[Atenolol and bisoprolol in the treatment of mild and moderately severe hypertension]. A prospective, randomized, open-label, active-controlled, clinical trial to assess central haemodynamic effects of bisoprolol and atenolol in hypertensive patients Adjunctive sympathoplegic therapy to ACE inhibition in Blacks with congestive heart failure: a comparison of alpha-1 with beta-1 blockade on exercise tolerance and cardiac sympathovagal reflex activity. Effects of chronic administration of selective betablockers on peripheral circulation of the lower limbs in patients with essential hypertension. Effects of β blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. Relative value of beta blockers and thiazides for initiating antihypertensive therapy. Beta blockers or thiazides in hypertension. Role of High-Dose Beta-Blockers in Patients with Heart Failure with Preserved Ejection Fraction and Elevated Heart Rate. Effect of beta 1 blockade with atenolol on progression of heart failure in patients pretreated with high-dose enalapril. Antihypertensive efficacy and side effects of three beta‐blockers and a diuretic in elderly hypertensives: a report from the STOP‐Hypertension study Effects of Losartan or Atenolol in Hypertensive Patients without Clinically Evident Vascular Disease: A Substudy of the LIFE Randomized Trial Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled tri Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH). The IPPPSH Collaborative Group. Comparison of the Effects of Antihypertensive Agents on Central Blood Pressure and Arterial Stiffness in Isolated Systolic Hypertension Influence of pretreatment systolic blood pressure on the effect of carvedilol in patients with severe chronic heart failure: the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study. A comparison of the efficacy and safety of a beta-blocker, a calcium channel blocker, and a converting enzyme inhibitor in hypertensive blacks. Differential effects of beta-blockers in patients with heart failure: A prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol.
Atenolol and bisoprolol , two beta-1-selective blockers , were compared in patients with mild and medium severe hypertension . Forty patients with a diastolic blood pressure of 95 - 115 mm Hg were two weeks after discontinuation of treatment divided at r and om into two groups treated with 50 mg atenolol and 5 mg bisoprolol . If the blood pressure was not affected by this dosage , the dose was raised to 100 mg atenolol and 10 mg bisoprolol . The blood pressure readings , heart rate , side effects of the drugs , laboratory and echocardiographic values were followed up for a period of three months . The authors recorded a marked decline of pressure and heart rate after the first week of therapy , the pressure readings in an upright position did not differ statistically from values in a sitting position , orthostatic hypotension was not recorded . The rate of success of bisoprolol was 85 % , of atenolol 75 % . During treatment no serious side-effects were observed . The biochemical parameters and echocardiographic values were not altered significantly by treatment . Atenolol and bisoprolol are two effective beta-1-selective blockers with a comparable effect in the treatment of mild and medium severe hypertension . They are useful in monotherapy as well as in combination with other antihypertensive drugs . In hypertension associated with diabetes mellitus , incipient bronchopulmonary disease and pregnancy they are also indicated . They are well tolerated also by elderly patients , an advantage of bisoprolol may be that it has a smaller impact on pressure and heart rate during the night Objective : The results from the ASCOT CAFÉ study demonstrated the inferiority of beta blockers in reducing central aortic blood pressure . In this study , we wanted to demonstrate whether or not second-generation beta blockers with higher beta 1 selectivity , namely bisoprolol , may counterbalance the effect of bradycardia through reduced reflection wave magnitude result ing from the relative lack of increase in peripheral vascular resistance . Method : This was a prospect i ve , r and omized , open-label , active-controlled trial in 209 hypertensive patients to evaluate the effect of bisoprolol and atenolol on aortic pulse pressure . Patients received a once-daily 5 mg dose of bisoprolol ( n = 96 ) or 50 mg dose of atenolol ( n = 95 ) at baseline with titration up to bisprolol 10 mg and atenolol 100 mg allowed at the 4th week when the brachial blood pressure was above treatment goal ( average dose : bisoprolol : 5.4 mg , atenolol : 52.8 mg ) . Central blood pressure and augmentation index were measured at baseline and 12 weeks later , by pulse wave analysis with radial artery tonometry . The primary endpoint of the study was the difference in the central pulse pressure ( CPP ) at 12 weeks . Results : The results showed a significant reduction of CPP in both groups at week 12 of administration compared with the predose level ( P < 0.05 ) ; however , there was no significant difference in terms of CPP change  [ bisoprolol ( baseline CPP 47.49 ± 11.33 , follow-up 43.09 ± 11.67 ) vs. atenolol ( baseline CPP 45.93 ± 11.62 , follow-up 42.23 ± 9.92 ) , P = 0.594 ] . Conclusion : In this study , there was no significant difference between bisoprolol and atenolol in terms of reduction of aortic pulse pressure after 12 weeks of treatment OBJECTIVES Congestive heart failure ( CHF ) is characterized by an initial compensatory , but subsequently deleterious , activation of both the renin-angiotensin ( RAS ) and the sympathetic nervous system ( SNS ) . Incomplete suppression of the SNS may contribute to the residual mortality during optimal ACE inhibitor therapy in CHF . Carvedilol , a mixed alpha and beta-blocker with antioxidant properties , and other pure beta-adrenoceptor blockers reduce morbidity and mortality in Caucasians with CHF . However , beta-blocker monotherapy is of poor efficacy in Blacks with essential hypertension or in the treatment of glaucoma . The efficacy of beta-blockers in the treatment of African Americans with congestive heart failure is a controversial issue with conflicting findings . The aims of the present study were to examine and compare the cardiovascular , autonomic , and clinical effects of additional alpha-1 , or beta-1 blockade in ACE-inhibitor treated Black patients with moderate to severe CHF . METHODS Twenty-eight Nigerian patients with chronic CHF stabilized on digoxin and diuretics , were r and omized to 3 groups of similar demographics according to a single blind , parallel group design . The patients were aged 53 + /- 6 years , and comprised 14 men and 14 women , with a mean cardiothoracic ratio of 0.66 + /- 0.03 , and ejection fraction of 0.38 + /- 0.10 , 60 % hypertensive etiology . Group 1 patients received 5 mg enalapril alone , group 2 received 5 mg enalapril + 1 mg prazosin , and group 3 received 5 mg enalapril + 50 mg atenolol . All medication was taken daily for 4 weeks . Blood pressure , heart rate , pressure rate product , 6-minute walk test , NYHA class , and cardiac autonomic reflexes were measured at baseline and again at 2 and 4 weeks of treatment . Two-way repeated measures ANOVA , and a one-way ANOVA were used in data analysis . RESULTS The 3 treatments caused significant ( P<.001 ANOVA ) and similar improvements for the NYHA class ( -1.0 to -1.6 ) , and increased the 6-minute distance covered ( + 130 m to + 205 m ) . Although no treatment differences were observed , a trend suggesting a greater improvement with  enalapril + atenolol  became apparent . By the fourth week , the sympathoplegic treatments , enalapril + atenolol , and enalapril + prazosin , caused significant reductions in the pressure rate product ( -3726 + /- 1885 mm Hg x beats/min ; -3498 + /- 396 mm Hg beats/min , respectively ) , ( compared to enalapril alone ( -1349 + /- 894 mm Hg x beats/min ) ( P<.001 ANOVA ) . During the Valsalva maneuver , the phase IV bradycardia were significantly greater after treatment with enalapril + atenolol ( 944 + /- 66 msec ) or with enalapril + prazosin ( 825 + /- 48 msec ) , compared to enalapril alone ( 760 + /- 45 msec ) ( P<.001 ANOVA ) . The phase II Valsalva tachycardia were similar between treatments . The respiratory sinus arrhythmia ratio increased significantly ( P<.005 ANOVA ) and equally on all treatments . However , the pressor and chronotropic responses to forearm isometric h and grip increased significantly on the enalapril + prazosin combination ( P<.02 ) , compared to the other treatments . CONCLUSIONS Our findings demonstrated not only the safety of providing additional therapy with alpha-1 or beta-1 receptor blockade concurrent with ACE inhibition in Blacks with CHF , but also the result ant improvement in exercise tolerance and NYHA class . Compared to using ACE inhibition alone , the combined therapies caused a marked reduction in the pressure rate product , an index of myocardial oxygen consumption , and a greater enhancement of cardiac parasympathetic activity . Selective beta-1 blockade caused a greater enhancement of central baroreceptor vagal activity compared to alpha-1 blockade . Conversely , the pressor and chronotropic abnormalities during forearm isometric h and grip in CHF , were normalized by alpha-1 , but not beta-1 , blockade . Thus , the combined reflex cardiac vagal augmentation following selective beta-1 blockade , and the hemodynamic effects of alpha-1 antagonism with concurrent ACE inhibition , may be of major therapeutic and prognostic benefit in Blacks with non-ischemic ( hypertensive ) CHF stabilized on digoxin and diuretics This paper summarizes the results of two studies carried out to evaluate the effects of the cardioselective betablockers atenolol , acebutolol and metoprolol on peripheral circulation of the lower limbs . The 1st study was a double dummy double blind cross over placebo controlled trial carried out for 13 weeks to evaluate the effects of acebutolol ( 600 mg/die ) and metoprolol ( 300 mg/die ) , two cardioselective betablockers , on peripheral haemodynamics in patients suffering from mild to moderate hypertension . The 2nd study was a placebo controlled trial on the effects of atenolol ( 100 mg/day ) on haemodynamics at the calf carried out for 8 weeks in patients suffering from essential to severe moderate hypertension , part of which aged over 65 years and affected by arteriosclerosis obliterans of the lower limbs , stage I and II according to Fontaine 's classification .  Calf blood flow in basal condition ( R.F. ) and after ischemic stimulus ( P.F. ) was evaluated by strain gauge plethysmography ; basal ( B.V.R. ) and minimal ( M.V.R. ) vascular resistances at the calf by the ratio between M.B.P./R.F. and M.B.P./P.F. respectively , Windsor 's index ( W.I. ) by ultrasound . Neither the patients with hypertension only nor the elderly hypertensive suffering from arteriosclerosis obliterans of the lower limbs showed changes in R.F. and P.F. , in B.V.R. and M.V.R. and in W.I. after chronic treatment with cardioselective beta-blockers . Many patients --about 17 % of all patients , and 40 % of arteriopathics -- in the two trials had cold h and s and feet . These studies suggest that chronic administration of selective beta-blockers does not exert unfavourable effects on muscular blood flow at the calf in patients with hypertension with or without arteriosclerosis obliterans of the lower limbs at I and II stage . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND Analyses of some r and omised trials show that calcium-channel blockers reduce the risk of stroke more than expected on the basis of mean blood pressure alone and that beta blockers are less effective than expected . We aim ed to investigate whether the effects of these drugs on variability in blood pressure might explain these disparities in effect on stroke risk . METHODS The Anglo-Sc and inavian Cardiac Outcomes Trial Blood Pressure Lowering Arm ( ASCOT-BPLA ) compared amlodipine-based regimens with atenolol-based regimens in 19 257 patients with hypertension and other vascular risk factors and the Medical Research Council ( MRC ) trial compared atenolol-based and diuretic-based regimens versus placebo in 4396 hypertensive patients aged 65 - 74 years . We expressed visit-to-visit variability of blood pressure during follow-up in the two trials as st and ard deviation ( SD ) and as transformations uncorrelated with mean blood pressure . For ASCOT-BPLA , we also studied within-visit variability and variability on 24 h ambulatory blood-pressure monitoring ( ABPM ) . RESULTS In ASCOT-BPLA , group systolic blood pressure ( SBP ) SD was lower in the amlodipine group than in the atenolol group at all follow-up visits ( p<0.0001 ) , mainly because of lower within-individual visit-to-visit variability . Within-visit and ABPM variability in SBP were also lower in the amlodipine group than in the atenolol group ( all p<0.0001 ) . Analysis of changes from baseline showed that variability decreased over time in the amlodipine group and increased in the atenolol group . The lower risk of stroke in the amlodipine group ( hazard ratio 0.78 , 95 % CI 0.67 - 0.90 ) was partly attenuated by adjusting for mean SBP during follow-up ( 0.84 , 0.72 - 0.98 ) , but was abolished by also adjusting for within-individual SD of clinic SBP ( 0.99 , 0.85 - 1.16 ) . Findings were similar for coronary events . In the ABPM sub study , reduced variability in daytime SBP in the amlodipine group ( p<0.0001 ) partly accounted for the reduced risk of vascular events , but reduced visit-to-visit variability in clinic SBP had a greater effect . In the MRC trial , group SD SBP and all measures of within-individual visit-to-visit variability in SBP were increased in the atenolol group compared with both the placebo group and the diuretic group during initial follow-up ( all p<0.0001 ) . Subsequent temporal trends in variability in blood pressure during follow-up in the atenolol group correlated with trends in stroke risk . INTERPRETATION The opposite effects of calcium-channel blockers and beta blockers on variability of blood pressure account for the disparity in observed effects on risk of stroke and expected effects based on mean blood pressure . To prevent stroke most effectively , blood-pressure-lowering drugs should reduce mean blood pressure without increasing variability ; ideally they should reduce both CONTEXT Hypertensive patients are often given a calcium antagonist to reduce cardiovascular disease risk , but the benefit compared with other drug classes is controversial . OBJECTIVE To determine whether initial therapy with controlled-onset extended-release ( COER ) verapamil is equivalent to a physician 's choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized clinical trial conducted at 661 centers in 15 countries . A total of 16 602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31 , 2000 . After a mean of 3 years of follow-up , the sponsor closed the study before unblinding the results . INTERVENTION Initially , 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide . Other drugs ( eg , diuretic , beta-blocker , or an angiotensin-converting enzyme inhibitor ) could be added in specified sequence if needed . MAIN OUTCOME MEASURES First occurrence of stroke , myocardial infa rct ion , or cardiovascular disease-related death . RESULTS Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group . There were 364 primary cardiovascular disease-related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group ( hazard ratio [ HR ] , 1.02 ; 95 % confidence interval [ CI ] , 0.88 - 1.18 ; P = .77 ) . For fatal or nonfatal stroke , the HR was 1.15 ( 95 % CI , 0.90 - 1.48 ) ; for fatal or nonfatal myocardial infa rct ion , 0.82 ( 95 % CI , 0.65 - 1.03 ) ; and for cardiovascular disease-related death , 1.09 ( 95 % CI , 0.87 - 1.37 ) . The HR was 1.05 ( 95 % CI , 0.95 - 1.16 ) for any prespecified cardiovascular disease-related event and 1.08 ( 95 % CI , 0.93 - 1.26 ) for all-cause mortality . Nonstroke hemorrhage was more common with participants in the COER-verapamil group ( n = 118 ) compared with the atenolol or hydrochlorothiazide group ( n = 79 ) ( HR , 1.54 [ 95 % CI , 1.16 - 2.04 ] ; P = .003 ) . More cardiovascular disease-related events occurred between 6 AM and noon in both the COER verapamil ( 99/277 ) and atenolol or hydrochlorothiazide ( 88/274 ) groups ; HR , 1.15 ( 95 % CI , 0.86 - 1.53 ) . CONCLUSIONS The CONVINCE trial did not demonstrate equivalence of a COER verapamil-based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker . When considered in the context of other trials of calcium antagonists , these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or beta-blocker treatment Fifty-five patients with mild to moderate , renal or essential hypertension were admitted to a double blind cross-over trial of 18 weeks , involving treatment periods with placebo , the thiazide bendrofluazide ( 15 mg daily ) and the beta blocker atenolol ( 600 mg daily ) . Compared to the placebo period ( 190/117 mm Hg ) the hypotensive effect of atenolol ( -24/16 mm Hg ) was more pronounced than the hypotensive effect of bendrofluazide ( -17/6 mm Hg ) . Arguments in favor of initiating antihypertensive drug therapy with beta blocker were its more powerful hypotensive effect , the quicker onset of its action , less metabolic disturbance , decreased frequency of complaints and patient 's preference . On thiazides body weight and the frequency of swollen ankles decreased . Plasma renin concentration was not found to have a strong predicting power for the hypotensive effect of atenolol or bendrofluazide but low renin patients showed a more pronounced blood pressure decrease on bendrofluazide and high renin patients , especially essential hypertensives , on atenolol . While these points can be a guide to therapy today , the preference of one drug over the other must eventually be based on their relative efficacy in decreasing morbidity and mortality from the hypertensive disease BACKGROUND Beta-blockers in high target doses are recommended for heart failure with reduced ejection fraction ( HFrEF ) but not for preserved ejection fraction ( HFpEF ) . Treatment benefits are often more pronounced in high-risk subgroups , and patients with HFpEF with heart rate ≥70 beats per minute have emerged as such a high-risk subgroup . We examined the associations of high-dose beta-blocker use with outcomes in these patients . METHODS Of the 8462 hospitalized patients with heart failure with ejection fraction ≥50 % in the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure ( OPTIMIZE-HF ) registry , 5422 had a discharge heart rate ≥70 beats per minute . Of these , 4537 had no contraindications to beta-blocker use , of which 2797 ( 2592 with dose data ) received prescriptions  for beta-blockers . Of the 2592 , 730 received high-dose beta-blockers , defined as atenolol ≥100 mg/day , carvedilol ≥50 mg/day , metoprolol tartrate or succinate ≥200 mg/day , or bisoprolol ≥10 mg/day , and 1740 received no beta-blockers . Using propensity scores for the receipt of high-dose beta-blockers , we assembled a matched cohort of 1280 patients , balanced on 58 characteristics . RESULTS All-cause mortality occurred in 63 % and 68 % of matched patients receiving high-dose beta-blocker vs no beta-blocker , respectively , during 6 years ( median , 2.8 ) of follow-up ( hazard ratio , 0.86 ; 95 % confidence interval , 0.75 - 0.98 ; P = .027 ) . The hazard ratios ( 95 % confidence intervals ) for all-cause readmission and the combined endpoint of all-cause readmission or all-cause mortality associated with high-dose beta-blocker use were 0.90 ( 0.81 - 1.02 ) and 0.89 ( 0.80 - 1.00 ) , respectively . CONCLUSIONS In patients with HFpEF and heart rate ≥70 beats per minute , high-dose beta-blocker use was associated with a significantly lower risk of death . Future r and omized controlled trials are needed to examine this association BACKGROUND The survival benefit of beta-blocker treatment in patients with heart failure has been established in recent trials . Yet , the impact of beta-blockers added on high dose angiotensin converting enzyme inhibitors has not been reported . AIMS To investigate the effect of atenolol , a hydrophilic , selective beta1-adrenergic antagonist , added on enalapril 40 mg/day in patients with advanced left ventricular dysfunction in a double-blind placebo-controlled trial . METHODS One hundred and nineteen patients with class II or III heart failure , left ventricular ejection fraction < or = 25 % and treatment with 40 mg enalapril daily were given an initial challenge dose of atenolol 12 . 5 mg . One hundred patients ( 54 with idiopathic , 28 with ischemic , 18 with other dilated cardiomyopathy ) tolerated challenge and were r and omized to atenolol ( maintenance dose 89+/-11 mg/day , range 50 - 100 mg/day ) or placebo . The primary endpoint was combined worsening heart failure or death within 2 years , the secondary endpoint was hospitalization for cardiac events . RESULTS After 395+/-266 days interim analysis revealed a significant difference between the atenolol and placebo group ( log rank P<0.01 ) and the trial was concluded . Twenty-seven patients had developed worsening heart failure ( 8 in the atenolol group vs. 19 in the placebo group ) and 13 patients had died ( 5 in the atenolol vs. 8 in the placebo group ) . Overall there were 23 hospitalizations for cardiac events ( 6 in the atenolol group vs. 21 in the placebo group , P=0.07 ) ; 17 hospitalizations were due to worsening heart failure ( 5 in the atenolol group , 12 in the placebo-group , P=0.05 ) and 10 due to arrhythmias ( 1 in the atenolol group vs. 9 in the placebo group , P<0.01 ) CONCLUSIONS The data suggest that in patients with advanced left ventricular dysfunction , beta-blockers can provide substantial benefits supplementary to that already achieved with high dose enalapril treatment Objective : To compare the blood pressure‐lowering efficacy , the frequency of side effects and changes in laboratory values of three & bgr;‐blockers and a potassium‐sparing diuretic combination in elderly hypertensive patients . Design : The Swedish Trial in Old Patients with Hypertension ( STOP‐Hypertension ) was a prospect i ve , r and omized , double‐blind , multicentre trial comparing active antihypertensive treatment with placebo in patients aged 70‐84 years . Methods : The study group consisted of 1627 elderly hypertensive patients ( mean ± SD age 75.7 ± 3.7 years ; 37 % males , 63 % females ) . Supine and st and ing blood pressure , heart rate and side effects were recorded at each visit . Blood was drawn for routine analysis . The mean length of follow‐up was 25 months ( range 6‐65 ) . No patient was lost to follow‐up . Results : After 2‐months ' single‐drug therapy , all four active drugs were found to be equally effective in reducing diastolic blood pressure ( DBP ) . However , there were differences in their efficacy in reducing systolic blood pressure ( SBP ) ; the diuretic was significantly more effective than the & bgr;‐receptor blockers . The results of a series of multiple linear regression analyses showed that the observed differences in effect on SBP could not be explained by the different effects of the drugs on heart rate . More than two‐thirds of the patients were given supplementary treatment , most of them already by the 2‐month visit , after which there was no significant difference in blood pressure among the treatment regimens . The changes in laboratory values and in the prevalence of symptoms were minor for all four regimens . Conclusion : Metoprolol ( controlled release ) , atenolol , pindolol and the combination hydrochlorothiazide + amiloride were equally effective as single drugs in reducing DBP . There were differences in their efficacy in reducing SBP , the diuretic being more effective than the & bgr;‐blockers . After addition of supplementary treatment ( & bgr;‐blocker to diuretic , or vice versa ) there were no significant differences in blood pressure reduction among the groups . The changes in laboratory values and in the prevalence of symptoms were minor for all active treatment regimens . Thus , the satisfactory effect on cardiovascular morbidity and mortality was not impaired by low tolerability of the drugs 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 BACKGROUND The apparent shortfall in prevention of coronary heart disease ( CHD ) noted in early hypertension trials has been attributed to disadvantages of the diuretics and beta blockers used . For a given reduction in blood pressure , some suggested that newer agents would confer advantages over diuretics and beta blockers . Our aim , therefore , was to compare the effect on non-fatal myocardial infa rct ion and fatal CHD of combinations of atenolol with a thiazide versus amlodipine with perindopril . METHODS We did a multicentre , prospect i ve , r and omised controlled trial in 19 257 patients with hypertension who were aged 40 - 79 years and had at least three other cardiovascular risk factors . Patients were assigned either amlodipine 5 - 10 mg adding perindopril 4 - 8 mg as required ( amlodipine-based regimen ; n=9639 ) or atenolol 50 - 100 mg adding bendroflumethiazide 1.25 - 2.5 mg and potassium as required ( atenolol-based regimen ; n=9618 ) . Our primary endpoint was non-fatal myocardial infa rct ion ( including silent myocardial infa rct ion ) and fatal CHD . Analysis was by intention to treat . FINDINGS The study was stopped prematurely after 5.5 years ' median follow-up and accumulated in total 106 153 patient-years of observation . Though not significant , compared with the atenolol-based regimen , fewer individuals on the amlodipine-based regimen had a primary endpoint ( 429 vs 474 ; unadjusted HR 0.90 , 95 % CI 0.79 - 1.02 , p=0.1052 ) , fatal and non-fatal stroke ( 327 vs 422 ; 0.77 , 0.66 - 0.89 , p=0.0003 ) , total cardiovascular events and procedures ( 1362 vs 1602 ; 0.84 , 0.78 - 0.90 , p<0.0001 ) , and all-cause mortality ( 738 vs 820 ; 0.89 , 0.81 - 0.99 , p=0.025 ) . The incidence of developing diabetes was less on the amlodipine-based regimen ( 567 vs 799 ; 0.70 , 0.63 - 0.78 , p<0.0001 ) . INTERPRETATION The amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen . On the basis of previous trial evidence , these effects might not be entirely explained by better control of blood pressure , and this issue is addressed in the accompanying article . Nevertheless , the results have implication s with respect to optimum combinations of antihypertensive agents Myocardial infa rct ion , sudden cardiac death , cerebrovascular accidents , blood pressure control and treatment tolerability were studied in a r and omized double-blind trial conducted in 6357 men and women aged 40 - 64 years with uncomplicated essential hypertension ( diastolic blood pressures 100 - 125 mmHg ) . At the start of the trial 3185 patients received treatment based on a beta-blocker ( oxprenolol )  , while in the remaining 3172 placebo replaced oxprenolol .  Supplementary drugs , excluding beta-blockers , were used as necessary in both treatment groups , with the aim of reducing diastolic pressure to 95 mmHg or less . Patients were followed for 3 - 5 years , a total of 25 651 patient years at risk . In most respects the two groups fared equally well ; sudden death ( relative risk [ RR ] 1.08 ; 95 % confidence interval [ Cl ] 0.68 and 1.72 ) , myocardial infa rct ion ( RR 0.83 ; Cl 0.59 and 1.16 ) and cerebrovascular accident ( RR 0.97 ; Cl 0.64 and 1.47 ) rates were similar . Beta-blocker based therapy was associated with significantly lower average blood pressures , earlier ECG normalization , less hypokalaemia and fewer withdrawals from double-blind treatment for uncontrolled hypertension . Doctor-elicited and patient-assessed unwanted effects demonstrated overall good tolerability . In smokers the cardiac event rate was doubled . We propose that beta-blocker treatment effects depend on smoking status , with a significant interaction benefiting non-smoking men . Lower blood pressures during treatment were associated with substantially lower rates for cardiac as well as cerebrovascular events . Proportional hazards analysis also underlines the importance of other cardiovascular risk factors . The IPPPSH stresses the need for a comprehensive approach to the management of blood pressure and other risk factors in hypertensive patients Isolated systolic hypertension is an important risk factor for cardiovascular disease and results primarily from elastic artery stiffening . Although various drug therapies are used to lower peripheral blood pressure ( BP ) in patients with isolated systolic hypertension , the effects of the 4 major classes of antihypertensive agents on central BP , pulse pressure ( PP ) amplification , and arterial stiffness in this condition are not clear . Fifty-nine patients over the age of 60 years with untreated isolated systolic hypertension ( systolic BP ≥140 mm Hg and diastolic BP ≤90 mm Hg ) were r and omly assigned to receive 1 of the following 4 antihypertensive agents : perindopril , atenolol , lercanidipine , or bendrofluazide  . BP was measured using a mercury sphygmomanometer , and augmentation index and carotid-femoral ( aortic ) pulse wave velocity were measured at baseline , after 2 weeks of placebo therapy , and at the end of 10 weeks of active therapy . Peripheral systolic BP and peripheral PP were reduced similarly after treatment with all 4 classes of drug . However , central PP was only reduced significantly by perindopril , lercanidipine , and bendrofluazide , whereas atenolol had no effect . Lercanidipine reduced the augmentation index , whereas atenolol increased it . Aortic pulse wave velocity was not changed by any of the drugs . In summary , despite similar reductions in peripheral systolic and PPs with the 4 classes of drug , changes in central pressure and augmentation index varied . Because central PP and increased wave reflections are considered important risk factors in patients with isolated systolic hypertension , the choice of therapy may be influenced by these findings in the future OBJECTIVES We sought to evaluate the influence of pretreatment systolic blood pressure ( SBP ) on the efficacy and safety of carvedilol in patients with chronic heart failure ( CHF ) . BACKGROUND Although beta-blockers reduce the risk of death in CHF , there is little reported experience with these drugs in patients with a low pretreatment SBP , who may respond poorly to beta-blockade . METHODS We studied 2,289 patients with severe CHF who participated in the Carvedilol Prospect i ve R and omized Cumulative Survival ( COPERNICUS ) trial . RESULTS Compared with placebo , carvedilol improved the clinical status and reduced the risk of death and the combined risk of death or hospitalization for any reason , for a cardiovascular reason , or for worsening heart failure ( p < 0.001 for all ) . The relative magnitude of these benefits did not vary as a function of the pretreatment SBP ( all interaction : p > 0.10 ) . However , because patients with the lowest SBP were at highest risk of an event , they experienced the greatest absolute benefit from treatment with carvedilol . The lower the pretreatment SBP , the more likely that patients would report an adverse event , be intolerant of high doses of the study drug , or require permanent withdrawal of treatment ( p < 0.001 for all ) . However , these risks were primarily related to the severity of the underlying illness and not to treatment with carvedilol . CONCLUSIONS The current study provides little support for concerns about using beta-blockers ( particularly those with vasodilatory actions ) in patients with severe CHF who have a low SBP . Pretreatment blood pressure can identify patients who have the greatest need for risk reduction with carvedilol A double-blind , positively controlled , forced dose titration study comparing the efficacy and safety of atenolol , captopril , and verapamil sustained release as single agents in the treatment of black patients with mild to moderate hypertension ( diastolic blood pressure , 95 to 114 mm Hg ) was conducted . A total of 394 patients were r and omized to one of the three therapies .  Mean blood pressures during a 2- to 4-week placebo treatment period ( baseline ) ranged from 100.4 to 100.7 mm Hg diastolic and 151.7 to 152.5 mm Hg systolic for the three groups . Of the patients , 355 ( of whom 345 had assessable data ) completed the first treatment period , which consisted of therapy with either 50 mg/d of atenolol , 25 mg every 12 hours of captopril , or 240 mg/d of verapamil sustained release . During the second 4-week treatment period , which 319 patients completed ( 307 assessable ) , half of the patients had their antihypertensive medication increased and the other half continued the same dose . Goal blood pressure was defined as a supine diastolic pressure of less than 90 mm Hg or a 10-mm Hg or greater drop in supine diastolic blood pressure from pretreatment levels . Atenolol , captopril , and verapamil sustained release therapy was associated with goal blood pressure achievement during the first treatment period 55.1 % , 43.8 % , and 65.2 % of the time , respectively , and during the second treatment period 59.6 % , 57.1 % , and 73.0 % of the time . Side effects were minimal and comparable for all three drugs BACKGROUND Both metoprolol and carvedilol produce hemodynamic and clinical benefits in patients with chronic heart failure ;  carvedilol exerts greater antiadrenergic effects than metoprolol , but it is unknown whether this pharmacological difference results in hemodynamic and clinical differences between the 2 drugs . METHODS AND RESULTS We r and omized 150 patients with heart failure ( left ventricular ejection fraction < /=0.35 ) to double-blind treatment with either metoprolol or carvedilol . When compared with metoprolol ( 124+/-55 mg/d ) , patients treated with carvedilol ( 49+/-18 mg/d ) showed larger increases in left ventricular ejection fraction at rest ( + 10.9+/-11.0 versus + 7.2+/-7.7 U , P=0.038 ) and in left ventricular stroke volume and stroke work during exercise ( both P<0 . 05 ) after 13 to 15 months of treatment . In addition , carvedilol produced greater decreases in mean pulmonary artery pressure and pulmonary wedge pressure , both at rest and during exercise , than metoprolol ( all P<0.05 ) . In contrast , the metoprolol group showed greater increases in maximal exercise capacity than the carvedilol group ( P=0.035 ) , but the 2 drugs improved symptoms , submaximal exercise tolerance , and quality of life to a similar degree . After a mean of 23+/-11 months of follow-up , 21 patients in the metoprolol group and 17 patients in the carvedilol group died or underwent urgent transplantation . CONCLUSIONS The present study demonstrates that during long-term therapy , carvedilol improves cardiac performance to a greater extent than metoprolol when administered to patients with heart failure in the doses shown to be effective in clinical trials . These differences were likely related to a greater antiadrenergic activity of carvedilol
SBP-lowering effects were significantly increased for bisoprolol compared with placebo .
In conclusion , current evidence does not support carvedilol or bisoprolol as first-line therapy for adult hypertension without compelling indications
Although beta blockers have been used as initial therapy for ischemic heart diseases and heart failure , the beneficial effects of beta blockers are controversial compared with other antihypertensive agents as initial therapy for hypertension without compelling indications .
Moreover , atenolol has been most commonly used with beta blockers .
The objective of the present systematic review associated with the Japanese Society of Hypertension ( JSH ) 2019 Hypertension Guideline ( Clinical Question 6 ) was to assess the outcomes ( cardiocerebrovascular mortality , total cause mortality , hypotension , bradycardia , other adverse effects , and changes in systolic blood pressure ( SBP ) ) of currently used carvedilol and bisoprolol as initial therapy for adult hypertension without compelling indications .