertrophy. Candesartan- and Atenolol-Based Treatments Induce Different Patterns of Carotid Artery and Left Ventricular Remodeling in Hypertension Microalbuminuria Reduction With Valsartan in Patients With Type 2 Diabetes Mellitus: A Blood Pressure–Independent Effect Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project. Antihypertensive Effect and Tolerability of Perindopril in Indian Hypertensive and Type 2 Diabetic Patients Clinical Events in High-Risk Hypertensive Patients Randomly Assigned to Calcium Channel Blocker Versus Angiotensin-Converting Enzyme Inhibitor in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Effects of amlodipine and lisinopril on intima–media thickness in previously untreated, elderly hypertensive patients (the ELVERA trial) Role of Diuretics in the Prevention of Heart Failure: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Effects of nisoldipine and lisinopril on microvascular dysfunction in hypertensive Type I diabetes patients with nephropathy. Effects of nisoldipine and lisinopril on left ventricular mass and function in diabetic nephropathy. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. 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Equivalence of indapamide SR and enalapril on microalbuminuria reduction in hypertensive patients with type 2 diabetes: The NESTOR* study Long-Term Effects of Irbesartan and Atenolol on the Renin-Angiotensin-Aldosterone System in Human Primary Hypertension: The Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) Effects of antihypertensive drugs losartan and levamlodipine besylate on insulin resistance in patients with essential hypertension combined with isolated impaired fasting glucose The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: rationale, design, and methods. The LIFE Study Group. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial of cardiovascular events in hypertension. Rationale and design. 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abstract: Regression of hypertensive left ventricular hypertrophy ( LVH ) is associated with improved prognosis . The aim of this trial was to compare the effects of irbesartan versus atenolol on LVH in subjects with essential hypertension . Because electrocardiographic and echocardiographic parameters of LVH carry disparate prognostic information , both methods were applied in this trial . In the r and omized , double-blind , multicenter trial CardioVascular Irbesartan Project , 240 patients with essential hypertension were treated with irbesartan or atenolol for 18 months . Voltage criteria used for LVH were Sokolow index , Cornell index , Cornell voltage × QRS duration product and Lewis index . In parallel , left ventricular mass ( LVM ) was determined by 2-dimensional guided M-mode echocardiography . After 6 and 18 months , reductions of LVM and voltage criteria for LVH were only found in subjects treated with irbesartan . However , a reduction of LVM was only detectable in subjects within the highest quartile of baseline LVM but not overall . In contrast , reductions of voltage criteria for LVH were detectable after 6 and 18 months even within commonly used normal limits . In conclusion , treatment of hypertension with irbesartan result ed in a significant reduction in the voltage criteria for LVH , although an effect on LVM was only seen in subjects with high baseline LVM . In contrast , atenolol did not lead to reductions in electrocardiographic or echocardiographic parameters of LVH . Because voltage criteria for LVH have been shown to predict cardiovascular outcome independently from LVM , we suggest that both methods should be used to accurately assess the benefits of antihypertensive treatment Background — Heart failure ( HF ) developing in hypertensive patients may occur with preserved or reduced left ventricular ejection fraction ( PEF [ ≥50 % ] or REF [ < 50 % ] ) . In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , 42 418 high-risk hypertensive patients were r and omized to chlorthalidone , amlodipine , lisinopril , or doxazosin , providing an opportunity to compare these treatments with regard to occurrence of hospitalized HFPEF or HFREF . Methods and Results — HF diagnostic criteria were prespecified in the ALLHAT protocol . EF estimated by contrast ventriculography , echocardiography , or radionuclide study was available in 910 of 1367 patients ( 66.6 % ) with hospitalized events meeting ALLHAT criteria . Cox regression models adjusted for baseline characteristics were used to examine treatment differences for HF ( overall and by PEF and REF ) . HF case fatality rates were examined . Of those with EF data , 44.4 % had HFPEF and 55.6 % had HFREF . Chlorthalidone reduced the risk of HFPEF compared with amlodipine , lisinopril , or doxazosin ; the hazard ratios were 0.69 ( 95 % confidence interval [ CI ] , 0.53 to 0.91 ; P=0.009 ) , 0.74 ( 95 % CI , 0.56 to 0.97 ; P=0.032 ) , and 0.53 ( 95 % CI , 0.38 to 0.73 ; P<0.001 ) , respectively . Chlorthalidone  reduced the risk of HFREF compared with amlodipine or doxazosin ; the hazard ratios were 0.74 ( 95 % CI , 0.59 to 0.94 ; P=0.013 ) and 0.61 ( 95 % CI , 0.47 to 0.79 ; P<0.001 ) , respectively . Chlorthalidone was similar to lisinopril with regard to incidence of HFREF ( hazard ratio , 1.07 ; 95 % CI , 0.82 to 1.40 ; P=0.596 ) . After HF onset , death occurred in 29.2 % of participants ( chlorthalidone/amlodipine/lisinopril ) with new-onset HFPEF versus 41.9 % in those with HFREF ( P<0.001 ; median follow-up , 1.74 years ) ; and in the chlorthalidone/doxazosin comparison that was terminated early , 20.0 % of HFPEF and 26.0 % of HFREF patients died ( P=0.185 ; median follow-up , 1.55 years ) . Conclusions — In ALLHAT , with adjudicated outcomes , chlorthalidone significantly reduced the occurrence of new-onset hospitalized HFPEF and HFREF compared with amlodipine and doxazosin . Chlorthalidone also reduced the incidence of new-onset HFPEF compared with lisinopril . Among high-risk hypertensive men and women , HFPEF has a better prognosis than HFREF 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 In the main Valsartan Antihypertensive Long-Term Use Evaluation ( VALUE ) report , we investigated outcomes in 15 245 high-risk hypertensive subjects treated with valsartan- or amlodipine-based regimens .  In this report , we analyzed outcomes in 7080 patients ( 46.4 % ) who , at the end of the initial drug adjustment period ( 6 months ) , remained on monotherapy .  Baseline characteristics were similar in the  valsartan ( N=3263 ) and amlodipine ( N=3817 ) groups . Time on monotherapy was 3.2 years ( 78 % of treatment exposure time ) . The average in-trial blood pressure was similar in both groups . Event rates in the monotherapy group were 16 % to 39 % lower than in the main VALUE trial . In the first analysis , we censored patients when they discontinued monotherapy ( “ censored ” ) ; in the second , we counted events regardless of subsequent therapy ( intention-to-treat principle ) . We also assessed the impact of duration of monotherapy on outcomes . No difference was found in primary composite cardiac end points , strokes , myocardial infa rct ions , and all-cause deaths with both analyses . Heart failure in the valsartan group was lower both in the censored and intention-to-treat analyses ( hazard ratios : 0.63 , P=0.004 and 0.78 , P=0.045 , respectively ) . Longer duration of monotherapy amplified between-group differences in heart failure . New-onset diabetes was lower in the valsartan group with both analyses ( odds ratios : 0.78 , P=0.012 and 0.82 , P=0.034 ) . Thus , despite lower absolute event rates in monotherapy patients , the relative risks of heart failure and new-onset diabetes favored valsartan . Moreover , these findings support the feasibility of comparative prospect i ve trials in lower-risk hypertensive patients Hypertension is associated with reduced coronary vasodilatory capacity , possibly caused by structural changes in the coronary resistance vessels . Because vasodilatory treatment may correct abnormal structure better than nonvasodilating treatment , we compared whether long-term angiotensin-converting enzyme ( ACE ) inhibition has a greater effect on coronary reserve and cardiovascular structure than & bgr;-blockade in patients with essential hypertension . Thirty previously untreated hypertensive patients were r and omized in a double-blind design to treatment for 1 year with either perindopril ( 4 to 8 mg per day , n=15 ) or atenolol ( 50 to 100 mg per day , n=15 ) and furthermore compared with normotensive controls . Cardiac output and left ventricular mass were measured with echocardiography and resistance artery structure was determined in vitro . Using positron emission tomography , myocardial perfusion ( MP ) was determined at rest and during dipyridamole-induced hyperemia while still on medication . Perindopril  reduced left ventricular mass by 14±4 % ( P<0.01 ) , peripheral vascular resistance by 12±6 % ( P<0.01 ) , and media thickness-to-lumen diameter ratio of resistance arteries by 16±4 % ( P<0.05 ) , whereas atenolol had no effect . Resting MP was decreased both by perindopril ( −11±4 % , P<0.01 ) and by atenolol ( −25±4 % , P<0.01 ) in parallel to the reduction in rate pressure product . Hyperemic MP was unaltered by perindopril ( + 2±6 % , P = NS ) , but reduced by atenolol ( −32±5 % , P<0.01 ) . Compared with atenolol , perindopril treatment result ed in higher coronary reserve ( P<0.05 ) . We conclude that compared with & bgr;-blockade , ACE inhibition increases coronary reserve and results in regression of hypertensive resistance artery structure and left ventricular hypertrophy . Vasodilating may thus be superior to nonvasodilating treatment in repairing the hypertensive myocardial microcirculation The Losartan Intervention For Endpoint reduction in hypertension ( LIFE ) study showed that treatment with the angiotensin II type-1 receptor antagonist losartan reduces overall stroke risk compared with conventional therapy with the & bgr;-blocker atenolol . We conducted secondary analyses in LIFE to determine the extent to which the cerebrovascular benefits of losartan apply to different clinical subgroups and stroke subtypes and to assess the dependence of these benefits on baseline and time-varying covariates . Among 9193 hypertensive patients with electrocardiographic evidence of left ventricular hypertrophy , r and om allocation to losartan-based treatment lowered the risk of fatal ( hazard ratio [ HR ] , 0.65 ; 95 % confidence interval [ CI ] , 0.43 to 0.96 ; P=0.032 ) and atherothrombotic stroke ( HR , 0.72 ; 95 % CI , 0.59 to 0.88 ; P=0.001 ) compared with atenolol-based therapy . Although comparable risk reductions occurred for hemorrhagic and embolic stroke , these were not statistically significant . The number of neurological deficits per stroke was similar , but there were fewer strokes in the losartan group for nearly every level of stroke severity . Effects were consistent in all clinical subgroups except for those defined by age and ethnicity . The benefits of losartan on all strokes were independent of baseline and time-varying risk factors , including blood pressure . The number needed to treat for 5 years to prevent 1 stroke was 54 for the average participant , declining to 25 , 24 , and 9 for patients with cerebrovascular disease , isolated systolic hypertension , and atrial fibrillation , respectively . In conclusion , substantial cerebrovascular benefit could be realized with the institution of losartan-based therapy over conventional therapy among hypertensive patients with left ventricular hypertrophy across the spectrum of cardiovascular risk BACKGROUND Treatment of hypertension with diuretics , beta-blockers , or both leads to improved outcomes . It has been postulated that agents that inhibit the renin-angiotensin system confer benefit beyond the reduction of blood pressure alone . We compared the outcomes in older subjects with hypertension who were treated with angiotensin-converting-enzyme ( ACE ) inhibitors with the outcomes in those treated with diuretic agents . METHODS We conducted a prospect i ve , r and omized , open-label study with blinded assessment of end points in 6083 subjects with hypertension who were 65 to 84 years of age and received health care at 1594 family practice s. Subjects were followed for a median of 4.1 years , and the total numbers of cardiovascular events in the two treatment groups were compared with the use of multivariate proportional-hazards models . RESULTS At base line , the treatment groups were well matched in terms of age , sex , and blood pressure . By the end of the study , blood pressure had decreased to a similar extent in both groups ( a decrease of 26/12 mm Hg ) . There were 695 cardiovascular events or deaths from any cause in the ACE-inhibitor group ( 56.1 per 1000 patient-years ) and 736 cardiovascular events or deaths from any cause in the diuretic group ( 59.8 per 1000 patient-years ; the hazard ratio for a cardiovascular event or death with ACE-inhibitor treatment was 0.89 [ 95 percent confidence interval , 0.79 to 1.00 ] ; P=0.05 ) . Among male subjects , the hazard ratio was 0.83 ( 95 percent confidence interval , 0.71 to 0.97 ; P=0.02 ) ; among female subjects , the hazard ratio was 1.00 ( 95 percent confidence interval , 0.83 to 1.21 ; P=0.98 ) ; the P value for the interaction between sex and treatment-group assignment was 0.15 . The rates of nonfatal cardiovascular events and myocardial infa rct ions decreased with ACE-inhibitor treatment , whereas a similar number of strokes occurred in each group ( although there were more fatal strokes in the ACE-inhibitor group ) . CONCLUSIONS Initiation of antihypertensive treatment involving ACE inhibitors in older subjects , particularly men , appears to lead to better outcomes than treatment with diuretic agents , despite similar reductions of blood pressure BACKGROUND Cardiac effects of hypertension include increased left ventricular ( LV ) mass and LV hypertrophy , as well as increased left atrial size , a predictor of stroke and atrial fibrillation . Although literature on reduction of LV mass with antihypertensive therapy is extensive , little information is available on effects of treatment on left atrial size . METHODS AND RESULTS Patients with mild to moderate hypertension ( diastolic blood pressure 95 to 109 mm Hg ) were r and omly allocated to treatment with atenolol , captopril , clonidine , diltiazem , hydrochlorothiazide , or prazosin in a double-masked trial . Two-dimensional targeted M-mode echocardiography was used to assess left atrial size and LV mass at baseline , 8 weeks , and 1 and 2 years . Longitudinal analysis examined changes in left atrial size from the baseline study , statistically adjusting for age , race , pretreatment left atrial size and LV mass , and serial measurements of systolic blood pressure , body weight , urinary sodium excretion , and physical activity score . Without adjustment for covariates , only hydrochlorothiazide was associated with decreases in left atrial size from baseline at 8 weeks ( -1.0 + /- 5.2 mm ; P=0.052 ) , 1 year ( -2.0 + /- 5.1 mm ; P=0.02 ) , and 2 years ( 4.6+/-7.2 mm ; P=0.002 ) . After adjustment for effects of covariates , patients with normal left atrial size had greater reduction ( -3.3 mm ) in left atrial size at 2 years with hydrochlorothiazide than with any other drug . For patients with left atrial enlargement , left atrial size decreased significantly with hydrochlorothiazide , atenolol , clonidine , and diltiazem at 1 year and with all treatments at 2 years . However , reduction at 2 years was greater with hydrochlorothiazide than with captopril or prazosin . CONCLUSIONS Antihypertensive drugs differ in their effects on left atrial size .  Hydrochlorothiazide was associated with greater overall reduction of left atrial size than other drugs effective for the treatment of hypertension . Reduction of left atrial size with therapy is in part independent of factors known to influence left atrial size , including LV mass and reduction of LV mass with treatment . The clinical benefit of reducing left atrial size with antihypertensive treatment remains to be determined Background —The Prospect i ve R and omized Enalapril Study Evaluating Regression of Ventricular Enlargement ( PRESERVE ) study was design ed to test whether enalapril achieves greater left ventricular ( LV ) mass reduction than does a nifedipine gastrointestinal treatment system by a prognostically meaningful degree on a population basis ( 10 g/m2 ) . Methods and Results —An ethnically diverse population of 303 men and women with essential hypertension and increased LV mass at screening echocardiography were enrolled at clinical centers on 4 continents and studied by echocardiography at baseline and after 6- and 12-month r and omized therapy . Clinical examination and blinded echocardiogram readings 48 weeks after study entry in an intention-to-treat analysis of 113 enalapril-treated and 122 nifedipine-treated patients revealed similar reductions in systolic/diastolic pressure ( −22/12 versus −21/13 mm Hg ) and LV mass index ( −15 versus −17g/m2 , both P > 0.20 ) . No significant between-treatment difference was detected in population subsets defined by monotherapy treatment , sex , age , race , or severity of baseline hypertrophy . Similarly , there was no between-treatment difference in change in velocities of early diastolic or atrial phase transmitral blood flow . More enalapril-treated than nifedipine-treated patients required supplemental treatment with hydrochlorothiazide ( 59 % versus 34 % , P < 0.001 ) but not atenolol ( 27 % versus 22 % , NS ) . Conclusions —Once-daily antihypertensive treatment with enalapril or long-acting nifedipine , plus adjunctive hydrochlorothiazide and atenolol when needed to control blood pressure , both had moderately beneficial and statistically indistinguishable effects on regression of LV hypertrophy BACKGROUND Diabetes mellitus is a strong risk factor for cardiovascular and renal disease . We investigated whether the angiotensin-converting-enzyme ( ACE ) inhibitor ramipril can lower these risks in patients with diabetes . METHODS 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study , aged 55 years or older , who had a previous cardiovascular event or at least one other cardiovascular risk factor , no clinical proteinuria , heart failure , or low ejection fraction , and who were not taking ACE inhibitors , were r and omly assigned ramipril ( 10 mg/day ) or placebo , and vitamin E or placebo , according to a two-by-two factorial design . The combined primary outcome was myocardial infa rct ion , stroke , or cardiovascular death . Overt nephropathy was a main outcome in a sub study . FINDINGS The study was stopped 6 months early ( after 4.5 years ) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo . Ramipril lowered the risk of the combined primary outcome by 25 % ( 95 % CI 12 - 36 , p=0.0004 ) , myocardial infa rct ion by 22 % ( 6 - 36 ) , stroke by 33 % ( 10 - 50 ) , cardiovascular death by 37 % ( 21 - 51 ) , total mortality by 24 % ( 8 - 37 ) , revascularisation by 17 % ( 2 - 30 ) , and overt nephropathy by 24 % ( 3 - 40 , p=0.027 ) . After adjustment for the changes in systolic ( 2.4 mm Hg ) and diastolic ( 1.0 mm Hg ) blood pressures , ramipril still lowered the risk of the combined primary outcome by 25 % ( 12 - 36 , p=0.0004 ) . INTERPRETATION Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes . The cardiovascular benefit was greater than that attributable to the decrease in blood pressure . This treatment represents a vasculoprotective and renoprotective effect for people with diabetes OBJECTIVES We report on a sub analysis of the effects of losartan and atenolol on cardiovascular events in black patients in the Losartan Intervention For Endpoint reduction in hypertension ( LIFE ) study . BACKGROUND The LIFE study compared losartan-based to atenolol-based therapy in 9,193 hypertensive patients with left ventricular hypertrophy ( LVH ) . Overall , the risk of the primary composite end point ( cardiovascular death , stroke , myocardial infa rct ion ) was reduced by 13 % ( p = 0.021 ) with losartan , with similar blood pressure ( BP ) reduction in both treatment groups . There was a suggestion of interaction between ethnic background and treatment ( p = 0.057 ) . METHODS Exploratory analyses were performed that placed LIFE study patients into black ( n = 533 ) and non-black ( n = 8,660 ) categories , overall , and in the U.S. ( African American [ n = 523 ] ; non-black [ n = 1,184 ] ) . RESULTS A significant interaction existed between the dichotomized groups ( black/non-black ) and treatment ( p = 0.005 ) ; a test for qualitative interaction was also significant ( p = 0.016 ) . The hazard ratio  ( losartan relative to atenolol ) for the primary end point favored atenolol in black patients ( 1.666 [ 95 % confidence interval ( CI ) 1.043 to 2.661 ] ; p = 0.033 ) and favored losartan in non-blacks ( 0.829 [ 95 % CI 0.733 to 0.938 ] ; p = 0.003 ) . In black patients , BP reduction was similar in both groups , and regression of electrocardiographic-LVH was greater with losartan . CONCLUSIONS Results of the sub analysis are sufficient to generate the hypothesis that black patients with hypertension and LVH might not respond as favorably to losartan-based treatment as non-black patients with respect to cardiovascular outcomes , and do not support a recommendation for losartan as a first-line treatment for this purpose . The sub analysis is limited by the relatively small number of events BACKGROUND We sought to determine the incidence of newly diagnosed diabetes in treated elderly hypertensive patients and the prognostic impact of diabetes on long-term survival . METHODS The Second Australian National Blood Pressure ( ANBP2 ) study r and omized 6,083 hypertensive patients aged 65 - 84 years to angiotensin-converting enzyme inhibitor ( ACEI ) or thiazide diuretic-based therapy and followed them for a median of 4.1 years . Long-term survival was determined in 5,678 patients over an additional median of 6.9 years after ANBP2 ( post-trial ) . RESULTS After ANBP2 , the cohort was classified into preexisting ( 7.2 % ) , newly diagnosed ( 5.6 % ) , and no diabetes ( 87.2 % ) groups . A 44 % higher incidence of newly diagnosed diabetes was observed in patients r and omized to thiazide diuretic compared with ACEI-based treatment . The other predictors of newly diagnosed diabetes were having a higher body mass index , having a higher r and om blood glucose , and living in a regional location compared to major cities ( a geographical classification based on accessibility ) at study entry . After completion of ANBP2 , compared with those with no diabetes , the preexisting diabetes group experienced higher cardiovascular ( hazards ratio ( HR ) = 1.65 ; 95 % confidence interval ( CI ) = 1.03 - 2.65 ) and all-cause mortality ( HR = 1.40 ; 95 % CI = 1.02 - 1.92 ) when adjusted for age , sex , and treatment . A similar pattern was observed after including the post-trial period for cardiovascular ( HR = 1.52 ; 95 % CI = 1.20 - 1.93 ) and all-cause mortality ( HR = 1.50 ; 95 % CI = 1.29 - 1.73 ) . However , when the newly diagnosed group was compared with the no diabetes group , no significant difference was observed in cardiovascular ( HR = 0.33 ; 95 % CI = 0.11 - 1.05 ) or all-cause mortality ( HR = 0.76 ; 95 % CI = 0.47 - 1.23 ) either during the ANBP2 trial or including post-trial follow-up ( cardiovascular : HR = 0.82 ; 95 % CI = 0.58 - 1.17 ; all-cause mortality : HR = 1.04 ; 95 % CI = 0.85 - 1.27 ) . CONCLUSIONS Long-term presence of diabetes reduces survival . Compared with thiazide diuretics , ACEI-based antihypertensives may delay the development of diabetes in those at risk and thus potentially improve cardiovascular outcome in the elderly Background — Diuretics are recommended as first-line agents for the treatment of hypertension . This r and omized , double-blind , multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension . Methods and Results — After a 2- to 4-week placebo run-in , 1124 patients ( mean sitting diastolic blood pressure [ BP ] 95 to 109 mm Hg ) were r and omized to aliskiren 150 mg ( n=459 ) , hydrochlorothiazide 12.5 mg ( n=444 ) , or placebo ( n=221 ) once daily . Forced titration ( to aliskiren 300 mg or hydrochlorothiazide 25 mg ) occurred at week 3 ; at week 6 , patients receiving placebo were reassigned ( 1:1 ratio ) to aliskiren 300 mg or hydrochlorothiazide 25 mg . From week 12 , amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled . Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method . BP reductions ( mean sitting systolic BP/mean sitting diastolic BP ) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 ( −20.3/−14.2 versus −18.6/−13.0 mm Hg ; P<0.05 ) and were also greater at week 52 ( −22.1/−16.0 versus −21.2/−15.0 mm Hg ; P<0.05 for mean sitting diastolic BP ) . At the end of the monotherapy period ( week 12 ) , aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP ( −17.4/−12.2 versus −14.7/−10.3 mm H ; P<0.001 ) . Adverse event rates were similar with aliskiren- ( 65.2 % ) and hydrochlorothiazide-based therapy ( 61.5 % ) . Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy ( 17.9 % versus 0.9 % ; P<0.0001 ) . Conclusions — Aliskiren treatment , both as monotherapy and with optional addition of amlodipine , provided significantly greater BP reductions than the respective hydrochlorothiazide regimens . Aliskiren-based therapy was well tolerated . Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension Diuretic-based therapy is less effective in reducing the cardiac complications of hypertension than the risk of stroke and may be less effective in reducing left ventricular ( LV ) mass than is therapy with angiotensin converting enzyme ( ACE ) inhibition . In view of the strong association of LV hypertrophy with cardiovascular risk , this study was design ed to compare the impact of therapy with a diuretic and ACE inhibition on cardiac and vascular structure . Fifty essential hypertensives ( 74 % male , 88 % nonwhite ) participated in a double-blind study for 6 months and were r and omized to either ramipril or hydrochlorothiazide ( HCTZ ) . Echocardiography , carotid ultrasonography  , and  ambulatory blood pressure ( BP ) monitoring were performed at baseline and 3 and 6 months after initiation of therapy . The 22 ramipril patients were comparable to the 28 HCTZ patients at baseline in age , race , and 24-h BP . Although HCTZ result ed in a greater reduction in 24-h BP , only treatment with ramipril result ed in a decrease in LV mass ( 193 to 179 g , P < .005 , v 184 to 182 g , P = NS ) , attributable to a reduction in wall thicknesses but not in chamber diameter . In multivariate analysis , both change in BP and treatment group were independent predictors of change in LV mass . Importantly , although neither drug reduced carotid artery cross-sectional area , relative wall thickness increased due to a tendency for vessel diameter to decrease and wall thickness to increase , particularly in the diuretic group . Ramipril caused a sustained fall in plasma angiotensin II , whereas HCTZ increased angiotensin II levels . Although diuretic therapy was more effective in lowering ambulatory BP in this predominantly nonwhite population , only therapy with ACE inhibition was associated with regression of LV mass . Vascular geometry was altered consistent with the reduction in distending pressure result ing in vascular remodelling Background and Purpose — Angiotensin receptor blocker (ARB)–based treatment reduces cardiovascular events and stroke more than does β-blocker – based treatment despite similar blood pressure ( BP ) reduction . We investigated whether these treatments have different effects on cardiac and large-artery remodelling and evaluated the relation of arterial remodelling to hemodynamic changes in subjects with hypertension . Methods — We compared the treatment effects of an ARB ( c and esartan cilexetil)-based regimen and a β-blocker (atenolol)–based regimen for 52 weeks on common carotid artery ( CCA ) and left ventricular structure in hypertensive patients in a r and omized , double-blind study .  Clinic brachial BP and 24-hour ambulatory BP , carotid BP , left ventricular mass index , CCA intima-media thickness , lumen diameter , intima-media area , and carotid blood flow were measured . Distensibility , circumferential tensile stress , Young ’s elastic modulus ( Em ) , and shear stress ( & tgr ; ) in the CCA were also calculated . Results — Both c and esartan and atenolol  reduced intima-media thickness and intima-media area and increased distensibility to similar extents after 52 weeks of treatment . Despite similar reductions in BP , treatment with atenolol result ed in a lesser reduction in left ventricular mass index , a decrease in lumen diameter , and a reduction in carotid blood flow compared with c and esartan . Conclusions — BP-independent effects of ARB on cardiac and arterial structure may contribute to the beneficial effects of these agents on cardiovascular disease Background —Elevated urine albumin excretion ( UAER ) is a modifiable risk factor for renal and cardiovascular disease in type 2 diabetes . Blockade of the renin-angiotensin system lowers UAER , but whether this effect is independent of blood pressure ( BP ) reduction remains controversial . The MicroAlbuminuria Reduction With VALsartan ( MARVAL ) study was design ed to evaluate the BP-independent effect of valsartan on UAER in type 2 diabetic patients with microalbuminuria . Methods and Results —Three hundred thirty-two patients with type 2 diabetes and microalbuminuria , with or without hypertension , were r and omly assigned to 80 mg/d valsartan or 5 mg/d amlodipine for 24 weeks . A target BP of 135/85 mm Hg was aim ed for by dose-doubling followed by addition of bendrofluazide and doxazosin whenever needed . The primary end point was the percent change in UAER from baseline to 24 weeks . The UAER at 24 weeks was 56 % ( 95 % CI , 49.6 to 63.0 ) of baseline with valsartan and 92 % ( 95 % CI , 81.7 to 103.7 ) of baseline with amlodipine , a highly significant between-group effect ( P < 0.001 ) . Valsartan lowered UAER similarly in both the hypertensive and normotensive subgroups . More patients reversed to normoalbuminuria with valsartan ( 29.9 % versus 14.5%;P = 0.001 ) . Over the study period , BP reductions were similar between the two treatments ( systolic/diastolic 11.2/6.6 mm Hg for valsartan , 11.6/6.5 mm Hg for amlodipine ) and at no time point was there a between-group significant difference in BP values in either the hypertensive or the normotensive subgroup . Conclusions —For the same level of attained BP and the same degree of BP reduction , valsartan lowered UAER more effectively than amlodipine in patients with type 2 diabetes and microalbuminuria , including the subgroup with baseline normotension . This indicates a BP-independent antiproteinuric effect of valsartan OBJECTIVE The Captopril Prevention Project ( CAPPP ) evaluated the effects of an ACE inhibitor-based therapeutic regimen on  cardiovascular mortality and morbidity in hypertension .  One planned sub analysis of the CAPPP was to evaluate the outcome in the diabetic patient group . RESEARCH DESIGN AND METHODS In the CAPPP , 572 ( 4.9 % of 10,985 hypertensive patients ) had diabetes at baseline and were studied according to a prospect i ve , r and omized , open , blinded , end point trial design . Patients aged 25 - 66 years with diastolic blood pressure > or = 100 mmHg were included and r and omized to receive either captopril or conventional antihypertensive treatment ( diuretics and /or beta-blockers ) . RESULTS The primary end point , fatal and nonfatal myocardial infa rct ion and stroke as well as other cardiovascular deaths , was markedly lower in the captopril than in the conventional therapy group ( relative risk [ RR ] = 0.59 ; P = 0.018 ) . Specifically , cardiovascular mortality , defined as fatal stroke and myocardial infa rct ion , sudden death , and other cardiovascular death , tended to be lower in the captopril group ( RR = 0.48 ; P = 0.084 ) , and no difference was observed between the study groups for stroke ( RR = 1.02 ; P = 0.96 ) . Myocardial infa rct ions were less frequent in the captopril group than in the conventional therapy group ( RR = 0.34 ; P = 0.002 ) . Furthermore , total mortality was lower in the captopril as compared with the conventional therapy group ( RR = 0.54 ; P = 0.034 ) . Patients with impaired metabolic control seemed to benefit the most from ACE inhibitor-based therapy . CONCLUSIONS Captopril is superior to a diuretic/beta-blocker antihypertensive treatment regimen in preventing cardiovascular events in hypertensive diabetic patients , especially in those with metabolic decompensation Abstract Objective : This study compared the antihypertensive effect and acceptability of a perindopril-based group with that of an atenolol-based  group in Indian hypertensive type 2 ( non-insulin-dependent ) diabetic patients . Design and Setting : 100 ambulant patients aged between 35 and 69 years were recruited into this monocentric , r and omised , double-blind study in two parallel groups for 1 year after a 1-month washout period on placebo . The setting was a tertiary care institution . Patients : All patients had stable , essential hypertension between 95 mm Hg and 115 mm Hg , type 2 diabetes with glycosylated haemoglobin ( HbA1c ) < 12 % , and albuminuria between 300 mg and 3.5g/24 hours . There were 50 patients per treatment group and two patient population groups were studied , intention-to-treat ( ITT ) and per- protocol ( PP ) . The former constituted all patients , whilst the latter included those without major protocol deviation and who completed the 12-month study . Interventions : The study drugs were perindopril 4 to 8 mg once daily or atenolol 50 to 100 mg once daily . In each group therapeutic adjustment was planned by doubling the dose and then by the addition of hydrochlorothiazide 25 mg daily . Nifedipine 30 to 60 mg daily was subsequently added if the desired drop in blood pressure was not obtained . The ITT group was analysed by Student ’s t-test , and a 2-way analysis of variance was performed for the PP population . Main Outcome Measures : A comparison of the control of hypertension , biochemical abnormalities , blood sugar and adverse effects was performed in the atenolol group versus the perindopril group . Results : On single-dose therapy after 1 month 17 patients ( 60 % ) had normal blood pressure [ diastolic blood pressure ( DBP ) ≤90 mm Hg ] on atenolol 50 mg daily , while 13 % ( 30.23 % ) had normal blood pressure ( DBP ≤90 mm Hg ) on perindopril 4 mg daily ( p = 0.013 ) . In the ITT group the sitting systolic blood pressure ( SBP ) decreased by 14.4 ± 22.3 mm Hg at the end of the treatment period on atenolol from 174.4 ± 17.9 mm Hg at the initial period , and the sitting SBP decreased by 21.6 ± 20.3 mm Hg at the end of perindopril treatment from an initial value of 172.1 ± 20.3 mm Hg ( probability 0.091 ) . The sitting DBP decreased by 18.6 ± 8.7 mm Hg on atenolol from 100.5 ± 4.8 mm Hg at the initial period and by 15.8 ± 9.1 mm Hg on perindopril from 100.6 ± 5.2 mm Hg ( probability 0.112 ) . Glycaemic control was similar for HbA1c fasting and postpr and ial glucose in the ITT population , while fasting glucose increased over time from 10.7 ± 4.1 to 12.0 ± 3.4 mmol/L ; p < 0.001 in the PP population in the atenolol group . Conclusions : The percentage of normalised patients ( sitting DBP ≤90 mm Hg ) was similar in both groups . Patients on perindopril monotherapy required more additional antihypertensive drugs compared with atenolol monotherapy . There was a significant increase in fasting blood sugar in the atenolol-based group ( p < 0.001 ) The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial ( ALLHAT ) provides a unique opportunity to compare the long-term relative safety and efficacy of angiotensin-converting enzyme inhibitor and calcium channel blocker – initiated therapy in older hypertensive individuals . Patients were r and omized to amlodipine ( n=9048 ) or lisinopril ( n=9054 ) . The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infa rct ion , analyzed by intention-to-treat . Secondary outcomes included all-cause mortality , stroke , combined cardiovascular disease ( CVD ) , end-stage renal disease ( ESRD ) , cancer , and gastrointestinal bleeding . Mean follow-up was 4.9 years .  Blood pressure control was similar in nonblacks , but not in blacks . No significant differences were found between treatment groups for the primary outcome , all-cause mortality , ESRD , or cancer . Stroke rates were higher on lisinopril in blacks ( RR=1.51 , 95 % CI 1.22 to 1.86 ) but not in nonblacks ( RR=1.07 , 95 % CI 0.89 to 1.28 ) , and in women ( RR=1.45 , 95 % CI 1.17 to 1.79 ) , but not in men ( RR=1.10 , 95 % CI 0.92 to 1.31 ) . Rates of combined CVD were higher ( RR=1.06 , 95 % CI 1.00 to 1.12 ) because of higher rates for strokes , peripheral arterial disease , and angina , which were partly offset by lower rates for heart failure ( RR=0.87 , 95 % CI 0.78 to 0.96 ) on lisinopril compared with amlodipine .  Gastrointestinal bleeds and angioedema were higher on lisinopril . Patients with and without baseline coronary heart disease showed similar outcome patterns . We conclude that in hypertensive patients , the risks for coronary events are similar , but for stroke , combined CVD , gastrointestinal bleeding , and angioedema are higher and for heart failure are lower for lisinopril-based compared with amlodipine-based therapy . Some , but not all , of these differences may be explained by less effective blood pressure control in the lisinopril arm Objective To compare the effects of the calcium channel blocker amlodipine and the angiotensin-converting enzyme inhibitor lisinopril on intima – media thickness ( IMT ) in elderly , previously untreated hypertensive individuals . Design A double-blind r and omized parallel-group trial ( the ELVERA trial ) . Patients The study population comprised 166 newly diagnosed hypertensive individuals ( aged 60–75 years ) with diastolic blood pressure between 95 and 115 mmHg or systolic blood pressure between 160 and 220 mmHg , or both . Intervention Patients were allocated r and omly to groups to receive amlodipine 5–10 mg or lisinopril 10–20 mg for 2 years . Main outcome measures Before and after 1 and 2 years of treatment , IMT was measured in three carotid and two femoral arterial sites by B-mode ultrasound . The primary endpoint was the change from baseline of the combined mean maximum far wall IMT of carotid and femoral arteries , evaluated by repeated measurement analysis of the treatment effect in an intention-to-treat analysis . Results After 2 years of treatment , amlodipine  decreased IMT by 0.089 mm [ 95 % confidence interval ( CI ) 0.144 to 0.037 ] . Lisinopril  decreased IMT by 0.065 mm ( 95 % CI 0.124 to 0.010 ) . No differences between the two drugs were found ( P = 0.18 ) . Both treatment regimens achieved the greatest reduction of IMT after 1 year , with a slight increase after the second year , whereas the reduction in blood pressure was maintained . Comparing the carotid and femoral arteries , a significant treatment difference in the change from baseline in favour of amlodipine was observed in the IMT of the elastic common carotid artery ( P < 0.05 ) . The effects of the two drugs on the muscular common femoral artery were not different . Conclusion In a long-term study , amlodipine and lisinopril  reduce IMT to a similar extent in newly diagnosed elderly hypertensive patients . It is suggested that the two drugs have different effects on arteries that are not prone to atherosclerosis Background — Hypertension is a major cause of heart failure ( HF ) and is antecedent in 91 % of cases . The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) stipulated assessment of the relative effect of chlorthalidone , lisinopril , and amlodipine in preventing HF . Methods and Results — ALLHAT was a double-blind , r and omized , clinical trial in 33 357 high-risk hypertensive patients aged ≥55 years . Hospitalized/fatal HF outcomes were examined with proportional-hazards models . Relative risks ( 95 % confidence intervals ; P values ) of amlodipine or lisinopril versus chlorthalidone were 1.35 ( 1.21 to 1.50 ; < 0.001 ) and 1.11 ( 0.99 to 1.24 ; 0.09 ) . The proportional hazards assumption of constant relative risk over time was not valid . A more appropriate model showed relative risks of amlodipine or lisinopril versus chlorthalidone during year 1 were 2.22 ( 1.69 to 2.91 ; < 0.001 ) and 2.08 ( 1.58 to 2.74 ; < 0.001 ) , and after year 1 , 1.22 ( 1.08 to 1.38 ; P=0.001 ) and 0.96 ( 0.85 to 1.10 ; 0.58 ) . There was no significant interaction between prior medication use and treatment . Baseline blood pressures were equivalent ( 146/84 mm Hg ) and at year 1 were 137/79 , 139/79 , and 140/80 mm Hg in those given chlorthalidone , amlodipine , and lisinopril . At 1 year , use of added open-label atenolol , diuretics , angiotensin-converting enzyme inhibitors , and calcium channel blockers in the treatment groups was similar . Conclusions — HF risk decreased with chlorthalidone versus amlodipine or lisinopril use during year 1 . Subsequently , risk for those individuals taking chlorthalidone versus amlodipine remained decreased but less so , whereas it was equivalent to those given lisinopril . Prior medication use , follow-up blood pressures , and concomitant medications are unlikely to explain most of the HF differences . Diuretics are superior to calcium channel blockers and , at least in the short term , angiotensin-converting enzyme inhibitors in preventing HF in hypertensive individuals 1 . Our objective was to compare the effect of a long-acting calcium antagonist ( nisoldipine ) compared with an angiotensin-converting enzyme inhibitor ( lisinopril ) on the non-neurogenic regulation of the microvascular blood flow in hypertensive Type I diabetes patients with diabetic nephropathy.2 . We performed a 1-year double-blind , double-dummy r and omized controlled study comparing nisoldipine ( 20 - 40 mg once daily ) with lisinopril ( 10 - 20 mg once daily ) in 48 hypertensive Type I diabetes patients with diabetic nephropathy . For comparison , 22 age-matched normotensive healthy control subjects were included . Measurements were performed at baseline and after 1 year of antihypertensive treatment . The minimal vascular resistance and distensibility ( stiffness ) of resistance vessels in skin and skeletal muscle were measured using the local isotope washout method .3 . Mean arterial pressure was reduced to the same extent in both groups : nisoldipine , 113+/-2.1 to 105+/-1.6 mmHg ( P<0.001 ) ; lisinopril , 110+/-2.7 to 101+/-2.1 mmHg ( P<0.002 ) ( controls , 88+/-2.2 mmHg ; P<0.0001 compared with diabetic patients ) . Nisoldipine improved the skin vascular distensibility from 28+/-3.3 to 43+/-3.8 % ( P<0.005 ) and decreased skin minimal vascular resistance from 16.9+/-1.0 to 13.6+/-0.8 mmHg.ml-1.min.100 g ( P<0 . 02 ) . Lisinopril had no significant effect on skin vascular distensibility ( 40+/-4.0 % and 41+/-4.4 % ) , but minimal vascular resistance tended to diminish ( 18.1+/-0.9 to 15.8+/-1.3 mmHg.ml-1 . min.100 g ( P=0.09 ) . Nisoldipine significantly increased the skin distensibility ( P=0.05 ) after 1 year of antihypertensive treatment compared with lisinopril.4 . The control group had a skin vascular distensibility of 54+/-3.2 % and a minimal vascular resistance of 10 . 8+/-0.7 mmHg.ml-1.min.100 g , both significantly different from the values in the diabetic groups ( P<0.0001 for all ) . Skeletal muscle vascular distensibility was unaltered after 1 year of treatment with both nisoldipine ( 22+/-3.3 % and 19+/-2.7 % ) and lisinopril ( 19+/-2.1 % and 24+/-2.5 % ) , but was reduced compared with a control value of 43+/-3.7 % ( P<0.0001 for diabetes patients versus controls ) . However , neither nisoldipine nor lisinopril had any effect on the increased minimal vascular resistance or the reduced skeletal muscle distensibility.5 . Enhanced thickening of the basement membranes of the terminal arteriolar wall was found in skin biopsy specimens in 91 % of diabetic patients and 38 % only in control subjects ( P<0 . 000001 both before and after treatment for diabetic patients versus controls ) . There was no significant effect of antihypertensive treatment on arteriolar hyalinosis.6 . The reduction in systemic blood pressure was identical during 1 year of treatment with nisoldipine or lisinopril . The abnormal arteriolar stiffness was more pronounced in the group treated with nisoldipine than with lisinopril and only nisoldipine compared with lisinopril improved the abnormal arteriolar stiffness and minimal vascular resistance in the skin . This suggests that nisoldipine can reverse the peripheral skin perfusion and thereby improve the local protection against development of ischaemic skin lesions in Type I diabetes patients with clinical diabetic nephropathy OBJECTIVE To compare the effects of the calcium channel blocker , nisoldipine , and the ACE inhibitor , lisinopril , on left ventricular mass ( LVM ) and systolic function in type 1 diabetic patients with diabetic nephropathy . RESEARCH DESIGN AND METHODS M-mode echocardiography was performed in 50 hypertensive type 1 diabetic patients with diabetic nephropathy enrolled in a 1-year , r and omized , double-blind , parallel study of antihypertensive treatment with nisoldipine CC ( 20 - 40 mg/day ) or lisinopril ( 10 - 20 mg/day ) . Ambulatory 24-h blood pressure was measured with the Takeda TM 2420 device ( A & D , Tokyo , Japan ) every 3 months . Three patients dropped out and seven patients were excluded due to technical difficulties . RESULTS The 24-h diastolic blood pressure was reduced from 83 to 80 mmHg in the nisoldipine group ( P = 0.06 ) and from 85 to 80 mmHg in the lisinopril group ( P = 0.02 ) . The decline in systolic blood pressure was not significant with any of the two treatments , and no difference in reduction of blood pressure was seen between groups . LVM corrected for body surface area ( LVMI ) was comparable between groups at baseline and increased from 96 + /- 5 to 107 + /- 6 g/m2 ( mean + /- SEM ; P = 0.007 ) in the nisoldipine group and from 95 + /- 4 to 103 + /- 5 g/m2 ( P = 0.03 ) in the lisinopril group . The mean difference between the change in LVMI in the two groups was 2.9 ( 95 % CI 6.8 to 12.7 ) g/m2 . The prevalence of left ventricular hypertrophy rose from 18 ( 95 % CI 6 - 30 ) to 30 % ( 16 - 44 ) during the study period . A multiple linear regression analysis revealed that after 1 year of treatment , LVMI increased with higher systolic blood pressure level and declining glomerular filtration rate ( R2 = 0.25 ) . Fractional shortening was within normal range at baseline , 42 + /- 1 vs. 41 + /- 1 % with nisoldipine and lisinopril , respectively , and did not change during follow-up . CONCLUSIONS Antihypertensive treatment with nisoldipine or lisinopril to bring diastolic blood pressure level within the normal target range does not hinder a rise in LVMI in type 1 diabetic patients with diabetic nephropathy BACKGROUND It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure . METHODS We r and omly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan ( 300 mg daily ) , amlodipine ( 10 mg daily ) , or  placebo .  The target blood pressure was 135/85 mm Hg or less in all groups . We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration , the development of end-stage renal disease , or death from any cause . We also compared them with regard to the time to a secondary , cardiovascular composite end point . RESULTS The mean duration of follow-up was 2.6 years . Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group ( P=0.02 ) and 23 percent lower than that in the amlodipine group ( P=0.006 ) . The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group ( P=0.003 ) and 37 percent lower in the irbesartan group than in the amlodipine group ( P<0.001 ) . Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups ( P=0.07 for both comparisons ) . These differences were not explained by differences in the blood pressures that were achieved . The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group ( P=0.008 ) and 21 percent more slowly than in the amlodipine group ( P=0.02 ) . There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point . CONCLUSIONS The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes . This protection is independent of the reduction in blood pressure it causes Seventeen male untreated mild essential hypertensive patients aged 41 + /- 2 years agreed to participate in a double-blind r and omized trial to test the effects of antihypertensive treatment on the structure and function of subcutaneous resistance arteries . Patients were treated with either 50 to 100 mg/d atenolol or 2.5 to 5 mg/d cilazapril .  Blood pressure before treatment was 148 + /- 6/99 + /- 1 and 147 + /- 2/99 + /- 1 mm Hg , respectively . At 1 year of treatment blood pressure was 131 + /- 4/85 + /- 2 and 132 + /- 2/87 + /- 1 mm Hg , respectively . Resistance arteries ( 200 to 400 microns lumen diameter ) dissected from subcutaneous gluteal biopsies obtained before treatment and at 1 year showed that the media-lumen ratio of arteries from patients treated with cilazapril was reduced to 6.31 + /- 0.21 % from 7.54 + /- 0.31 % before treatment ( P < .05 ) , still slightly but significantly larger ( P < .05 ) than the media-lumen ratio of resistance arteries of normotensive control subjects ( 5.15 + /- 0.30 % ) . In contrast , in arteries from patients treated with atenolol there was no significant change with treatment ( 7.97 + /- 0.60 % before and 8.07 + /- 0.45 % after 1 year of treatment ) . Active wall tension responses to endothelin-1 were blunted in hypertensive patients and normalized in the cilazapril-treated patients . Depressed active media stress responses to norepinephrine , arginine vasopressin , and endothelin-1 were accordingly normalized in the patients receiving cilazapril as the media width became thinner but were unchanged in those taking atenolol . ( ABSTRACT TRUNCATED AT 250 WORDS A r and omized , double-blind , active-controlled , multicenter trial assigned 32,804 participants aged 55 years and older with hypertension and ≥ 1 other coronary heart disease risk factors to receive chlorthalidone ( n=15,002 ) , amlodipine ( n=8898 ) , or lisinopril ( n=8904 ) for 4 to 8 years , when double-blinded therapy was discontinued . Passive surveillance continued for a total follow-up of 8 to 13 years using national administrative data bases to ascertain deaths and hospitalizations . During the post-trial period , fatal outcomes and nonfatal outcomes were available for 98 % and 65 % of participants , respectively , due to lack of access to administrative data bases for the remainder . This paper assesses whether mortality and morbidity differences persisted or new differences developed during the extended follow-up . Primary outcome was cardiovascular mortality and secondary outcomes were mortality , stroke , coronary heart disease , heart failure , cardiovascular disease , and end-stage renal disease . For the post-trial period , data are not available on medications or blood pressure levels . No significant differences ( P<.05 ) appeared in cardiovascular mortality for amlodipine ( hazard ratio [ HR ] , 1.00 ; 95 % confidence interval [ CI ] , 0.93 - 1.06 ) or lisinopril ( HR , 0.97 ; CI , 0.90 - 1.03 ) , each compared with chlorthalidone . The only significant differences in secondary outcomes were for heart failure , which was higher with amlodipine ( HR , 1.12 ; CI , 1.02 - 1.22 ) , and stroke mortality , which was higher with lisinopril ( HR , 1.20 ; CI , 1.01 - 1.41 ) , each compared with chlorthalidone . Similar to the previously reported in-trial result , there was a significant treatment-by-race interaction for cardiovascular disease for lisinopril vs chlorthalidone .  Black participants had higher risk than non-black participants  taking lisinopril compared with chlorthalidone . After accounting for multiple comparisons , none of these results were significant . These findings suggest that neither calcium channel blockers nor angiotensin-converting enzyme inhibitors are superior to diuretics for the long-term prevention of major cardiovascular complications of hypertension BACKGROUND The multicenter double-blind , r and omized Bergamo Nephrologic Diabetes Complications Trial ( BENEDICT ) was design ed to assess whether angiotensin-converting-enzyme inhibitors and non-dihydropyridine calcium-channel blockers , alone or in combination , prevent microalbuminuria in subjects with hypertension , type 2 diabetes mellitus , and normal urinary albumin excretion . METHODS We studied 1204 subjects , who were r and omly assigned to receive at least three years of treatment with tr and olapril  ( at a dose of 2 mg per day ) plus verapamil ( sustained-release formulation , 180 mg per day ) , tr and olapril alone ( 2 mg per day ) , verapamil alone ( sustained-release formulation , 240 mg per day ) , or placebo .  The target blood pressure was 120/80 mm Hg . The primary end point was the development of persistent microalbuminuria ( overnight albumin excretion , > or = 20 microg per minute at two consecutive visits ) . RESULTS The primary outcome was reached in 5.7 percent of the subjects receiving tr and olapril plus verapamil , 6.0 percent of the subjects receiving tr and olapril , 11.9 percent of the subjects receiving verapamil , and 10.0 percent of control subjects receiving placebo . The estimated acceleration factor ( which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression ) adjusted for predefined baseline characteristics was 0.39 for the comparison between verapamil plus tr and olapril and placebo ( P=0.01 ) , 0.47 for the comparison between tr and olapril and placebo ( P=0.01 ) , and 0.83 for the comparison between verapamil and placebo ( P=0.54 ) . Tr and olapril plus verapamil and tr and olapril alone delayed the onset of microalbuminuria by factors of 2.6 and 2.1 , respectively . Serious adverse events were similar in all treatment groups . CONCLUSIONS In subjects with type 2 diabetes and hypertension but with normoalbuminuria , the use of tr and olapril plus verapamil and tr and olapril alone decreased the incidence of microalbuminuria to a similar extent . The effect of verapamil alone was similar to that of placebo Background —Prevalent atrial fibrillation ( AF ) is associated with a higher sudden cardiac death ( SCD ) rate in some population s , and incident AF predicts increased mortality risk in the general population and after myocardial infa rct ion . However , the relationship of SCD to new-onset AF is unclear . Methods and Results —The relationship of SCD to new-onset AF was evaluated in 8831 hypertensive patients with electrocardiographic left ventricular hypertrophy with no history of AF , in sinus rhythm on their baseline electrocardiogram , r and omly assigned to losartan- or atenolol-based treatment . During 4.7±1.1 years mean follow-up , new-onset AF occurred in 701 patients ( 7.9 % ) and SCD in 151 patients ( 1.7 % ) . In univariate Cox analyses , new-onset AF was associated with a > 4-fold higher risk of SCD ( hazard ratio , 4.69 ; 95 % CI interval , 2.96–7.45 ; P<0.001 ) . In multivariate Cox analyses adjusting for age , sex , race , diabetes mellitus , history of heart failure , myocardial infa rct ion , ischemic heart disease , stroke , smoking , serum high-density lipoprotein cholesterol , creatinine , glucose , and urine albumin/creatinine ratio as st and ard risk factors , and for incident myocardial infa rct ion , in-treatment use of digoxin , systolic and diastolic pressure , heart rate , QRS duration , Cornell voltage- duration product , and Sokolow-Lyon voltage left ventricular hypertrophy treated as time-varying covariates , new-onset AF remained associated with a > 3-fold increased risk of SCD ( hazard ratio , 3.13 ; 95 % confidence interval , 1.87–5.24 ; P<0.001 ) . Conclusions —Development of new-onset AF identifies hypertensive patients at  increased risk of SCD . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00338260 OBJECTIVES To compare the effects of three antihypertensive medications on cerebral hemodynamic and cognitive function in hypertensive individuals with executive dysfunction . DESIGN Double-blind r and omized clinical trial . SETTING Community . PARTICIPANTS Fifty-three individuals aged 60 and older with hypertension and executive dysfunction . INTERVENTION Lisinopril , c and esartan , or hydrochlorothiazide for 1 year . MEASUREMENTS Cerebral blood flow velocity ( BFV ; transcranial Doppler ultrasonography during rest , sitting , st and ing , hypercapnia , and hypocapnia ) , cognition , and blood pressure were measured at baseline and after 6 and 12 months . Linear mixed models were used to compare the three groups . RESULTS Of the 53 participants , 47 had successful insonation ( mean age 72 ; 70 % white ; 57 % women ) . There was a tendency toward an increase in BFV in the c and esartan group and a decrease in the lisinopril and hydrochlorothiazide groups ( between-group P = .57 ) that was significant in those with low BFV at baseline ( < median 27.6 cm/s , between-group P = .03 ) . The c and esartan group also had the greatest improvement in executive function ( Trail Making Test Part B improved by 17.1 seconds , vs hydrochlorothiazide improved by 4.2 seconds and lisinopril worsened by 14.4 seconds , P = .008 ) . Carbon dioxide vasoreactivity and vasomotor range declined significantly in the lisinopril ( within-group P = .001 for vasoreactivity and .02 for vasomotor range ) and hydrochlorothiazide groups ( within-group P = .10 and .009 , respectively ) but not in the c and esartan group ( within-group P = .25 and .38 , respectively ; between-group P = .30 and .46 , respectively ) . CONCLUSION Angiotensin receptor blockers may preferentially preserve cerebral hemodynamics and executive function in individuals with executive dysfunction . These findings warrant further investigation in a larger trial Hypertension has been associated with changes in endothelial function in both large muscular arteries and small resistance arteries . We evaluated the relationship between blood flow velocity and dilatation of the brachial artery following transient forearm ischemia and acetylcholine‐induced relaxation in subcutaneous small arteries and the influence of antihypertensive therapy on both in patients with essential hypertension . Thirty‐one previously untreated hypertensive patients were r and omized in a double‐blind fashion to treatment with either the angiotensin‐converting enzyme ( ACE ) inhibitor perindopril or the beta‐blocker atenolol and compared with 17 healthy normotensive controls . Before and after 1 year of treatment , while still on active medication , flow‐mediated dilatation ( FMD ) was measured in the brachial artery using ultrasound while relaxation to acetylcholine in small arteries was tested in vitro in a myograph . FMD correlated inversely to resting brachial artery diameter ( r = −0.38 , p<0.05 ) . FMD corrected for resting diameter ( FMDcorr ) was lower in patients ( 3.0±0.2 % ) compared with controls ( 4.2±0.3 % , p<0.01 ) . In both patients and controls , FMDcorr was related to flow velocity in a non‐linear way with FMDcorr reaching a maximum despite increasing flow velocities , and in the patients , FMDcorr was only reduced at high flow velocities . Furthermore , patients had a reduced acetylcholine‐induced relaxation in small arteries ( p = 0.04 ) . Perindopril and atenolol  reduced blood pressure to similar levels and both drugs improved FMDcorr to a similar degree without any effects on relaxation to acetylcholine in small arteries . The present study demonstrates the role of correcting for differences in baseline diameter during measurements of FMD and a non‐linear relationship between flow velocity and FMD in the brachial artery . Furthermore , the results suggest different effects of antihypertensive treatment on endothelial function in large and small arteries Objective The FGB gene codes for fibrinogen-&bgr ; , a polypeptide of the coagulation factor fibrinogen , which is positively associated with cardiovascular diseases . Studies show that angiotensin-converting enzyme ( ACE ) inhibitors lower plasma fibrinogen concentrations , whereas diuretics and calcium-channel blockers do not . As carriers of the FGB-455 minor ‘ A ’ allele have higher levels of fibrinogen while ACE inhibitors lower it , we hypothesize that ‘ A ’ allele carriers benefit more from antihypertensive treatment with ACE inhibitors than calcium-channel blockers or diuretics , relative to ‘ GG ’ genotype individuals . Methods The Genetics of Hypertension Associated Treatment ( GenHAT ) study [ ancillary to Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) ] genotyped hypertensive participants for several hypertension-related c and i date genes , making this a post-hoc analysis of a r and omized trial . In total , 90.1 % of the ALLHAT population was successfully genotyped for FGB-455 . We included participants ( n=30 076 ) r and omized to one of three antihypertensive medications ( lisinopril , amlodipine , chlorthalidone )  , with two treatment comparisons : lisinopril versus chlorthalidone and lisinopril versus amlodipine . The primary outcome of ALLHAT/GenHAT was coronary heart disease , defined as fatal coronary heart disease or non-fatal myocardial infa rct ion , and secondary outcomes included stroke , heart failure , all-cause mortality , and end-stage renal disease ( ESRD ) with mean follow-up time of 4.9 years . Genotype-by-treatment interactions ( pharmacogenetic effects ) were tested with the Cox regression . Results Stroke : common ‘ GG ’ homozygotes had higher risk on lisinopril versus amlodipine [ hazard ratio (HR)=1.38 , P<0.001 ] , whereas minor ‘ A ’ allele carriers had slightly lower risk ( HR=0.96 , P=0.76 ; P value for interaction=0.03 ) . Mortality : ‘ GG ’ homozygotes had higher risk on lisinopril versus amlodipine ( HR=1.12 , P=0.02 ) or chlorthalidone ( 1.05 , P=0.23 ) , whereas ‘ A ’ allele carriers had slightly lower risk ( HR=0.92 , P=0.33 for lisinopril versus amlodipine ; HR=0.88 , P=0.08 for lisinopril versus chlorthalidone ; P value for interactions 0.04 and 0.03 , respectively ) . ESRD : ‘ GG ’ homozygotes had higher risk on lisinopril versus chlorthalidone ( HR=1.27 , P=0.08 ) , whereas ‘ A ’ allele carriers had lower risk ( HR=0.64 , P=0.12 ; P value for interaction=0.03 ) . Conclusion There was evidence of pharmacogenetic effects of FGB-455 on stroke , ESRD , and mortality , suggesting that relative to those homozygous for the common allele , variant allele carriers of the FGB gene at position −455 have a better outcome if r and omized to lisinopril than chlorthalidone ( for mortality and ESRD ) or amlodipine ( for mortality and stroke ) . For the models in which a pharmacogenetic effect was observed , the outcome rates among ‘ GG ’ homozygotes were higher in those r and omized to lisinopril versus amlodipine or chlorthalidone , whereas minor ‘ A ’ allele carriers had lower event rates when r and omized to lisinopril versus the other medications OBJECTIVE The Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial is a prospect i ve r and omized blinded clinical trial that compares the effects of intensive versus moderate blood pressure control on the incidence and progression of type 2 diabetic complications . The current article discusses the results of 5.3 years of follow-up of 470 patients with hypertension and evaluates the effects of intensive and moderate blood pressure therapy using nisoldipine versus enalapril as the initial antihypertensive medication for nephropathy , retinopathy , and neuropathy . RESEARCH DESIGN AND METHODS The 470 hypertensive subjects , defined as having a baseline diastolic blood pressure of > or = 90 mmHg , were r and omized to intensive blood pressure control ( diastolic blood pressure goal of 75 mmHg ) versus moderate blood pressure control ( diastolic blood pressure goal of 80 - 89 mmHg ) . RESULTS The mean blood pressure achieved was 132/78 mmHg in the intensive group and 138/86 mmHg in the moderate control group . During the 5-year follow-up period , no difference was observed between intensive versus moderate blood pressure control and those r and omized to nisoldipine versus enalapril with regard to the change in creatinine clearance . After the first year of antihypertensive treatment , creatinine clearance stabilized in both the intensive and moderate blood pressure control groups in those patients with baseline normo- or microalbuminuria . In contrast , patients starting with overt albuminuria demonstrated a steady decline in creatinine clearance of 5 - 6 ml.min-1.1.73 m-2 per year throughout the follow-up period whether they were on intensive or moderate therapy . There was also no difference between the interventions with regard to individuals progressing from normoalbuminuria to microalbuminuria ( 25 % intensive therapy vs. 18 % moderate therapy , P = 0.20 ) or microalbuminuria to overt albuminuria ( 16 % intensive therapy vs. 23 % moderate therapy , P = 0.28 ) . Intensive therapy demonstrated a lower overall incidence of deaths , 5.5 vs. 10.7 % , P = 0.037 . Over a 5-year follow-up period , there was no difference between the intensive and moderate groups with regard to the progression of diabetic retinopathy and neuropathy . In addition , the use of nisoldipine versus enalapril had no differential effect on diabetic retinopathy and neuropathy . CONCLUSIONS Blood pressure control of 138/86 or 132/78 mmHg with either nisoldipine or enalapril as the initial antihypertensive medication appeared to stabilize renal function in hypertensive type 2 diabetic patients without overt albuminuria over a 5-year period . The more intensive blood pressure control decreased all-cause mortality OBJECTIVE  Hypertension ( HTN ) is a major risk factor for cardiovascular disease ( CVD ) in the setting of diabetes . There is no consensus on how best to treat hypertension among those with diabetes . Here we describe the characteristics of a cohort of hypertensive adults with diabetes who are part of a large prospect i ve blood pressure study . This study will help clarify the treatment of HTN in the setting of diabetes . RESEARCH DESIGN AND METHODS The Antihypertensive and Lipid-Lowering high-risk hypertensive participants , ages > or = 55 years , design ed to determine whether the incidence of fatal and nonfatal coronary heart disease ( CHD ) and combined cardiovascular events ( fatal and nonfatal CHD , revascularization surgery , angina pectoris , congestive heart failure , and stroke ) differs between diuretic ( chlorthalidone ) treatment and three alternative antihypertensive therapies : a calcium channel blocker ( amlodipine ) , an ACE inhibitor ( lisinopril ) , and an alpha-adrenergic blocker ( doxazosin ) . The planned follow-up is an average of 6 years , to be completed March 2002 . RESULTS There are 15,297 diabetic individuals in the ALLHAT study ( 36.0 % of the entire cohort ) . Of these individuals , 50.2 % are male , 39.4 % are African-American , and 17.7 % are Hispanic . Demographic and laboratory characteristics of the cohort are similar to those of other studies of the U.S. elderly population with HTN . The sample size has 42 and 93 % confidence , treatments for the two study outcomes . CONCLUSIONS The diabetic cohort in ALLHAT wil be able to provide valuable information about the treatment of hypertension in older diabetic patients at risk for incident CVD 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 Objective To compare the effects of the angiotensin II antagonist , losartan , with those of atenolol on left ventricular hypertrophy ( LVH ) , blood pressure and neurohormone concentrations in hypertensive patients with LVH . Design A multinational , r and omized , double-blind trial . Setting Hospital . Patients Hypertensive patients with an echocardiographically documented left ventricular mass index ( LVMI ) > 120 g/m2 ( men ) or > 105 g/m2 ( women ) . Interventions Patients allocated r and omly to groups received either losartan or atenolol 50 mg/day for 36 weeks , with possible titration to 100 mg/day , and addition of hydrochlorothiazide 12.5 or 25 mg/day . Main outcome measures Changes in LVMI and sitting systolic ( SBP ) and diastolic ( DBP ) blood pressures after 36 weeks of treatment ( study powered for non-inferiority hypothesis ) . All echocardiographic data were read in a central laboratory by staff blinded to the treatments and sequence of echocardiographic tapes . Results The estimated treatment difference between the losartan and atenolol regimens ( mean change from baseline at week 36 ) in LVMI was −2.5 g/m2 [ 95 % confidence interval ( CI ) −7.36 to 2.37 g/m2 ] in favor of losartan , indicating that losartan was significantly non-inferior ( P < 0.001 , non-inferiority limit 8 g/m2 ) and numerically superior to atenolol in reducing LVMI . The losartan-based regimen significantly reduced LVMI after 36 weeks compared with baseline ( −6.56 g/m2 , 95 % CI −10.24 to −2.88 g/m2 , P < 0.001 ) , whereas the atenolol-based regimen had no significant effect ( −3.71 g/m2 , 95 % CI −7.75 to 0.32 g/m2 , P = NS ) . In a subset of 82 patients , significant changes in serum concentrations of atrial natriuretic peptide , brain natriuretic peptide and immunoreactive amino-terminal pro-brain natriuretic peptide were recorded in losartan-treated ( P < 0.01 ) but not atenolol-treated patients . Losartan and atenolol significantly decreased SBP and DBP from baseline after 6 , 12 , 24 and 36 weeks . The changes from baseline in DBP were greater in the atenolol group at weeks 6 and 36 [ difference −2.6 mmHg ( P = 0.016 ) at week 36 ] . However , both treatment regimens achieved similar SBP/DBP values at week 36 ( 141.1 ± 12.8/86.8 ± 8.2 mmHg for losartan and 141.4 ± 17.2/85.0 ± 10.1 mmHg for atenolol , respectively ) . Overall , losartan treatment was associated with significantly fewer drug-related clinical adverse events , compared with atenolol ( 10 and 22 % , respectively , P = 0.028 ) . Conclusions Both losartan- and atenolol-based regimens effectively decreased blood pressure . Losartan was non-inferior and numerically superior to atenolol in regression of LVH . The reduction in hypertrophy with losartan treatment was accompanied by reductions in circulating concentrations of cardiac natriuretic peptides . Losartan , by specifically blocking angiotensin II , may therefore have effects on the heart beyond those expected from the decrease in blood pressure alone . Losartan was better tolerated than atenolol Nitric oxide synthase 3 ( NOS3 ) catalyzes production of NO in the endothelium and may play a role in cardiovascular disease ( CVD ) . We assessed the pharmacogenetic associations of three NOS3 polymorphisms and three antihypertensive drugs with CVD outcomes . Hypertensive subjects ( n = 30,280 ) from a multi-center , double-blind clinical trial were r and omized to chlorthalidone , amlodipine , or lisinopril treatment ( mean follow up , 4.9 years ) . Outcomes included coronary heart disease ( CHD : fatal CHD and nonfatal myocardial infa rct ion ) ; stroke ; heart failure ( fatal , requiring hospitalization , or outpatient treatment ) ; all-cause mortality ; and end-stage renal disease ( ESRD ) . Main effects of NOS3 variants on outcome and genotype-treatment interactions were tested . For NOS3 −690 C > T ( rs3918226 ) , a higher hazard ratio ( HR ) was found in minor allele carriers for CHD ( CC = 1.00 , CT+TT = 1.12 ( 95 % confidence interval ( CI ) = 1.00–1.26 ) , P = 0.048 ) . For NOS3 −922 A > G ( rs1800779 ) , a higher HR was found in minor allele carriers for heart failure ( AA = 1.00 , AG+GG = 1.10 ( CI = 1.00–1.21 ) , P = 0.046 ) . Significant pharmacogenetic findings were observed for stroke and all-cause mortality . For −690 C > T , a lower HR was observed for stroke in minor allele carriers when treated with amlodipine versus lisinopril ( CC = 0.85 ( CI = 0.73–0.99 ) , CT+TT = 0.49 ( CI = 0.31–0.80 ) , P = 0.04 ) . For glu298asp G > T ( rs1799983 ) , a lower HR was observed for all-cause mortality in minor allele carriers when treated with amlodipine versus lisinopril ( GG = 1.01 ( CI = 0.91–1.13 ) , GT+TT = 0.85 ( CI = 0.75–0.97 ) , P = 0.04 ) . We observed significant associations with NOS3 variants and CHD and heart failure and significant pharmacogenetic effects for stroke and all cause mortality . This suggests that NOS3 variants may potentially provide useful clinical information with respect to treatment decisions in the future CONTEXT Hypertension is a leading cause of end-stage renal disease ( ESRD ) in the United States , with no known treatment to prevent progressive declines leading to ESRD . OBJECTIVE To compare the effects of 2 levels of blood pressure ( BP ) control and 3 antihypertensive drug classes on glomerular filtration rate ( GFR ) decline in hypertension . DESIGN R and omized 3 x 2 factorial trial with enrollment from February 1995 to September 1998 . SETTING AND PARTICIPANTS A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease ( GFR , 20 - 65 mL/min per 1.73 m(2 ) ) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years . INTERVENTIONS Participants were r and omly assigned to 1 of 2 mean arterial pressure goals , 102 to 107 mm Hg ( usual ; n = 554 ) or 92 mm Hg or less ( lower ; n = 540 ) , and to initial treatment with either a beta-blocker ( metoprolol 50 - 200 mg/d ; n = 441 ) , an angiotensin-converting enzyme inhibitor ( ramipril 2.5 - 10 mg/d ; n = 436 ) or a dihydropyridine calcium channel blocker , ( amlodipine 5 - 10 mg/d ; n = 217 ) . Open-label agents were added to achieve the assigned BP goals . MAIN OUTCOME MEASURES Rate of change in GFR ( GFR slope ) ; clinical composite outcome of reduction in GFR by 50 % or more ( or > or = 25 mL/min per 1.73 m2 ) from baseline , ESRD , or death . Three primary treatment comparisons were specified : lower vs usual BP goal ; ramipril vs metoprolol ; and amlodipine vs metoprolol . RESULTS Achieved BP averaged ( SD ) 128/78 ( 12/8 ) mm Hg in the lower BP group and 141/85 ( 12/7 ) mm Hg in the usual BP group . The mean ( SE ) GFR slope from baseline through 4 years did not differ significantly between the lower BP group ( -2.21 [ 0.17 ] mL/min per 1.73 m2 per year ) and the usual BP group ( -1.95 [ 0.17 ] mL/min per 1.73 m2 per year ; P = .24 ) , and the lower BP goal did not significantly reduce the rate of the clinical composite outcome ( risk reduction for lower BP group = 2 % ; 95 % confidence interval [ CI ] , -22 % to 21 % ; P = .85 ) . None of the drug group comparisons showed consistent significant differences in the GFR slope . However , compared with the metoprolol and amlodipine groups , the ramipril group manifested risk reductions in the clinical composite outcome of 22 % ( 95 % CI , 1%-38 % ; P = .04 ) and 38 % ( 95 % CI , 14%-56 % ; P = .004 ) , respectively . There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups . CONCLUSIONS No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal . Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline Background In the Valsartan Antihypertensive Long-term Use Evaluation ( VALUE ) trial the primary outcome ( cardiac morbidity and mortality ) did not differ between valsartan and amlodipine-based treatment groups , although systolic blood pressure ( SBP ) and diastolic blood pressure reductions were significantly more pronounced with amlodipine . Stroke incidence was non-significantly , and myocardial infa rct ion was significantly lower in the amlodipine-based regimen , whereas cardiac failure was non-significantly lower on valsartan . Objectives The study protocol specified additional analyses of the primary endpoint according to : sex ; age ; race ; geographical region ; smoking status ; type 2 diabetes ; total cholesterol ; left ventricular hypertrophy ; proteinuria ; serum creatinine ; a history of coronary heart disease ; a history of stroke or transient ischemic attack ; and a history of peripheral artery disease . Additional subgroups were isolated systolic hypertension and classes of antihypertensive agents used immediately before r and omization . Methods The 15 245 hypertensive patients participating in VALUE were divided into subgroups according to baseline characteristics . Treatment by subgroup interaction analyses were carried out by a Cox proportional hazard model . Within each subgroup , treatment effects were assessed by hazard ratios and 95 % confidence intervals . Results For cardiac mortality and morbidity , the only significant subgroup by treatment interaction was of sex ( P = 0.016 ) , with the hazard ratio indicating a relative excess of cardiac events with valsartan treatment in women but not in men , but SBP differences in favour of amlodipine were distinctly greater in women . No other subgroup showed a significant difference in the composite cardiac outcome between valsartan and amlodipine-based treatments . For secondary endpoints , a sex-related significant interaction was found for heart failure ( P < 0.0001 ) , with men but not women having a lower incidence of heart failure with valsartan . Conclusion As in the whole VALUE cohort , in no subgroup of patients were there differences in the incidence of the composite cardiac endpoint with valsartan and amlodipine-based treatments , despite a greater blood pressure decrease in the amlodipine group . The only exception was sex , in which the amlodipine-based regimen was more effective than valsartan in women , but not in men , whereas the valsartan regimen was more effective in preventing cardiac failure in men than in women BACKGROUND The Valsartan Antihypertensive Long-term Use Evaluation ( VALUE ) trial was design ed to test the hypothesis that for the same blood-pressure control , valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk . METHODS 15?245 patients , aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a r and omised , double-blind , parallel-group comparison of therapy based on valsartan or amlodipine . Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint , defined as a composite of cardiac mortality and morbidity .  Patients from 31 countries were followed up for a mean of 4.2 years . FINDINGS Blood pressure was reduced by both treatments , but the effects of the amlodipine-based regimen were more pronounced , especially in the early period ( blood pressure 4.0/2.1 mm Hg lower in amlodipine than valsartan group after 1 month ; 1.5/1.3 mm Hg after 1 year ; p<0.001 between groups ) . The primary composite endpoint occurred in 810 patients in the valsartan group ( 10.6 % , 25.5 per 1000 patient-years ) and 789 in the amlodipine group ( 10.4 % , 24.7 per 1000 patient-years ; hazard ratio 1.04 , 95 % CI 0.94 - 1.15 , p=0.49 ) . INTERPRETATION The main outcome of cardiac disease did not differ between the treatment groups . Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes . The findings emphasise the importance of prompt blood-pressure control in hypertensive patients at high cardiovascular risk We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide , c and esartan or lisinopril on urinary albumin excretion , endothelial function and inflammatory activity in hypertensive type II diabetic individuals . A total of 70 hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a r and omized , double-blind , double-dummy design . Blood pressure was titrated to levels below 130/85 mmHg or a decrease in systolic pressure of 10 % with a diastolic pressure below 85 mmHg . After titration , patients were treated for 12 months . Mean blood pressures changed from 157/93 , 151/94 and 149/93 at baseline to 135/80 , 135/82 and 131/80 mmHg after titration in the hydrochlorothiazide ( n=24 ) , c and esartan ( n=24 ) and lisinopril ( n=22 ) groups . About 70 % reached target blood pressures . However , only 45 % had blood pressures < 130/85 mmHg . Urinary albumin excretion and levels of soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 decreased ( GEE regression coefficients , −2.40 mg/24 h ( P<0.001 ) , −85 ng/ml ( P=0.01 ) and −50 ng/ml ( P=0.02 ) ) , but brachial artery endothelium-dependent and -independent vasodilation and levels of von Willebr and factor and C-reactive protein did not change ( GEE regression coefficients , 0.21 mm ( P=0.07 ) , 0.04 mm ( P=0.43 ) , 0.04 IU/ml ( P=0.33 ) and −1.15 mg/l ( P=0.64 ) ) . No differences in outcome variables between treatment groups were observed . These data show that achievement of target blood pressures below 130/85 mmHg in hypertensive type II diabetes is difficult . Aggressive antihypertensive therapy can improve urinary albumin excretion , endothelial function and inflammatory activity in hypertensive type II diabetic individuals , regardless of the type of antihypertensive therapy used BACKGROUND Treatment of hypertensive patients with a losartan-based regimen  was associated with greater regression of electrocardiographic ( ECG ) left ventricular hypertrophy ( LVH ) than atenolol-based therapy in the Losartan Intervention for Endpoint Reduction in Hypertension ( LIFE ) study , independent of blood pressure ( BP ) changes . However , whether concomitant hydrochlorothiazide ( HCTZ ) therapy in > 70 % of LIFE patients was associated with greater regression of LVH independent of BP changes and whether this effect differed between treatment arms has not been examined . METHODS Changes in Cornell product and Sokolow-Lyon voltage LVH were assessed in 9,193 hypertensive patients r and omly assigned to treatment with losartan or atenolol  , with additional HCTZ therapy added as necessary to achieve target BP goal per study protocol . RESULTS After controlling for baseline and change in systolic and diastolic pressure , age , sex , race , prior antihypertensive treatment , baseline and year-4 body mass index and baseline LVH by either Cornell product or Sokolow-Lyon voltage , at year-4 follow-up HCTZ therapy was associated with greater regression of Cornell product LVH ( -244 + /- 788 vs. -172 + /- 771 mm.msec , P < 0.05 ) and Sokolow-Lyon voltage ( -4.2 + /- 6.7 vs. -3.0 + /- 7.0 mm , P < 0.001 ) and this effect was significantly greater in patients on losartan ( -341 + /- 743 vs. -189 + /- 775 mm.msec and -5.2 + /- 6.6 vs. -3.3 + /- 6.6 mm ) than in patients on atenolol ( -142 + /- 822 vs. -158 + /- 765 mm.msec and -3.1 + /- 6.6 vs. -2.7 + /- 7.4 mm ; both P < 0.001 for interaction of HCTZ with losartan vs. atenolol therapy ) . CONCLUSIONS HCTZ use was associated with greater regression of ECG LVH and this effect was greater in patients on losartan- than atenolol-based therapy , independent of baseline severity of ECG LVH and hypertension and changes in BP BACKGROUND AND PURPOSE Angiotensin II promotes cell growth and has been implicated in the development and maintenance of left ventricular ( LV ) hypertrophy and of structural vascular changes . We wished to examine whether an angiotensin receptor blocker ( ARB ) would influence structural vascular changes beyond the effects of blood pressure reduction . METHODS Hypertensive patients with LV hypertrophy ( age 55 + /- 9 years , blood pressure 162 + /- 19/104 + /- 8 mmHg , LV mass index 148 + /- 31 g m(-2 ) ; mean + /- SD ) were r and omized double-blind to the ARB irbesartan ( n=52 ) or the beta(1 ) receptor blocker atenolol  ( n=56 ) for 48 weeks . Ultrasonography of the left and right common carotid artery ( CCA ) and echocardiography were performed at week 0 and 48 . RESULTS With similar reductions in blood pressure , CCA intima-media thickness ( IMT ) was reduced by irbesartan ( from 0.92 + /- 0.14 by 0.01 + /- 0.10 mm , NS ) , whereas it was increased by atenolol ( from 0.94 + /- 0.21 by 0.03 + /- 0.12 mm , P=0.018 ; P=0.002 between groups ) . CCA lumen diameter was less reduced by irbesartan than by atenolol . Thus , CCA intima-media area was reduced by irbesartan ( from 21.3 + /- 5.0 by 0.90 + /- 2.45 mm(2 ) , P=0.034 ) but not by atenolol ( from 21.3 + /- 6.1 by 0.18 + /- 2.71 mm(2 ) , NS ; P=0.037 between groups ) . Changes in CCA IMT or area did not relate to changes in LV mass . CONCLUSIONS The favourable effects by irbesartan on CCA IMT with an outward vascular remodelling suggest that angiotensin II mediates structural vascular changes , beyond the effects of blood pressure . This may be important in the prevention of cerebrovascular events Objectives To test whether microalbuminuria in patients with type 2 diabetes and hypertension is primarily dependent on the severity of hypertension , and to compare the effectiveness of two antihypertensive drugs with opposite effects on the renin – angiotensin system [ the diuretic , indapamide sustained release ( SR ) , and an angiotensin-converting enzyme inhibitor , enalapril ] in reducing microalbuminuria . Design A multinational , multicentre , controlled , double-blind , double-dummy , r and omized , two-parallel-groups study over 1 year . Methods After a 4-week placebo run-in period , 570 patients ( ages 60.0 ± 9.9 years , 64 % men ) with type 2 diabetes , essential hypertension [ systolic blood pressure ( SBP ) 140–180 mmHg , and diastolic blood pressure ( DBP ) < 110 mmHg ] , and persistent microalbuminuria ( 20–200 μg/min ) were allocated r and omly to groups to receive indapamide SR 1.5 mg ( n = 284 ) or enalapril 10 mg ( n = 286 ) once a day . Amlodipine , atenolol , or both were added , if necessary , to achieve the target blood pressure of 140/85 mmHg . Results There was a significant reduction in the urinary albumin : creatinine ratio . Mean reductions were 35 % [ 95 % confidence interval ( CI ) 24 to 43 ] and 39 % ( 95 % CI 30 to 47 % ) in the indapamide SR and enalapril groups , respectively . Equivalence was demonstrated between the two groups [ 1.08 ( 95 % CI 0.89 to 1.31 % ) ; P = 0.01 ] . The reductions in mean arterial pressure ( MAP ) were 16.6 ± 9.0 mmHg for the indapamide SR group and 15.0 ± 9.1 mmHg for the enalapril group ( NS ) ; the reduction in SBP was significantly greater ( P = 0.0245 ) with indapamide SR . More than 50 % of patients in each group required additional antihypertensive therapy , with no differences between groups . Both treatments were well tolerated . Conclusions Indapamide-SR-based therapy is equivalent to enalapril-based therapy in reducing microalbuminuria with effective blood pressure reduction in patients with hypertension and type 2 diabetes We examined long-term influence of the angiotensin II type 1-receptor blocker irbesartan and the beta1-adrenergic receptor blocker atenolol on some neurohormonal systems implicated in the pathophysiology of cardiac hypertrophy . Thus , 115 hypertensive patients with left ventricular hypertrophy were r and omized to receive double-blind irbesartan or atenolol , with additional therapy if needed . Neurohormone measurements and echocardiography were performed at weeks 0 , 12 , 24 , and 48 . Left ventricular mass was reduced more by irbesartan than by atenolol ( −26 g/m2 versus −14 g/m2 , P = 0.024 ) , despite similar reductions in blood pressure . Plasma renin activity and angiotensin II increased ( P < 0.001 ) by irbesartan ( 0.9 ± 0.7 to 3.4 ± 4.2 ng/mL × h , and 3.0 ± 1.6 to 13.0 ± 17.7 pmol/L ) , but decreased ( P < 0.01 ) by atenolol ( 1.0 ± 0.6 to 0.7 ± 0.6 ng/mL × h , and 3.4 ± 1.6 to 3.2 ± 2.2 pmol/L ) . Serum aldosterone decreased ( P < 0.05 ) by both irbesartan ( 346 ± 140 to 325 ± 87 pmol/L ) and atenolol ( 315 ± 115 to 283 ± 77 pmol/L ) . Changes in left ventricular mass  by irbesartan related inversely to changes in plasma renin activity , angiotensin II , and aldosterone ( all P < 0.05 ) . Plasma levels and 24-hour urinary excretions of catecholamines , plasma leptin , proinsulin , insulin and insulin sensitivity remained largely unchanged in both groups . Thus , the renin-angiotensin aldosterone system appears to be an important non-hemodynamic factor in the regulation of left ventricular mass The objective of this study was to observe the antihypertensive effect of losartan and levamlodipine besylate on insulin resistance in patients with essential hypertension ( EH ) combined with isolated impaired fasting glucose ( i-IFG ) . Patients ( n=244 ) were r and omly assigned to losartan potassium tablets ( 50–100 mg per day ) or levamlodipine besylate tablets ( 2.5–5.0 mg per day ) for intensive antihypertensive treatment with no lifestyle interventions for 3 years . The changes in fasting plasma glucose , fasting insulin ( FINS ) and insulin sensitivity index ( ISI ) from before to after treatment were observed . Blood pressure ( BP ) in each group was significantly reduced by treatment ( P<0.05 ) . After 12 months of treatment , the FINS level in the losartan potassium group was significantly decreased and ISI was significantly increased compared with before treatment ( P<0.05 ) and compared with the levamlodipine besylate group ( P<0.05 ) . After 24 and 36 months of treatment , FINS was significantly decreased and ISI was significantly improved in both groups compared with baseline ( P<0.05 ) , and there was no difference between the groups ( P>0.05 ) . The incidence of new-onset diabetes mellitus was not significantly different between two groups . The antihypertensive effect of losartan and levamlodipine besylate could amoliorate insulin resistance in patients with EH combined with i-IFG . The improvement of insulin resistance by losartan potassium at 12 months might be better than that by levamlodipine besylate ; however , after 24 and 36 months of follow-up , both agents significantly alleviated insulin resistance . These results suggest that the effects of these two drugs on insulin resistance are not significantly different 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 Essential hypertension is a major Public Health issue . Although the number of treated hypertensive patients has increased , only 25 % of treated patients have their blood pressure levels under control . The benefit of treating hypertension has been proven , but cardiovascular morbidity and mortality rates remain high . The ideal antihypertensive drug should not only normalize blood pressure levels , but also reduce the associated cardiovascular morbidity and mortality rates . The role of angiotensin II in systemic hypertension and its complications has been recently redefined . The potent trophic effects of angiotensin II on blood vessels and on cardiac cells have been well demonstrated , especially the role of angiotensin II in left ventricular hypertrophy , vascular hypertrophy , endothelial dysfunction , and congestive heart failure . Of all ongoing mortality and morbidity trials in systemic hypertension , VALUE ( Valsartan Antihypertensive Long-term Use Evaluation ) is the only one comparing an angiotensin II antagonist ( valsartan ) with a third-generation calcium channel blocker ( amlodipine ) . The main hypothesis of the VALUE trial is that , for an equivalent decrease in blood pressure , valsartan will be more effective than amlodipine in decreasing cardiac mortality and morbidity . VALUE is a prospect i ve , multinational , multicentre , double-blind , r and omized , active-controlled , 2-arm parallel group comparison with a response-dependent dose titration scheme . VALUE involves 14,400 patients in over 30 countries , who will be followed for 4 years or until 1450 patients experience a primary endpoint . The population to be included in VALUE consists of hypertensive men and women , aged 50 years or older , and at a relatively high risk of sustaining a cardiovascular event . The high risk profile is defined taking into account age , gender , and a list of cardiovascular risk factors and disease factors . Risk factors are cigarette smoking , hypercholesterolaemia , diabetes mellitus , uncomplicated left ventricular hypertrophy , proteinuria , and high serum creatinine . Disease factors include documented history of myocardial infa rct ion , peripheral vascular disease , stroke or transient ischaemic attack , or the presence of left ventricular hypertrophy with strain on the ECG . A unique feature of VALUE is the assessment of the predictive power of this cardiovascular risk factor scale in a large population of treated hypertensive patients . The trial started on 10 September 1997 OBJECTIVE To compare the long-term effects of the angiotensin-converting enzyme (ACE)-inhibitor quinapril and the cardioselective beta-adrenergic blocking agent metoprolol on glycaemic control , with glycosylated haemoglobin ( HbA1c ) as the principal variable , in non-insulin-dependent diabetes mellitus ( NIDDM ) patients with hypertension . DESIGN A r and omized , double-blind , double-dummy , multicentre study during 6 months preceded by a 4 week wash-out and a 3 week run-in placebo period . Quinapril ( 20 mg ) and metoprolol ( 100 mg , conventional tablets ) were given once daily . No change was made in the treatment of diabetes ( diet and hypoglycaemic agents ) . SUBJECTS Seventy-two patients fulfilling the criteria were r and omized and entered the double-blind period . Twelve patients did not complete the study . Sixty patients , 26 on quinapril and 34 on metoprolol , were available for the final analysis . MAIN OUTCOME MEASURES The effect was assessed by changes in HbA1c , the fasting serum glucose and the post-load serum glucose , C-peptide and insulin levels during the oral glucose tolerance test . RESULTS In the quinapril group , the fasting serum glucose , oral glucose tolerance and the C-peptide and insulin responses , determined as the incremental area under the curves ( AUC ) , showed no change , but the mean HbA1c level increased from 6.2 + /- 1.1 % to 6.5 + /- 1.3 % ( P < 0.05 ) . In the metoprolol group , the rise in the mean level of HbA1c , from 6.3 + /- 1.0 % to 6.8 + /- 1.3 % ( P < 0.01 ) , tended to be more marked than after quinapril , although there was no significant difference between the increments . The mean fasting serum glucose showed an increase from 9.1 + /- 1.9 mM to 10.1 + /- 2.8 mM ( P < 0.01 ) which correlated significantly with the duration of diabetes ( P < 0.01 ) and the increase in fasting serum triglycerides ( P < 0.001 ) . Moreover , in the metoprolol group we found significant decreases in the oral glucose tolerance as well as C-peptide and insulin responses to the glucose load . CONCLUSIONS Treatment with quinapril for 6 months appears to have advantages over metoprolol in NIDDM patients with hypertension . Although treatment with quinapril  or  metoprolol over 6 months was concomitant with a rise in the HbA1c , increased fasting blood glucose , decreased oral glucose tolerance and decreased C-peptide and insulin responses to a glucose challenge were observed only in patients treated with metoprolol As the population ages , the incidence of type 2 diabetes will increase as will the incidence of concomitant vascular complications . Hypertension substantially increases the risk of cardiovascular disease in patients with diabetes . Results from the recent Appropriate Blood Pressure Control in Diabetes ( ABCD ) trial demonstrated an advantage of an angiotensin-converting enzyme ( ACE ) inhibitor ( enalapril ) over a long-acting calcium antagonist ( nisoldipine ) with regard to the incidence of cardiovascular events over a 5-year follow-up period in hypertensive persons with type 2 diabetes . This trial was a prospect i ve , r and omized , blinded study comparing the effects of moderate blood pressure control ( target diastolic pressure 80 - 89 mm Hg ) with those of intensive control ( target diastolic pressure 75 mm Hg ) on the incidence and progression of diabetic vascular complications . The study also compared nisoldipine with enalapril as first-line antihypertensive therapy in terms of prevention and progression of complications of diabetes . In 470 hypertensive patients , the incidence of fatal and nonfatal myocardial infa rct ions was significantly ( p = 0.001 ) higher among those receiving nisoldipine ( n = 25 ) compared with those receiving enalapril ( n = 5 ) . Comparison with previous studies suggests that the difference observed between nisoldipine and enalapril result ed from a beneficial effect of enalapril rather than a deleterious effect from nisoldipine . Since these findings in the ABCD trial are based on a secondary endpoint , they require confirmation . Nevertheless , they suggest that ACE inhibitors should be the initial antihypertensive medication used in patients with type 2 diabetes and hypertension Objective Beta-blockers and angiotensin II receptor blockers have different effects on lipids . Methods We examined lipid levels in the Losartan Intervention For Endpoint reduction in hypertension study and their impact on the primary composite endpoint of cardiovascular death , myocardial infa rct ion , or stroke . We measured total and high-density lipoprotein cholesterol at baseline and annually during 4.8 years of losartan-based compared with atenolol-based treatment in 8611 patients with hypertension and left ventricular hypertrophy . Results Patients r and omized to  losartan-based or atenolol-based treatment had similar baseline total ( 6.04 ± 1.12 vs. 6.05 ± 1.13 mmol/l , NS ) and high-density lipoprotein ( HDL ) cholesterol ( 1.50 ± 0.44 vs. 1.49 ± 0.44 mmol/l , NS ) . Total cholesterol decreased significantly but equally ( −0.37 ± 1.05 vs. −0.34 ± 1.09 mmol/l , NS ) , whereas HDL cholesterol decreased less during the first 2 years in patients r and omized to losartan compared with atenolol ( −0.13 ± 0.24 vs. −0.19 ± 0.25 mmol/l ) and remained higher each year ( 1.38 , 1.37 , 1.42 , 1.47 , and 1.48 mmol/l vs. 1.32 , 1.30 , 1.36 , 1.40 , and 1.42 mmol/l , all P < 0.001 ) independent of hydrochlorothiazide or statin treatment . In Cox regression analysis , baseline total cholesterol [ hazard ratio ( HR ) = 1.08 ( 1.02–1.14 ) per mmol/l , P < 0.01 ] , HDL cholesterol [ HR = 0.56 ( 0.48–0.66 ) per mmol/l , P < 0.001 ] , and treatment allocation [ HR = 0.86 ( 0.76–0.98 ) , P < 0.05 ] predicted composite endpoint independently . Using time-varying analyses , the predictive strength of HDL cholesterol was increased [ HR = 0.36 ( 0.30–0.44 ) per mmol/l , P < 0.001 ] , whereas that of total cholesterol [ HR = 1.03 ( 0.97–1.09 ) per mmol/l , NS ] and treatment allocation [ HR = 0.91 ( 0.80–1.03 ) , NS ] were reduced . Conclusion Losartan blunted the decrease in HDL cholesterol during antihypertensive treatment in the LIFE study . Higher intreatment HDL cholesterol was associated with fewer composite endpoints and may partly explain the better outcome of losartan-based treatment BACKGROUND It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications . Because this issue remains controversial , we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were r and omly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study . METHODS The Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial is a prospect i ve , r and omized , blinded trial comparing the effects of moderate control of blood pressure ( target diastolic pressure , 80 to 89 mm Hg ) with those of intensive control of blood pressure ( diastolic pressure , 75 mm Hg ) on the incidence and progression of complications of diabetes . The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes . In the current study , we analyzed data on a secondary end point ( the incidence of myocardial infa rct ion ) in the subgroup of patients in the ABCD Trial who had hypertension . RESULTS Analysis of the 470 patients in the trial who had hypertension ( base-line diastolic blood pressure , > or = 90 mm Hg ) showed similar control of blood pressure , blood glucose and lipid concentrations , and smoking behavior in the nisoldipine group ( 237 patients ) and the enalapril group ( 233 patients ) throughout five years of follow-up . Using a multiple logistic-regression model with adjustment for cardiac risk factors , we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infa rct ions ( a total of 24 ) than enalapril ( total , 4 ) ( risk ratio , 9.5 ; 95 percent confidence interval , 2.7 to 33.8 ) . CONCLUSIONS In this population of patients with diabetes and hypertension , we found a significantly higher incidence of fatal and nonfatal myocardial infa rct ion among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril . Since our findings are based on a secondary end point , they will require confirmation Context Previously published results of this r and omized , double-blind trial showed that high-risk patients with type 2 diabetic nephropathy had better renal protection if they were treated with irbesartan rather than amlodipine in addition to conventional antihypertensive therapy . Contribution These detailed analyses showed no differences in overall cardiovascular outcomes between patients given irbesartan or amlodipine .  Fewer patients given irbesartan had heart failure and fewer patients given amlodipine had heart attacks . Caution s The trial had limited power to detect important differences between groups in mortality or strokes , and most patients received several antihypertensive agents . The Editors Patients with diabetes have an increased risk for cardiovascular complications and death ( 1 ) . Studies that analyzed the effects of inhibition of the reninangiotensin system on the risk for cardiovascular complications included a substantial number of patients with diabetes ( 2 - 5 ) or were done exclusively in patients with diabetes ( 6 - 8 ) . The meta- analysis of these studies ( 9 ) , the analysis of the diabetic cohorts in the Heart Outcomes Prevention Evaluation ( HOPE ) study ( 2 ) , and the Losartan Intervention for Endpoint Reduction in Hypertension ( LIFE ) trial ( 5 ) demonstrated that angiotensin-converting enzyme ( ACE ) inhibitors ( 2 , 9 ) and angiotensin-receptor blockers ( 5 ) had a statistically significant advantage over placebo or alternative agents in decreasing the risk for several cardiovascular events . These studies r and omly assigned few patients with renal involvement and overt proteinuria . Overt proteinuria occurred in fewer than 20 % of the 470 patients in the Appropriate Blood Pressure Control in Diabetes ( ABCD ) trial ( 6 ) , and only 11 % of the 1195 patients in the LIFE trial ( 5 ) . The Captopril Prevention Project ( CAPP ) ( 3 ) and the Swedish Trial in Old Patients with Hypertension-2 ( STOP Hypertension-2 ) ( 4 ) did not state the number of patients with diabetes and overt proteinuria . There were no such patients in the Fosinopril versus Amlodipine Cardiovascular Events Trial ( FACET ) ( 7 ) , and patients with dipstick-positive albuminuria were excluded from the HOPE trial ( 2 ) . Since proteinuria is an independent risk factor for cardiovascular disease ( 10 , 11 ) , the data obtained in the aforementioned trials can not be extrapolated to patients with type 2 diabetes and overt nephropathy . Trials performed in such patients have reported a blood pressureindependent effect of two different angiotensin-receptor blocker agents to protect against nephropathy ( 12 , 13 ) without a change in all-cause mortality . Apart from studies in heart failure , few cardiovascular data exist for receptor blockers compared with either placebo or calcium-channel blockers . We report on the analysis of the cardiovascular end points that were monitored as secondary end points in the Irbesartan Diabetic Nephropathy Trial ( IDNT ) ( 12 ) and assess whether an angiotensin II receptor blocker or a calcium-channel blocker alters the risk for cardiovascular events beyond those observed by blood pressure reduction alone without such agents . Methods Patients The IDNT was a r and omized , double-blind study on the effect of treatment with irbesartan or amlodipine compared with placebo in patients with type 2 diabetic nephropathy . The protocol of this study has been published ( 12 , 14 ) . Entry criteria required that patients be between 30 and 70 years of age and have type 2 diabetes mellitus and overt nephropathy , as evidence d by current treatment for hypertension or by a protein excretion rate of 900 mg/d or greater , serum creatinine level of 89 mol/L ( 1.0 mg/dL ) to 266 mol/L ( 3.0 mg/dL ) in women or of 106 mol/L ( 1.2 mg/dL ) to 266 mol/L ( 3.0 mg/dL ) in men , and baseline seated blood pressure greater than 135/85 mm Hg . The institutional review boards of each center approved the protocol . All patients gave written informed consent . Treatment and R and omization Patients were r and omly assigned central ly by computer to receive treatment with irbesartan , 300 mg/d ( Avapro , Bristol-Myers Squibb , Princeton , New Jersey ) ; amlodipine , 10 mg/d ( Norvasc , Pfizer , New York ) ; or matched placebo . To minimize any center effect , r and omization was blocked by center . All patients had blood pressure controlled to the same blood pressure goal of less than 135/85 mm Hg by using antihypertensive agents other than ACE inhibitors , angiotensin II receptor blocking agents , or calcium-channel blockers . For the analysis of cardiovascular end points , patients were followed to initiation of treatment for end-stage renal failure ( dialysis or renal transplantation ) , reaching a serum creatinine level of 530.4 mol/L ( 6.0 mg/dL ) or higher , death , or administrative censoring in December 2000 . Outcomes We prospect ively established cardiovascular outcomes , defined in the Appendix Table . Appendix Table . Classification for Fatal and Nonfatal Cardiovascular Events Ascertainment of Cardiovascular Events Information about hospitalizations and adverse events were screened at Bristol-Myers Squibb , Princeton , New Jersey , by trained , blinded clinical research associates to identify potential cardiovascular events . Investigators used study forms to report and characterize all cardiovascular outcomes . For all potential events , records , including laboratory values , electrocardiograms , and radiographic reports were obtained for clarification . Since myocardial infa rct ions may go unrecognized , a central electrocardiogram reading center was established at Brigham and Women 's Hospital , Boston , Massachusetts , where two cardiologists review ed every electrocardiogram . Electrocardiography was performed at baseline , 6 months , 12 months , and annually thereafter . A total of 5698 electrocardiograms were review ed at the center . When a new Q-wave infa rct ion was found , the cardiologists asked whether a clinical myocardial infa rct ion was reported . Even when myocardial infa rct ions were not clinical ly reported , these Q-wave infa rct ions were adjudicated as myocardial infa rct ions . Adjudication of Cardiovascular Events Investigators at each center reported cardiovascular events , defined in the Appendix Table . The information on all potential events was referred to one member of the Outcomes Confirmation and Classification Committee ( Appendix ) . If the committee member agreed with the judgment of the center investigator , their combined judgment was accepted . If the center investigator and the committee member differed , the case material was review ed by the membership of the committee , whose decision was accepted . Deaths were adjudicated by a Mortality Committee ( Appendix ) . Each death was review ed by two members of the committee and presented to the membership , whose decision was accepted as final . Statistical Analysis For graphical presentation ( Figure ) and overall testing for statistically significant differences among the three treatment groups , time to the first occurrence of either a specific cardiovascular outcome or one of the composite outcomes was analyzed by product-limit survival curves and the log-rank test ( 15 ) . We used proportional hazards modeling to determine hazard ratios . For the cardiovascular death outcome , which could occur only once , we used the st and ard proportional hazards model ( 16 ) , with treatment assignment as the only independent covariate . For other cardiovascular outcomes , which could occur more than once , we used the And ersonGill formulation of the proportional hazards model ( 17 ) , in which patients are considered at risk for the first event from r and omization to the first event , at risk for the second event from the day following the first event to the second event , and so forth , permitting use of all the data . In accordance with the method of Lee and colleagues ( 18 ) , we used a robust variance estimate that accounts for the possibility of correlation of risk for several events within a patient . We believed that occurrence of a first event of a given type increases the likelihood of a subsequent similar event . Therefore , both treatment assignment and a time-dependent covariate indicating whether the event was the first of its type or a subsequent event were included in these analyses . The time-dependent covariate was statistically significant in each case , confirming the above assumption . There was no statistically significant interaction between treatment and the time-dependent covariatethe effects of treatment assignment were similar for first and subsequent events and inclusion of the time-dependent covariate did not change either the estimates of the treatment effect or their statistical significance s. Figure . Time to first cardiovascular composite event as a function of treatment assignment . P Data management and computations were done by using SAS software for Windows , version 8 ( SAS Institute , Inc. , Cary , North Carolina ) , or S-Plus for Windows , version 6.0 ( Insightful Corp. , Seattle , Washington ) . Statistical tests were two sided . A P value of 0.05 or less , unadjusted for the multiple comparisons , was considered statistically significant . Role of the Funding Sources The funding sources were involved in the data collection but not in the analysis or interpretation or the decision to su bmi t the manuscript for publication . Results The baseline characteristics of the three groups are shown in Table 1 . A flow diagram of the study is shown in the Appendix Figure . Table 1 . Baseline Characteristics Appendix Figure . Flow diagram for the Irbesartan Diabetic Nephropathy Trial . Clinical Management During the study , the blood pressure decreased from the baseline values to 140/77 mm Hg in the irbesartan group , 141/77 mm Hg in the amlodipine group , and 144/80 mm Hg in the placebo group . Blood pressure in the two active treatment groups did not differ ; values in both groups were statistically significantly lower than in the placebo group ( P = 0.001 ) . The distribution of non study drugs used to achieve the target blood pressure was similar Postmenopausal women are at greater risk for hypertension-related cardiovascular disease .  Antihypertensive therapy may help alleviate arterial stiffness that represents a potential modifiable risk factor of hypertension . This r and omized controlled study investigated the difference between an angiotensin receptor blocker and a calcium channel blocker in reducing arterial stiffness . Overall , 125 postmenopausal hypertensive women ( age , 61.4 ± 6 years ; systolic blood pressure/diastolic blood pressure [ SBP/DBP ] , 158 ± 11/92 ± 9 mm Hg ) were r and omized  to valsartan 320 mg ± hydrochlorothiazide ( HCTZ ) ( n = 63 ) or amlodipine 10 mg ± HCTZ ( n = 62 ) . The primary outcome was carotid-to-femoral pulse wave velocity ( PWV ) changes after 38 weeks of treatment . Both treatments lowered peripheral blood pressure ( BP ) ( -22.9/-10.9 mm Hg for valsartan and -25.2/-11.7 mm Hg for amlodipine , P = not significant ) and central BP ( -15.7/-7.6 mm Hg for valsartan and -19.2/-10.3 mm Hg for amlodipine , P<.05 for central DBP ) . Both treatments similarly reduced the carotid-femoral PWV ( -1.9 vs -1.7 m/s ; P = not significant ) . Amlodipine was associated with a higher incidence of peripheral edema compared with the valsartan group ( 77 % vs 14 % , P<.001 ) . BP lowering in postmenopausal women led to a reduction in arterial stiffness as assessed by PWV measurement . Both regimens reduced PWV to a similar degree after 38 weeks of treatment despite differences in central BP lowering , suggesting that the effect of valsartan on PWV is mediated through nonhemodynamic effects AIMS Treatment of hypertension in patients with chronic renal failure has been shown to postpone the decline in renal function . Treatment with an ACE inhibitor has been shown to be superior to conventional antihypertensive treatment , but it is not known how an ACE inhibitor compares to treatment with a calcium channel blocker or to treatment with a combination of these drugs . The aim of the study was to evaluate the rate of decline in GFR in patients with chronic renal failure and hypertension treated with isradipine and spirapril as monotherapy and in combination . METHODS Sixty patients with chronic renal failure and hypertension were enrolled in the study . After enrollment , patients were followed prospect ively for 6 months in the outpatient clinic on their usual antihypertensive medication , and then r and omized to a double-blinded comparison of either spirapril 6 mg daily , isradipine 5 mg daily or spirapril 3 mg and isradipine 2.5 mg daily . After r and omization , patients were followed for 21 months or until the need for dialysis . Every 3 months before and 3.5 months after r and omization the glomerular filtration rate was measured by 51Cr-EDTA clearance and the effective renal plasma flow evaluated using the renal clearance of paraaminohippuric acid . RESULTS Blood pressure and the decline in glomerular filtration rate did not differ between the groups before r and omization . After r and omization , the mean decline in the glomerular filtration rate was -0.32 ml/(min x month x 1.73 m2 ) in the spirapril group , -0.58 ml/(min x month x 1.73 m2 ) in the isradipine group and -0.14 ml/(min x month x 1.73 m2 ) in the combination group ( p = 0.38 ) . Twelve patients , 4 in each group , reached end-stage renal failure . No significant difference was found with respect to diastolic ( p = 0.10 ) or systolic blood pressure ( p = 0.08 ) during the treatment period , but a trend towards a better blood pressure control in the combination group was present . During treatment , the rate of decline in renal plasma flow did not differ significantly between the groups ( p = 0.09 ) , neither did the changes in filtration fraction ( FF ) ( p = 0.58 ) nor the mean FF ( p = 0.22 ) during the treatment . CONCLUSIONS Our study indicated differences between the 3 treatment modalities in favor of combined therapy with respect to both the rate of decline in GFR and blood pressure control , but the differences where insignificant . Thus , the treatments might differ , but we were unable to confirm this because of large variation in GFR and small sample size Abstract Background and objectives : Hypertension is a significant cause of chronic renal injury and its effective treatment is capable of reducing the rate of renal failure . β-Adrenoceptor antagonists ( β-blockers ) have been reported to induce a deterioration in renal function , while several data have indicated a renoprotective effect of treatment with the angiotensin II type 1 receptor antagonist losartan . Previous studies of the interaction between the selective β1-blocker bisoprolol and kidney function were performed only for short- and medium-term periods . The aim of this study was to compare the antihypertensive efficacy and renal and cardiac haemodynamic effects of bisoprolol with those of losartan over a 1-year time period in patients with essential hypertension . Methods : Seventy-two patients ( 40 males ) with recently diagnosed uncomplicated ( European Society of Hypertension [ ESH ] criteria stage 1–2 ) hypertension ( mean ± SD age 52 ± 12 years ) were enrolled in the study . After a run-in period of 14 days on placebo , the patients were r and omized in a double-blind , prospect i ve study to receive either bisoprolol 5 mg or losartan 50 mg , administered once daily for 1 year . At recruitment and 12 months after treatment , cardiac output and renal haemodynamics and function were evaluated by echocardiography and radionuclide studies , respectively . Results : There were no significant differences in baseline clinical data , including glomerular filtration rate and blood pressure , between the two treatment groups . At 1 year , blood pressure had decreased significantly ( p < 0.001 ) with both treatments , and heart rate was reduced only in the group taking bisoprolol . The long-term effects on renal haemodynamics and cardiac function were similar with both drugs , the only change being a significant reduction in the filtration fraction for each group . Conclusions : These data suggest that both bisoprolol and losartan are effective agents for the treatment of patients with recently diagnosed ESH stage 1–2 hypertension . Over a 1-year period , both agents maintained good renal and cardiac performance and haemodynamics OBJECTIVES We conducted a subgroup analysis in the Losartan Intervention For Endpoint reduction in hypertension ( LIFE ) study to determine whether aspirin interacted with the properties of losartan , an angiotensin-II receptor antagonist . BACKGROUND Negative interactions between angiotensin-converting enzyme inhibitors and aspirin have been reported . There are no data reported from clinical trials about possible interactions between angiotensin-II receptor antagonists and aspirin . METHODS The LIFE study assigned 9,193 patients with hypertension and left ventricular hypertrophy ( LVH ) to losartan- or atenolol-based therapy for a mean of 4.7 years , with 1,970 ( 21.4 % ) taking aspirin at baseline . The primary composite end point ( CEP ) included cardiovascular death , stroke , and myocardial infa rct ion ( MI ) . The present cohort was stratified by aspirin use at baseline . RESULTS Blood pressures were reduced similarly in the losartan with aspirin ( n = 1,004 ) and atenolol with aspirin ( n = 966 ) groups . The CEP was reduced by 32 % ( 95 % confidence interval 0.55 to 0.86 , p = 0.001 ) with losartan with aspirin compared to atenolol with aspirin , adjusted for Framingham risk score and LVH . The test for treatment versus aspirin interaction , excluding other covariates , was significant for the CEP ( p = 0.016 ) and MI ( p = 0.037 ) . CONCLUSIONS There was a statistical interaction between treatment and aspirin in the LIFE study , with significantly greater reductions for the CEP and MI with losartan in patients using aspirin than in patients not using aspirin at baseline . Further studies are needed to clarify whether this represents a pharmacologic interaction or a selection by aspirin use of patients more likely to respond to losartan treatment Background . Low serum potassium ( K ) is associated with increased blood pressure , impaired cardiac function and renal dysfunction . Although lower serum K is associated with cardiac hypertrophy in animal models , the relationship of low serum K to the presence and severity of electrocardiographic left ventricular hypertrophy ( LVH ) is unclear . Methods . Baseline and yearly Cornell product LVH levels were examined in relation to low serum K ( serum K ≤ 3.90 mEq/l , the lowest quartile of baseline K levels ) in 8586 patients with baseline K levels . Patients were r and omized to losartan-vs atenolol-based treatment and additional hydrochlorothiazide ( HCTZ ) therapy as needed . Results . After adjusting for age , sex , race , prior antihypertensive treatment , losartan vs atenolol therapy , HCTZ use , baseline diastolic and systolic pressure , body mass index , serum creatinine and urine albumin/creatinine ratio , baseline serum K ≤ 3.90 was associated with significantly higher mean baseline Cornell product LVH ( 2898 vs 2801 mm•ms , p = 0.001 ) and a 24 % higher risk of Cornell product LVH > 2440 mm•ms at baseline ( OR 1.24 , 95 % CI 1.11–1.38 , p < 0.001 ) . After also adjusting for baseline Cornell product and changes in diastolic and systolic pressure between baseline and each year of measurement , in-treatment serum K ≤ 3.90 determined yearly was associated with significantly higher mean Cornell product LVH at years 1–3 and with statistically significant 16–32 % increased risks of LVH by Cornell product at years 1–4 . Conclusions . A low serum K is independently associated with a greater likelihood and severity of Cornell product LVH during antihypertensive therapy OBJECTIVE To compare six antihypertensive interventions for the treatment of mild hypertension . DESIGN R and omized , double-blind , placebo-controlled clinical trial . SETTING Four hypertension screening and treatment centers in the United States . PARTICIPANTS Hypertensive men and women , aged 45 to 69 years , with diastolic blood pressure less than 100 mm Hg . INTERVENTION Sustained nutritional-hygienic advice to all participants to reduce weight , dietary sodium intake , and alcohol intake , and increase physical activity . Participants were r and omly allocated to take ( 1 ) placebo ( n = 234 ) ; ( 2 ) chlorthalidone ( n = 136 ) ; ( 3 ) acebutolol ( n = 132 ) ; ( 4 ) doxazosin mesylate ( n = 134 ) ; ( 5 ) amlodipine maleate ( n = 131 ) ; or ( 6 ) enalapril maleate ( n = 135 ) . MAIN OUTCOME MEASURES Blood pressure , quality of life , side effects , blood lipid levels and analysis of other serum components , echocardiographic and electrocardiographic changes , and incidence of cardiovascular events over an average of 4.4 years of follow-up . RESULTS Blood pressure reductions were sizable in all six groups , and were significantly greater for participants assigned to drug treatment than placebo ( -15.9 vs -9.1 mm Hg for systolic blood pressure and -12.3 vs -8.6 mm Hg for diastolic blood pressure ; P < .0001 ) . After 4 years , 59 % of participants assigned to placebo and 72 % of participants given drug treatment continued on their initial medication as monotherapy . A smaller percentage of participants assigned to the drug-treatment groups died or experienced a major nonfatal cardiovascular event than those assigned to the placebo group ( 5.1 % vs 7.3 % ; P = .21 ) . After including other clinical events , the percentage of participants affected was 11.1 % for those in the drug-treatment groups and 16.2 % for those in the placebo group ( P = .03 ) . Incidence rates of most resting electrocardiographic abnormalities were lower and quality of life was improved more for those assigned to drug-treatment groups rather than the placebo group . Differences among the five drug treatments did not consistently favor one group in terms of regression of left ventricular mass , blood lipid levels , and other outcome measures . CONCLUSIONS As an initial regimen , drug treatment in combination with nutritional-hygienic intervention was more effective in preventing cardiovascular and other clinical events than was nutritional-hygienic treatment alone . Drug-treatment group differences were minimal . Pending results from large-scale clinical trials to evaluate drug treatments for their effect on cardiovascular clinical events , these findings support the recommendations of the new fifth Joint National Committee report regarding treatment choices for people with stage 1 ( " mild " ) hypertension Background The Swedish irbesartan left ventricular hypertrophy investigation versus atenolol ( SILVHIA ) . Objective Angiotensin II induces myocardial hypertrophy . We hypothesized that blockade of angiotensin II subtype 1 ( AT1 ) receptors by the AT1-receptor antagonist irbesartan would reduce left ventricular mass ( as measured by echocardiography ) more than conventional treatment with a beta blocker . Design and methods This double-blind study r and omized 115 hypertensive men and women with left ventricular hypertrophy to receive either irbesartan 150 mg q.d . or atenolol 50 mg q.d . for 48 weeks . If diastolic blood pressure remained above 90 mmHg , doses were doubled , and additional medications ( hydrochlorothiazide and felodipine ) were prescribed as needed . Echocardiography was performed at weeks 0 , 12 , 24 and 48 . Results Baseline mean blood pressure was 162/104 mmHg , and mean left ventricular mass index was 157 g/m2 for men and 133 g/m2 for women . Systolic and diastolic blood pressure reductions were similar in both treatment groups . Both irbesartan ( P < 0.001 ) and atenolol ( P < 0.001 ) progressively reduced left ventricular mass index , e.g. by 26 and 14 g/m2 ( 16 and 9 % ) , respectively , at week 48 , with a greater reduction in the irbesartan group ( P = 0.024 ) . The proportion of patients who attained a normalized left ventricular mass ( i.e. ⩽ 131 g/m2 for men and ⩽ 100 g/m2 for women ) tended to be greater with irbesartan ( 47 versus 32 % , P = 0.108 ) . Conclusions Left ventricular mass was reduced more in the irbesartan group than in the atenolol group . These results suggest that blocking the action of angiotensin II at AT1-receptors may be an important mechanism , beyond that of lowering blood pressure , in the regulation of left ventricular mass and geometry in patients with hypertension Summary We have studied 250 patients with mild to moderate essential hypertension ( diastolic blood pressure 95 – 114 mmHg ) and dyslipidaemia ( high-density lipoprotein cholesterol ( HDL-C ) below 1.03 mmol·l−1 , total cholesterol 5.17–9.05 mmol·l−1 , and triglycerides 2.26–5.64 mmol·l−1 ) in a controlled double-blind , multicentre , parallel group trial . The patients took a fat-modified diet . After a 4-week placebo period , patients who continued to fulfil the selection criteria were r and omly allocated to treatment with either carvedilol ( a vasodilating β-blocker ) 25–50 mg o.d . ( n=116 ) or captopril ( an ACE inhibitor ) 25–50 mg o.d . ( n=117 ) for 6 months . In both groups there were favourable effects on the serum lipids . The relative changes ( medians ) in the carvedilol and captopril group were respectively : increase in HDL-C by 11 % and 8 % , decrease in total cholesterol by 11 % and 10 % , in low-density lipoprotein cholesterol by 16 % and 12 % , and in triglycerides by 13 % and 14 % . Equivalence of the two treatments was confirmed for the target variable change in HDL-C at a significance level of 5%.Reductions in supine systolic/diastolic blood pressures were comparable in the two groups ( carvedilol : 23/19 mmHg , captopril : 20/18 mmHg).The improvement in lipid metabolism in patients treated with carvedilol is probably due to its α1-blocking properties We examined long-term changes in cognitive function and quality of life ( QL ) in hypertensive patients by comparing the antihypertensive effect of hydrochlorothiazide ( HCTZ ) and losartan . We studied 69 patients ( age range , 30 to 73 years ) with mild-to-moderate hypertension . All patients , in a double-blind study , were r and omly allocated to either treatment with 50 mg losartan once daily or 25 mg HCTZ once daily . The sample in each treatment group was divided by age ( younger than 60 years or 60 years or older ) . At baseline and after 26 months , a QL question naire appropriate for the hypertensive patients was given . Cognitive function was evaluated , at baseline and after 26 months , by psychometric tests consisting of items from the  Mini-Mental State Examination ( MMSE ) and the S and oz Clinical Assessment Geriatric ( SCAG ) . A score of less than 24 on the MMSE and more than 40 on the SCAG was predictive of cognitive impairment . The losartan group had a significant improvement in SCAG ( P<.001 ) and MMSE ( P<.001 ) . No significant changes were observed in the HCTZ group ( SCAG , P = .1 ; MMSE , P = .2 ) . Sixty-five percent of the elderly had a MMSE score less than 24 and 70 % had a SCAG score greater than 40 , v. 35 % and 48 % , respectively , in younger patients . The health state index of QL improved significantly in both groups ( losartan group , P<.01 ; HCTZ group , P<.02 ) ; the improvement in QL scores in patients using HCTZ was significant only in subjects aged 60 years and older ( P<.04 ) . These results suggest that losartan can have a positive effect not only on blood pressure but also on impaired cognitive function , reversing even minimal cognitive deficits induced by hypertension . The elderly patients in our sample had worse scores and cognitive performance was lower than in younger patients , even if in the losartan group the score improvement was the same at all ages . The same could not be said for HCTZ OBJECTIVES To assess the peripheral and central haemodynamics , in particular the effect on minimal resistance in the h and , with an ACE inhibitor in comparison with a diuretic . DESIGN Double-blind r and omized parallel group study . SUBJECTS Twenty-eight previously untreated men with essential hypertension ( supine diastolic blood pressure > 95 mmHg repeatedly on placebo ) . METHODS /INTERVENTION : Causal and intra-arterial blood pressure , dye-dilution technique , water plethysmography at rest and at ischaemia , enalapril ( n = 14 ) , hydrochlorothiazide ( n = 14 ) . RESULTS After 6 months the mean arterial pressure was reduced from 112.7 to 96.9 mmHg ( change -15.9 mmHg ; 95 % confidence interval ( CI ) -21.9 , -9.8 ) on enalapril and from 110.1 to 101.5 mmHg ( change -8.6 mmHg ; CI -14.4 , -2.8 ) . Heart rate did not change on any of the therapies . Enalapril reduced blood pressure mainly through a reduction in total peripheral resistance ( delta -3.0 PRU100 ; CI -5.6 , -0.4 ) while hydrochlorothiazide reduced blood pressure mainly through a reduction in cardiac output ( delta -0.8 l/min-1 ; CI -1.5 , -0.07 ) . Minimal vascular resistance ( mean of right and left h and ) displayed a significant time x treatment interaction indicating a different trend with enalapril than hydrochlorothiazide with a change of -0.12 PRU100 ( CI -0.33 , 0.05 ) on enalapril and a change of 0.14 ( CI -0.29 , 0.56 ) on hydrochlorothiazide . The resistance level after 6 months was significantly higher on hydrochlorothiazide than on enalapril ( P = 0.0105 ) . CONCLUSION Enalapril reduced blood pressure through vasodilatation and hydrochlorothiazide through decreased cardiac output . The two therapies also affected minimal vascular resistance ( an indirect measure of vascular wall thickness ) differently ; with enalapril showing a favourable response in contrast to hydrochlorothiazide The Losartan Intervention For Endpoint reduction in hypertension ( LIFE ) study reported that a losartan-based antihypertensive regimen reduced cardiovascular morbidity and mortality ( composite of cardiovascular death , stroke , and myocardial infa rct ion ) more than therapy based on atenolol in patients with left ventricular hypertrophy and isolated systolic hypertension ( ISH ) . Patients aged 55 - 80 years with blood pressures 160 - 200/<90 mm Hg were followed for a mean of 4.7 years .  Blood pressure was similarly reduced in the losartan ( n=660 ) and atenolol ( n=666 ) ISH groups . There were 88 ( 6.6 % ) patients who experienced a stroke , 18 of which were fatal . Of patients experiencing strokes , 72.7 % had an ischemic stroke .  ISH patients in LIFE compared to the non-ISH group had a higher incidence of any stroke and embolic stroke , and similar incidences of fatal , atherosclerotic , and hemorrhagic/other strokes . The incidence of any stroke ( 40 % risk reduction [ RR ] , p=0.02 ) , fatal stroke ( 70 % RR , p=0.035 ) , and atherothrombotic stroke ( 45 % RR , p=0.022 ) was significantly lower in losartan-treated compared to the atenolol-treated patients . The 36 % RR for embolic strokes in the losartan group was not statistically significantly ( p=0.33 ) different from the atenolol group . These data suggest that losartan-based treatment is more effective than an atenolol-based treatment for patients with ISH and a high risk for stroke CONTEXT Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality , but the optimal first-step therapy is unknown . OBJECTIVE To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease ( CHD ) or other cardiovascular disease ( CVD ) events vs treatment with a diuretic . DESIGN The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , active-controlled clinical trial conducted from February 1994 through March 2002 . SETTING AND PARTICIPANTS A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers . INTERVENTIONS Participants were r and omly assigned to receive chlorthalidone , 12.5 to 25 mg/d ( n = 15 255 ) ; amlodipine , 2.5 to 10 mg/d ( n = 9048 ) ; or lisinopril , 10 to 40 mg/d ( n = 9054 ) for planned follow-up of approximately 4 to 8 years . MAIN OUTCOME MEASURES The primary outcome was combined fatal CHD or nonfatal myocardial infa rct ion , analyzed by intent-to-treat . Secondary outcomes were all-cause mortality , stroke , combined CHD ( primary outcome , coronary revascularization , or angina with hospitalization ) , and combined CVD ( combined CHD , stroke , treated angina without hospitalization , heart failure [ HF ] , and peripheral arterial disease ) . RESULTS Mean follow-up was 4.9 years . The primary outcome occurred in 2956 participants , with no difference between treatments . Compared with chlorthalidone ( 6-year rate , 11.5 % ) , the relative risks ( RRs ) were 0.98 ( 95 % CI , 0.90 - 1.07 ) for amlodipine ( 6-year rate , 11.3 % ) and 0.99 ( 95 % CI , 0.91 - 1.08 ) for lisinopril ( 6-year rate , 11.4 % ) . Likewise , all-cause mortality did not differ between groups . Five-year systolic blood pressures were significantly higher in the amlodipine ( 0.8 mm Hg , P = .03 ) and lisinopril ( 2 mm Hg , P<.001 ) groups compared with chlorthalidone , and 5-year diastolic blood pressure was significantly lower with amlodipine ( 0.8 mm Hg , P<.001 ) . For amlodipine vs chlorthalidone , secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine ( 10.2 % vs 7.7 % ; RR , 1.38 ; 95 % CI , 1.25 - 1.52 ) . For lisinopril vs chlorthalidone , lisinopril had higher 6-year rates of combined CVD ( 33.3 % vs 30.9 % ; RR , 1.10 ; 95 % CI , 1.05 - 1.16 ) ; stroke ( 6.3 % vs 5.6 % ; RR , 1.15 ; 95 % CI , 1.02 - 1.30 ) ; and HF ( 8.7 % vs 7.7 % ; RR , 1.19 ; 95 % CI , 1.07 - 1.31 ) . CONCLUSION Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive . They should be preferred for first-step antihypertensive therapy Microalbuminuria and hypertension are risk factors for diabetic nephropathy in Type 2 diabetic patients . Recent data suggest that blockade of the renin-angiotensin system slows the progression of diabetic nephropathy ; in contrast , the results on the renoprotective effect of calcium channel antagonists are conflicting . We evaluated the effectiveness of lercanidipine , in comparison with ramipril , on the reduction in albumin excretion rate ( AER ) and blood pressure in mild-to-moderate hypertensive patients with Type 2 diabetes and persistent microalbuminuria . A total of 277 patients were enrolled in a multicentric , r and omized , double-blind , active-controlled , parallel-group trial ; 180 were r and omized to receive 10 - 20 mg/day of  lercanidipine or 5 - 10 mg/day of ramipril and followed up for 9 - 12 months . The primary outcome was the change in AER from baseline . After 9 - 12 months of follow-up , a reduction in AER of -17.4+/-65 microg/min ( p<0.05 ) and -19.7+/-52.5 ( p<0.05 ) in the lercanidipine and ramipril group , respectively , was observed , without differences between the groups . A significant reduction in systolic and diastolic blood pressure was observed in both the lercanidipine and ramipril-based treatment groups ( p<0.0001 for both ) . This study demonstrated that treatment with lercanidipine 10 - 20 mg/day does not worsen albuminuria in microalbuminuric Type 2 diabetic patients with hypertension . Indeed , both lercanidipine and ramipril treatments result ed in a significant reduction in AER without a statistically significant difference between the two groups CONTEXT Renin profiling and age-race subgroup may help select single-drug therapy for stage 1 and stage 2 hypertension . OBJECTIVE To compare the plasma renin profiling and age-race subgroup methods as predictors of response to single-drug therapy in men with stage 1 and 2 hypertension as defined by the Joint National Committee on Prevention , Detection , Evaluation and Treatment of High Blood Pressure . DESIGN The Veterans Affairs Cooperative Study on Single-Drug Therapy of Hypertension , a r and omized controlled trial . SETTING Fifteen Veterans Affairs hypertension centers . PATIENTS A total of 1105 ambulatory men with entry diastolic blood pressure ( DBP ) of 95 to 109 mm Hg , of whom 1031 had valid plasma and urine sample s for renin profiling . INTERVENTIONS R and omization to 1 of 6 antihypertensive drugs : hydrochlorothiazide , atenolol , captopril , clonidine , diltiazem ( sustained release ) , or prazosin . MAIN OUTCOME MEASURE Treatment response as assessed by percentage achieving goal DBP ( < 90 mm Hg ) in response to a single drug that corresponded to patients ' renin profile vs a single drug that corresponded to patients ' age-race subgroup . RESULTS Clonidine and diltiazem had consistent response rates regardless of renin profile ( 76 % , 67 % , and 80 % for low , medium , and high renin , respectively , for clonidine and 83 % , 82 % , and 83 % , respectively , for diltiazem for patients with baseline DBP of 95 - 99 mm Hg ) . Hydrochlorothiazide and prazosin were best in low- and medium-renin profiles ;  captopril was best in medium- and high-renin profiles ( low- , medium- , and high-renin response rates were 82 % , 78 % , and 14 % , respectively , for hydrochlorothiazide ; 88 % , 67 % , and 40 % , respectively , for prazosin ; and 51 % , 83 % , and 100 % , respectively , for captopril for patients with baseline DBP of 95 - 99 mm Hg ) . Response rates for patients with baseline DBP of 95 to 99 mm Hg by age-race subgroup ranged from 70 % for clonidine to 90 % for prazosin for younger black men , from 50 % for captopril to 97 % for diltiazem for older black men , from 70 % for hydrochlorothiazide to 92 % for atenolol for younger white men , and from 84 % for hydrochlorothiazide to 95 % for diltiazem for older white men . Patients with a correct treatment for their renin profile but incorrect for age-race subgroup had a response rate of 58.7 % ; patients with an incorrect treatment for their renin profile but correct for age-race subgroup had a response rate of 63.1 % ( P = .30 ) . After controlling for DBP and interactions with treatment group , age-race subgroup ( P<.001 ) significantly predicted response to single-drug therapy , whereas renin profile was of borderline significance ( P= .05 ) . CONCLUSIONS In these men with stage 1 and stage 2 hypertension , therapeutic responses were consistent with baseline renin profile , but age-race subgroup was a better predictor of response -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 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 Left ventricular ( LV ) hypertrophy is associated with a substantial risk for malignant arrhythmias and sudden death . The effects of antihypertensive therapy on QT dispersion , which reflects cardiac repolarization heterogeneity , in relation to changes in LV mass has not been well studied . Repeat echocardiography and QT measurements ( st and ard 12-lead electrocardiograms ) were performed in hypertensive patients with LV hypertrophy , who were r and omized double-blind to receive the angiotensin II type 1-receptor blocker irbesartan ( n = 44 ) or the beta(1)-receptor blocker atenolol ( n = 48 ) for 48 weeks , and in 37 matched hypertensive control subjects without LV hypertrophy .  LV mass index was related to QT dispersion ( r = 0.34 , p < 0.001 ) . The reduction in LV mass was greater using irbesartan than using atenolol ( -27 + /- 28 vs -15 + /- 21 g/m(2 ) at 48 weeks , p = 0.021 ) , with similar reductions in blood pressure . Irbesartan decreased QT dispersion ( from 56 + /- 24 ms to 45 + /- 20 ms at 48 weeks ; p < 0.001 ) and QTc dispersion ( from 57 + /- 24 to 44 + /- 19 ms at 48 weeks ; p < 0.001 ) . In contrast , atenolol had minor effects . The decreases in QT and QTc dispersions were greater using irbesartan than using atenolol ( p = 0.001 and p = 0.011 , respectively ) ; the same results were found when changes in LV mass , blood pressure , and heart rate were also included in multivariate analyses . Thus , heterogeneity of ventricular repolarization is related to the degree of LV hypertrophy . Irbesartan , but not atenolol , reduces QT and QTc dispersions independent of changes in LV mass , blood pressure , or heart rate , and thus seems to induce structural and electrical remodeling in a direction that could decrease the risk of fatal events in hypertensive patients Context The Losartan Intervention for Endpoint reduction in hypertension ( LIFE ) trial showed that losartan-based treatment improved cardiovascular outcomes more than atenolol-based treatment in patients with hypertension and left ventricular hypertrophy . Because the study sample was heterogeneous , clinicians wondered about effects in the lower-risk participants . Contribution This analysis of lower-risk participants without known vascular disease showed that both losartan and atenolol reduced blood pressure similarly . Cardiovascular events , particularly strokes , and new-onset diabetes occurred less frequently with losartan than with atenolol . Implication s Patients with hypertension and left ventricular hypertrophy but no known vascular disease benefit more from losartan than atenolol . The Editors Benefits of lowering blood pressure by using antihypertensive treatment are well established , especially in high-risk individuals ( 1 ) . However , treated hypertensive patients still have more cardiovascular events than matched normotensive adults . Possible reasons are failure to normalize blood pressure ; adverse effects of reninangiotensin system overactivity ; and residual target organ damage , such as left ventricular hypertrophy ( LVH ) . Recent evidence has supported the hypothesis that reversal of LVH has prognostic benefit independent of blood pressure lowering ( 2 , 3 ) . Reducing cardiovascular event rates by reninangiotensin system inhibition was initially shown by a comparison of the angiotensin-converting enzyme inhibitor ramipril with placebo in patients with clinical ly evident vascular disease in the Heart Outcomes Prevention Evaluation ( HOPE ) trial ( 4 ) . Subsequently , the Losartan Intervention for Endpoint reduction in hypertension ( LIFE ) study ( 5 ) showed that the angiotensin II AT1-receptor antagonist losartan reduced cardiovascular morbidity and mortality compared with active antihypertensive therapy with the -blocker atenolol ( 6 - 8 ) . This study also linked this benefit to hypertrophy regression ( 9 ) . The LIFE trial enrolled hypertensive patients with electrocardiogram-defined LVH and included patients at especially high risk because of clinical ly evident vascular disease ( 5 , 10 ) . Thus , antagonism of potentially toxic angiotensin II effects has been shown to reduce cardiovascular events in trials conducted wholly or partly in patients with preexisting atherosclerotic disease , but whether this is also true in most hypertensive patients without clinical ly evident vascular disease has not been extensively analyzed . Accordingly , we performed a subgroup analysis in the LIFE study to determine whether angiotensin II AT1-receptor antagonism with losartan reduces cardiovascular morbidity and mortality , compared with active therapy with established -blockerbased therapy , in hypertensive participants with electrocardiogram-defined LVH who did not have clinical ly evident coronary , cerebral , or peripheral arterial disease at the time of enrollment . Methods Study Design The LIFE study is an investigator-initiated , multinational , multicenter , double-blind , double-dummy , r and omized , active-controlled , parallel-group study . The primary objective was to evaluate the long-term effects of once-daily losartan-based antihypertensive therapy compared with atenolol-based antihypertensive therapy in patients with hypertension and electrocardiogram-defined LVH on cardiovascular morbidity and mortality . The complete LIFE study protocol , with study design , organization , clinical measures , end point definitions , choice of comparative agent , statistical considerations , recruitment details , patient characteristics , and main outcomes , has been published ( 5 - 9 , 11 ) . Patients gave informed consent under protocol s approved by the concerned ethics committees ; an independent data and safety monitoring board oversaw the trial . Target Population , Treatment , and Measurement of LVH A total of 9193 patients 55 to 80 years of age with previously treated or untreated hypertension and electrocardiogram-defined LVH ( 5 ) were r and omly assigned after 1 to 2 weeks of placebo use to losartan or atenolol if trough sitting blood pressures were 160 to 200/95 to 115 mm Hg . The present analysis included all LIFE participants , with particular focus on the subgroup without previous diagnoses of coronary , cerebral , or peripheral vascular disease by either self-report or report of treating physicians . Patients in the present subgroup analysis were enrolled from 26 June 1995 through 2 May 1997 . A total of 6886 r and omly assigned patients from centers in Denmark ( 1030 ) , Finl and ( 1237 ) , Icel and ( 96 ) , Norway ( 1112 ) , Sweden ( 1634 ) , the United Kingdom660 , and the United States ( 1067 ) did not have clinical ly evident vascular disease . Patients were followed for 4 years or longer with regular visits and upward titration of the medication dose to reach the goal blood pressure of less than 140/90 mm Hg ( 5 , 10 ) . Electrocardiogram Coding and LVH Criteria All screening , baseline , annual , and end point electrocardiograms were evaluated at one core reading center . Patients were accepted into the study if a screening electrocardiogram fulfilled the LVH criteria ( 5 , 10 ) . On the basis of evidence that combined electrocardiogram assessment of QRS voltage and duration enhances sensitivity for LVH detection at acceptable levels of specificity ( 12 , 13 ) , the product of QRS duration multiplied by Cornell voltage ( with sex adjustment of 8 mm in women [ 14 ] and a partition value of > 2440 mm ms ) was chosen to recognize hypertrophy . Because of evidence that the sex adjustment was excessive and that patients with LVH by traditional electrocardiogram criteria were being missed , two changes were made for patients recruited after 30 April 1996 :  Sex adjustment of Cornell voltage was reduced to 6 mm , and SokolowLyon voltage greater than 38 mm was accepted as an alternative criterion ( 10 ) . As previously described , it was estimated ( and later confirmed with electrocardiography in a sub study of 960 patients [ 15 ] ) that more than 70 % of patients who met LIFE electrocardiogram criteria from one screening electrocardiogram had anatomic LVH . Outcome Measures The primary end point of cardiovascular morbidity and death was a composite of the first occurrence of cardiovascular death , stroke , or clinical ly evident myocardial infa rct ion . Other prespecified outcomes were total mortality , angina pectoris or heart failure requiring hospitalization , coronary or peripheral revascularization procedures , resuscitated cardiac arrest , and new-onset diabetes . An end point committee , blinded to therapy , separately review ed clinical records for all events reported by clinical centers to determine whether they met protocol end point criteria . The Electrocardiogram Core Center evaluated regression of hypertrophy on the electrocardiogram . New-onset diabetes , defined according to 1985 World Health Organization criteria ( 16 ) , was reported by investigators on the basis of fasting hyperglycemia on two occasions or a positive result on a glucose tolerance test . Sitting blood pressure was measured at trough ( that is , 24 hours after dose ; range , 22 to 26 hours ) . Adverse experiences , classified as drug-related or nondrug-related , as well as serious or nonserious , according to International Conference on Harmonization guidelines for good clinical practice , were recorded by investigators using open-ended worksheets at every visit . The LIFE study ran its full course , and end point follow-up was stopped at midnight local time , 16 September 2001 , which was the time-point for the last end point to count . After the stopping date , patients had a follow-up clinic visit or at least a check of vital status within 6 weeks . Statistical Analysis Allocation numbers were associated with treatment groups by using a computer-generated allocation schedule ; patients were considered r and omly assigned when they received an allocation number . Blinding was maintained in a double-dummy fashion : All patients received both blinded losartan and blinded atenolol : One tablet consisted of active treatment and one tablet consisted of placebo . All cardiovascular end points were analyzed by using the intention-to-treat approach ; all r and omly assigned patients were included in their assigned treatment group , and all available follow-up information was included from r and omization through the end of the study . Only events confirmed by the end point committee were analyzed . Patients with several end points were counted as having had an event in all relevant end point analyses ; however , only the first event in a specific category counted in individual analyses . Safety analyses included all r and omly assigned patients from r and omization through 16 September 2001 or permanent discontinuation of therapy with blinded study medication , whichever came first . Differences between treatment groups in rates of clinical events were assessed by Cox regression models with degree of LVH ( using Cornell voltage duration product and SokolowLyon voltage as continuous variables ) and the Framingham risk score ( 17 ) defined by baseline characteristics as covariates . This adjusted analysis was chosen a priori as primary to account for differences in key risk predictors at baseline . Secondary unadjusted analyses were performed to vali date the adjusted results . Interaction between treatment and vascular disease status was tested by including indicators for these factors and the product of these indicators in a Cox regression model . Treatment effects were measured by hazard ratios ( relative risks ) , and their 95 % CIs were calculated from Cox regression models . The risk reduction for losartan versus atenolol was calculated as : 100 ( 1 relative risk ) . Event rates over time are presented as KaplanMeier curves . Adjustment for blood pressure was based on Cox regression models with blood pressure values throughout the trial as time-varying covariates . Differences between groups in changes in electrocardiogram Objective To compare the effects of a calcium antagonist ( nitrendipine ) and an angiotensin converting enzyme inhibitor ( enalapril ) with those of placebo on left ventricular mass in patients with non-insulin-dependent diabetes mellitus and hypertension . Design A double-blind r and omized , placebo-controlled trial . Setting General practitioners referred patients to the trial physician . Patients The study population comprised 121 patients with non-insulin-dependent diabetes mellitus . Inclusion criteria for blood pressure were diastolic blood pressure 90–115 mmHg and systolic blood pressure ⩽ 200 mmHg , while subjects were not being administered blood-pressure-lowering drugs for 3 weeks . Intervention Patients were r and omly allocated to receive nitrendipine ( n = 40 ) , enalapril ( n = 40 ) or placebo ( n = 41 ) . The treatment period was 48 weeks . Main outcome measures The effect of nitrendipine was defined as the difference in change in left ventricular mass index from baseline between nitrendipine treatment and placebo after 48 weeks of treatment . The effects of nitrendipine compared with that of enalapril and of enalapril compared with placebo were defined similarly . Left ventricular mass was measured by M-mode echocardiography . Results Use of nitrendipine and enalapril led to significant and almost identical reductions in systolic and diastolic blood pressures . During 48 weeks left ventricular mass index decreased by 5 % for patients in the nitrendipine group ( decrease by 12 g/m2 , 95 % confidence interval 1–23 ) , remained about the same for patients in the enalapril group ( decrease by 1 g/m2 , 95 % confidence interval decrease by 10 to increase by 9 ) and increased by 9 % for patients in the placebo group ( increase by 9 g/m2 , 95 % confidence interval 2–16 ) . Conclusion These results indicate that administration of nitrendipine to patients with non-insulin-dependent diabetes mellitus and hypertension  reduces left ventricular mass index . Enalapril appears not to induce regression , but perhaps prevents progression with an effect that is intermediate between those of nitrendipine and placebo . J Hypertens 16:689–696 © 1998 Lippincott-Raven Publishers BACKGROUND Elevated blood glucose levels are reported with thiazide-type diuretic treatment of hypertension . The significance of this finding is uncertain . Our objectives were to compare the effect of first-step antihypertensive drug therapy with thiazide-type diuretic , calcium-channel blocker , or angiotensin-converting enzyme inhibitor on fasting glucose ( FG ) levels and to determine cardiovascular and renal disease risks associated with elevated FG levels and incident diabetes mellitus ( DM ) in 3 treatment groups . METHODS We performed post hoc subgroup analyses from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) among nondiabetic participants who were r and omized to receive treatment with chlorthalidone ( n = 8419 ) , amlodipine ( n = 4958 ) , or lisinopril ( n = 5034 ) and observed for a mean of 4.9 years . RESULTS Mean FG levels increased during follow-up in all treatment groups . At year 2 , those r and omized to the chlorthalidone group had the greatest increase ( + 8.5 mg/dL [ 0.47 mmol/L ] vs + 5.5 mg/dL [ 0.31 mmol/L ] for amlodipine and + 3.5 mg/dL [ 0.19 mmol/L ] for lisinopril ) . The odds ratios for developing DM with lisinopril ( 0.55 [ 95 % confidence interval , 0.43 - 0.70 ] ) or amlodipine ( 0.73 [ 95 % confidence interval , 0.58 - 0.91 ] ) vs chlorthalidone at 2 years were significantly lower than 1.0 ( P<.01 ) . There was no significant association of FG level change at 2 years with subsequent coronary heart disease , stroke , cardiovascular disease , total mortality , or end-stage renal disease . There was no significant association of incident DM at 2 years with clinical outcomes , except for coronary heart disease ( risk ratio , 1.64 ; P = .006 ) , but the risk ratio was lower and nonsignificant in the chlorthalidone group ( risk ratio , 1.46 ; P = .14 ) . CONCLUSIONS Fasting glucose levels increase in older adults with hypertension regardless of treatment type . For those taking chlorthalidone vs other medications , the risk of developing FG levels higher than 125 mg/dL ( 6.9 mmol/L ) is modestly greater , but there is no conclusive or consistent evidence that this diuretic-associated increase in DM risk increases the risk of clinical events The antihypertensive effect of indapamide has never been clearly understood , particularly in hypertensive patients with diabetes mellitus . A total of 565 patients were r and omly selected to receive either indapamide 1.5 mg or enalapril 10 mg daily for 12 months . Brachial blood pressure ( BP ) and plasma and urinary electrolytes were measured at baseline and at the end of follow-up . Sodium and potassium levels and excretion rates were measured in overnight urine collection s. After 12 months ' treatment , similar significant reductions were observed in systolic and diastolic BP and pulse pressure levels in both treatment arms ( P < .001 ) . However , age , body mass index , diabetes duration , and plasma sodium reductions were shown to be major , independent factors influencing BP reduction with indapamide , but not with enalapril . Regression coefficients were positive for age and plasma sodium reductions ( P ≤ .009 ) but negative for body mass index and diabetes duration ( P ≤ .008 ) . Similar findings were observed for pulse pressure . These results were more notable in elderly patients , did not differ regardless of whether BP reduction was measured in absolute or percent values , and were associated with increased sodium and potassium excretion rates . Indapamide is more effective than enalapril at reducing BP in elderly diabetic hypertensives with marked sodium retention Objective Hypertension causes arteriolar narrowing and rarefaction in the retinal circulation , but the extent to which these changes are reversible by antihypertensive treatment is not well studied . We compared the effect of antihypertensive treatment with a calcium-channel-blocker-based regimen and an angiotensin-converting-enzyme-inhibitor-based regimen on the retinal microvasculature . Methods Twenty-five patients ( 17 men , age range 24–71 years ) with untreated hypertension were r and omized to treatment with an amlodipine-based ( n = 12 ) or lisinopril-based ( n = 13 ) regimen in a double-blind , prospect i ve parallel limb trial for 52 weeks . Measurements of blood pressure and the retinal microvasculature were made at baseline and at the end of the study . Results Both the amlodipine-based and lisinopril-based treatments reduced blood pressure to similar extents . Blood pressure reduction was associated with a reduction in arteriolar narrowing , a widening of arteriolar branch angle and an increase in arteriolar density . There were no significant differences between the two treatment regimens . Conclusion Antihypertensive treatment is associated with improvement in arteriolar narrowing and rarefaction . Improved microvascular structure may contribute to the beneficial effects of antihypertensive treatment in hypertension The effects of an ACE-inhibitor ( ramipril ) , a calcium antagonist ( felodipine ) and placebo on glomerular filtration rate ( GFR ) , urinary albumin/creatinine ratio , blood pressure ( BP ) and vasoactive hormones were investigated in a r and omized , prospect i ve , double-blind , placebo-controlled study of patients with chronic glomerulonephritis and hypertension , with measurements at entrance and after 12 and 24 months . In total , 33 patients were included : 21 completed the study with 7 patients in each group .  GFR was measured as 51Cr-EDTA clearance and the vasoactive hormones with radioimmunoassays . The reduction in GFR was significantly more pronounced in the felodipine group ( -7 ml/min ) than in the ramipril group ( 0 ml/min ) but the same as in the placebo group ( -6 ml/min ) . The urinary albumin/creatinine ratio was significantly more reduced in the ramipril group ( -74 mg/mmol ) than in the placebo group ( -11 mg/mmol ) , which did not deviate from the felodipine group ( -10 mg/mmol ) . BP was significantly reduced by ramipril and felodipine , but not by placebo .  Angiotensin II and aldosterone in plasma increased or tended to increase in the felodipine and placebo groups , but were unchanged in the ramipril group . Endothelin increased only in the placebo group , and vasopressin , atrial natriuretic peptide , and brain natriuretic peptide were not significantly changed in any of the groups . It is concluded that ramipril seems to be superior to felodipine in chronic glomerulonephritis owing to better preservation of GFR BACKGROUND Hypertension is a common complication in autosomal dominant polycystic kidney disease ( ADPKD ) . This prospect i ve r and omized double-blind study was performed to compare the renal and cardiac effects of the ACE inhibitor ramipril and the beta-blocker metoprolol as first line therapy in ADPKD patients with hypertension . METHODS Forty-six hypertensive ADPKD patients were r and omized to either ramipril ( n = 23 ) or metoprolol ( n = 23 ) . Twenty-four hour ( 24-h ) ambulatory blood pressure ( BP ) , glomerular filtration rate ( GFR ) as calculated by the Cockcroft and Gault formula , urinary albumin excretion ( albumin/creatinine ratio ) , and left ventricular mass index ( LVMI ) were established at baseline and at yearly intervals . The total follow-up was 3 years . Baseline characteristics were similar in both groups . RESULTS Mean arterial pressure ( MAP ) decreased significantly in both the ramipril and the metoprolol group (-8 + /- 2 and -6 + /- 2 mmHg ; both P < 0.01 ) . There was a significant decline in renal function during follow-up which was similar in patients treated with ramipril or metoprolol ( -2.5 + /- 0.7 vs -2.9 + /- 0.8 ml/min/year ; P = NS ) . After the 3 years follow-up , no differences in GFR , LVMI and urinary albumin excretion were observed between the ramipril and the metoprolol group ( 80.7 + /- 10.7 vs 78.0 + /- 7.6 ml/min , 102.6 + /- 6.8 vs 100.3 + /- 5.4 g/m(2 ) ; and 42.6 + /- 12.3 vs 70.3 + /- 32.5 mg/g , respectively ; all P = NS ) . A post-hoc analysis evaluating the effects of BP control , revealed that LVMI increased in patients with st and ard BP control while it remained stable in patients with rigorous BP control with a significant difference in LVMI between the groups after 3 years of follow-up ( 110.5 + /- 6.3 vs 90.9 + /- 4.7 g/m(2 ) ; P = 0.017 ) . Also , by the end of the study albuminuria was lower in patients with rigorous vs st and ard BP control ( 23.5 + /- 6.7 vs 94.8 + /- 35.4 mg/g ; P = 0.05 ) . CONCLUSIONS In our study population of hypertensive ADPKD patients , no differences in renal function , urinary albumin excretion and LVMI were detected between those treated with ramipril or metoprolol , respectively , during a 3 years follow-up . Rigorous BP control prevented an increase in LVMI and reduced urinary albumin excretion , suggesting a crucial role of BP control for slowing progression of cardiac and renal organ damage in ADPKD BACKGROUND Placebo-controlled trials have found that angiotensin-converting enzyme inhibitors ( ACEIs ) decrease proteinuria and slow the progression of nondiabetic nephropathies . However , head-to-head comparisons of ACEIs and calcium channel blockers ( CCBs ) have shown conflicting results . Indeed , a recent meta analysis concluded that there is still uncertainty about the greater renoprotection seen with ACEIs or angiotensin II receptor blockers in nondiabetic patients with renal disease , particularly when using true glomerular filtration rate ( GFR ) as the primary outcome . OBJECTIVE The objective of this 3-year , r and omized , multicenter , double-blind , placebo-controlled study was to compare true GFR decline ( measured by yearly 51Cr-EDTA blood clearance ) in nondiabetic , nonnephrotic adult hypertensive patients with estimated creatinine clearance of 20 to 60 mL/min.1.73 m(2 ) , when r and omized to a CCB ( amlodipine , 5 - 10 mg/d ) or an ACEI ( enalapril , 5 - 20 mg/d ) . METHODS Patients ( aged 18 - 80 years ) entered a 4-week placebo run-in washout period and previous antihypertensive drugs were tapered off over 2 weeks . Add-on treatments were atenolol ( 50 - 100 mg/d ) , loop diuretics ( furosemide , 20 - 500 mg/d or torsemide , 5 - 200 mg/d ) , alpha-blockers ( prazosin , 2.5 - 5 mg/d or doxazosin , 1 - 16 mg/d ) , and central ly acting drugs ( rilmenidine , 1 - 2 mg/d or methyldopa , 250 - 500 mg/d ) . The primary end point was true GFR measured by yearly (51)Cr-EDTA blood clearance . Secondary end points included a clinical composite of renal events and tolerability collected by a full clinical and laboratory evaluation at each study visit . Post hoc analyses for the change in GFR , proteinuria , and time to clinical events were also planned on baseline proteinuria subgroups ( < 1 and > or=1 g/d ) before unblinding the data base . RESULTS Three hundred eighteen patients entered the run-in period and 263 patients ( 156 men/107 women ; mean age , 58 years ) were r and omized to receive either amlodipine ( 5 mg/d , n=132 ) or enalapril ( 5 mg/d , n=131 ) . Blood pressure declined from 165/102 mm Hg to 138/84 mm Hg and 138/85 mm Hg with amlodipine and enalapril , respectively ( no between-group significance ) . Only 20.8 % of the patients r and omized to ACEI treatment received diuretics at the last observation . No statistically significant difference was found between amlodipine and enalapril in GFR decline ( -4.92 and -3.98 mL/min.1.73 m(2 ) , respectively , at last observation ) and composite secondary end point after a median follow-up of 2.9 years , including in the subgroup of patients with proteinuria > 1 g/d at baseline . Protein excretion rate decreased significantly from baseline in patients taking enalapril plus diuretics ( median -270 mg/d ; P<0.001 ) but not in patients taking amlodipine plus diuretics ( -25 mg/d at last observation ) . CONCLUSION In this cohort of nondiabetic , nonnephrotic hypertensive patients , no statistically significant difference in true GFR decline was found over 3 years between amlodipine-treated patients and enalapril-treated patients with main add-on treatment with ss-blockers , including in the subgroup of patients with proteinuria > 1 g/d 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 CONTEXT The NPPA gene codes for the precursor of atrial natriuretic polypeptide , suggesting that NPPA may modulate the efficacy of some antihypertensive drugs . OBJECTIVE To test whether participants with minor NPPA alleles in the T2238C or G664A variants had different rates of cardiovascular disease or blood pressure (  BP ) changes than common allele homozygotes when treated with a diuretic vs other antihypertensive medications . DESIGN , SETTING , AND PATIENTS Post hoc analysis of 38,462 participants with hypertension from ALLHAT , a multicenter r and omized clinical trial conducted in the United States and Canada . Genotyping was performed from February 2004 to January 2005 . INTERVENTION Participants were r and omly assigned to receive a diuretic ( chlorthalidone ; n = 13,860 ) , a calcium antagonist ( amlodipine ; n = 8174 ) , an angiotensin-converting enzyme inhibitor ( lisinopril ; n = 8233 ) , or an alpha-blocker ( doxazosin ; n = 8195 ) . MAIN OUTCOME MEASURE The primary outcome measure was coronary heart disease ( CHD ) , defined as fatal CHD or nonfatal myocardial infa rct ion ( mean follow-up , 4.9 years ) . Secondary outcomes were stroke , all-cause mortality , combined cardiovascular disease outcomes , and 6-month systolic and diastolic BP changes . Genotype x treatment interactions were tested where genotypes were modeled additively and dominantly . RESULTS Depending on genotype , the event rates per 1000 person-years were 15.3 to 19.7 for CHO , 9.6 to 15.4 for stroke , and 27.4 to 30.7 for all-cause mortality . For the NPPA T2238C variant , lower event rates were found for the C allele carriers than for the TT homozygous individuals when comparing chlorthalidone and amlodipine ( CHD : CC = 0.86 ; TC = 0.90 ; TT = 1.09 ; P = .03 [ dominant model ] ; stroke : CC = 1.18 ; TC = 0.82 ; TT = 1.26 ; P = .01 [ additive and dominant models ] ; all-cause mortality : CC = 0.87 ; TC = 0.98 ; TT = 1.12 ; P = .05 [ dominant model ] ) . Combined end points yielded similar results . Consistent with these clinical findings , 6-month changes in systolic BP for those with the CC genotype showed larger reductions with chlorthalidone ( -6.5 mm Hg ) than with amlodipine ( -3.8 mm Hg ) , lisinopril ( -2.4 mm Hg ) , or doxazosin ( -3.8 mm Hg ) . Among those with the TT genotype , systolic BP differences between drugs were less ( range , -5.4 to -7.5 mm Hg ; P value , < .001 to .003 for interaction ) ; diastolic BP showed similar results . We found no pharmacogenetic associations with the NPPA G664A variant . CONCLUSIONS The NPPA T2238C variant was associated with modification of antihypertensive medication effects on cardiovascular disease and BP . Minor C allele carriers experienced more favorable cardiovascular disease outcomes when r and omized to receive a diuretic , whereas TT allele carriers had more favorable outcomes when r and omized to receive a calcium channel blocker Abstract Background . Pulse pressure ( PP ) has been related to risk of cardiovascular events in hypertension . However , less is known about modification of this risk marker during antihypertensive treatment in patients with left ventricular ( LV ) hypertrophy . Methods . Associations of in-treatment PP with LV systolic function and cardiovascular events was assessed in 883 patients with electrocardiographic LV hypertrophy during 4.8 years of r and omized losartan- or atenolol-based treatment within the echocardiographic sub study of the Losartan Intervention For Endpoint reduction in hypertension ( LIFE ) study . Results . PP was similarly reduced by both treatments . In different multiple regression models , lower in-treatment PP was independently associated with lower in-treatment LV ejection fraction ( β=0.16 ) , stress-corrected midwall shortening ( β=0.20 ) , stroke volume ( β=0.11 ) and cardiac index ( β=0.07 , all p<0.05 ) . In time-varying Cox regression models , 10mmHg lower in-treatment PP was associated with a 28 % higher rate of cardiovascular events [ hazard ratio , HR = 1.28 ( 1.09 – 1.52 ) , p<0.01 ] independent of in-treatment LV mass and ejection fraction , history of ischemic heart disease , Framingham risk score and study treatment allocation . Conclusion . During systematic antihypertensive treatment in hypertensive patients with electrocardiographic LV hypertrophy , lower in-treatment PP was associated with lower in-treatment LV function and cardiac output as well as higher rate of cardiovascular events WHAT IS KNOWN AND OBJECTIVE There is considerable interest in pharmacogenetic and molecular biomarkers . Our aim was to evaluate the effects of enalapril/lercanidipine combination on some emerging biomarkers for cardiovascular risk stratification of hypertensive patients , such as lipoprotein(a ) [ Lp(a ) ] , soluble advanced glycation end products ( sRAGE ) , soluble CD40 lig and ( sCD40L ) and serum myeloperoxidase ( MPO ) . RESEARCH DESIGN AND METHODS Three hundred and forty-five patients were enrolled in this r and omized , double-blind , clinical trial : 120 hypertensive patients were r and omized to enalapril 20 mg , 110 to lercanidipine 10 mg and 115 to enalapril/lercanidipine 20/10 mg fixed combination .  We measures the following markers at baseline and after 6 , 12 , 18 and 24 months : blood pressure , fasting plasma glucose ( FPG ) , lipid profile , Lp(a ) , sRAGE , sCD40L and MPO . RESULTS There was a decrease in blood pressure in all groups compared with baseline , even if , as expected , enalapril/lercanidipine combination was more effective in reducing blood pressure compared with the monotherapies . No variations in lipid profile or FPG were recorded in any of the groups . Lercanidipine , but not enalapril , improved Lp(a ) levels compared with baseline . The combination enalapril/lercanidipine improved it more than the single therapies . All treatments increased sRAGE levels , and decreased sCD40L and MPO , with a better effect seen with the enalapril/lercanidipine combination compared with single monotherapies . WHAT IS NEW AND CONCLUSION The combination enalapril/lercanidipine seems to be better than the single monotherapies in reducing not only blood pressure , but also the levels of some emerging biomarkers , potentially useful for cardiovascular risk stratification of hypertensive patients
target: We found predominantly moderate quality evidence that all-cause mortality is similar when first-line RAS inhibitors are compared to other first-line antihypertensive agents .
  First-line thiazides caused less HF and stroke than first-line RAS inhibitors .
  Compared with first-line CCBs , first-line RAS inhibitors reduced HF but increased stroke .
  The magnitude of the reduction in HF exceeded the increase in stroke .
  The small differences in effect on blood pressure between the different classes of drugs did not correlate with the differences in the primary outcomes
background: BACKGROUND Renin-angiotensin system ( RAS ) inhibitors are widely prescribed for treatment of hypertension , especially for diabetic patients on the basis of postulated advantages for the reduction of diabetic nephropathy and cardiovascular morbidity and mortality .
  Despite widespread use of angiotensin converting enzyme ( ACE ) inhibitors and angiotensin receptor blockers ( ARBs ) for hypertension in both diabetic and non-diabetic patients , the efficacy and safety of RAS inhibitors compared to other antihypertensive drug classes remains unclear .
  OBJECTIVES To evaluate the benefits and harms of first-line RAS inhibitors compared to other first-line antihypertensive drugs in patients with hypertension .