title: Resting heart rate is a risk factor for cardiovascular and noncardiovascular mortality: the Chicago Heart Association Detection Project in Industry. Hypotensive effect of oxprenolol in mild to moderate hypertension: a multicentre controlled study Atenolol and bendrofluazide in hypertension. Efficacy of eprosartan in combination with HCTZ in patients with essential hypertension Antihypertensive Effects of Valsartan/Hydrochlorothiazide Combination in Essential Hypertension Improved antihypertensive efficacy of the felodipine-metoprolol extended-release tablet compared with each drug alone. Diltiazem and atenolol in essential hypertension: additivity of effects on blood pressure and cardiac conduction with combination therapy. Effects of once daily indapamide and pindolol on blood pressure, plasma aldosterone concentration and plasma renin activity in a general practice setting Systolic Blood Pressure, Diastolic Blood Pressure, and Pulse Pressure as Predictors of Risk for Congestive Heart Failure in the Framingham Heart Study Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide. Nifedipine and acebutolol in combination for the treatment of moderate to severe essential hypertension. Atenolol and Sustained Release Nifedipine Alone and in Combination in Hypertension A Randomised, Double-Blind, Crossover Study Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial Clinical evaluation of labetalol alone and combined with chlorthalidone in essential hypertension: A double-blind multicentre controlled study Antihypertensive Efficacy and Tolerability of a Fixed Combination of Metoprolol and Felodipine in Comparison with the Individual Substances in Monotherapy Enalapril and atenolol in essential hypertension: attenuation of hypotensive effects in combination. Indapamide and atenolol in the treatment of hypertension: double-blind comparative and combination study. Nicardipine and propranolol in the treatment of essential hypertension. Factorial antihypertensive study of an extended-release metoprolol and hydrochlorothiazide combination. Chlorthalidone Alone or in Fixed Combination with Slow-Release Metoprolol in the Management of Arterial Hypertension: A Long-Term Study of 545 Patients [The treatment of hypertension in the elderly using a beta-blocker: acebutolol (author's transl)]. Effectiveness of antihypertensive medications in office and ambulatory settings: a placebo-controlled comparison of atenolol, metoprolol, chlorthalidone, verapamil, and an atenolol-chlorthalidone combination. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Comparison of once daily atenolol, nitrendipine and their combination in mild to moderate essential hypertension. The treatment of hypertension with propranolol and bendrofluazide. Atenolol and chlorthalidone in combination for hypertension. Evaluation of the effect of timolol alone and in combination with hydrochlorothiazide and amiloride in the treatment of mild to moderate arterial hypertension: a double-blind, controlled study. Low-dose atenolol-chlorthalidone combination for treatment of mild hypertension. Beta blockade, diuretics, and salt restriction for the management of mild hypertension: a randomised double blind trial. Assessment of a fixed-dosage combination of atenolol and chlorthalidone (Tenoretic) in hypertensive Nigerians. Combination of verapamil and beta blockers in systemic hypertension. Felodipine, metoprolol and their combination compared with placebo in isolated systolic hypertension in the elderly. Placebo-controlled comparison of the effects of nebivolol and low-dose hydrochlorothiazide as monotherapies and in combination on blood pressure and lipid profile in hypertensive patients. The fixed combination of propranolol and bendrofluazide in the treatment of hypertension.
abstract: In a prospect i ve cohort study , associations of resting heart rate with  risk of coronary , cardiovascular disease , cancer , and all-cause mortality in age-specific cohorts of black and white men and women were examined over 22 years of follow-up . Participants were employees from 84 companies and organizations in the Chicago , Illinois , area who volunteered for a screening examination . Participants included 9,706 men aged 18 - 39 years , 7,760 men aged 40 - 59 years , 1,321 men aged 60 - 74 years , 6,928 women aged 18 - 39 years , 6,915 women aged 40 - 59 years , and 1,151 women aged 60 - 74 years at the baseline examination in 1967 - 1973 . Vital status was ascertained through 1992 . For fatal coronary disease , multivariate-adjusted relative risks associated with a 12 beats per minute higher heart rate ( one st and ard deviation ) were as follows : for men aged 18 - 39 years , relative risk ( RR ) = 1.27 ( 95 % confidence interval ( CI ) 1.08 - 1.48 ) ; for men aged 40 - 59 years , RR = 1.13 ( 95 % CI 1.05 - 1.21 ) ; for men aged 60 - 74 years , RR = 1.00 ( 95 % CI 0.89 - 1.12 ) ; for women aged 40 - 59 years , RR = 1.21 ( 95 % CI 1.07 - 1.36 ) ; and for women aged 60 - 74 years , RR = 1.16 ( 95 % CI 0.99 - 1.37 ) . Corresponding risks for all fatal cardiovascular diseases were similar to those for coronary death alone . Deaths from cancer were significantly associated with heart rate in men and women aged 40 - 59 years . All-cause mortality was associated with higher heart rate in men aged 18 - 39 years ( RR = 1.11 , 95 % CI 1.01 - 1.20 ) , men aged 40 - 59 years ( RR = 1.16 , 95 % CI 1.11 - 1.21 ) , and women aged 40 - 59 years ( RR = 1.20 , 95 % CI 1.13 - 1.27 ) . Heart rate was not associated with mortality in women aged 18 - 39 years . In summary , heart rate was a risk factor for mortality from coronary disease , all cardiovascular diseases , and all causes in younger men and in middle-aged men and women , and for cancer mortality in middle-aged men and women Summary In a multicentre , double-blind , between-patient study the hypotensive effect of oxprenolol was investigated in 329 patients with mild to moderate hypertension . A factorial experimental design with three factors was chosen : oxprenolol — none or daily doses of 20 , 40 , 60 and 80 mg ; dihydralazine and hydrochlorothiazide , respectively , none or 30 mg daily . Each treatment was given for 4 weeks after an adequate period of withdrawal from any other possible hypotensive therapy and one week of placebo wash-out . Irrespective of the association with dihydralazine and /or hydrochlorothiazide , oxprenolol had a hypotensive effect linearly related to dose for st and ing systolic ( P<0.05 ) and diastolic ( P<0.01 ) pressure , and for lying diastolic ( P<0.05 ) pressure . The addition of dihydralazine enhanced the time-course of the hypotensive effect of oxprenolol , particularly the 80 mg dose level . In general , the combination of oxprenolol with dihydralazine and hydrochlorothiazide caused larger reductions in blood pressure , particularly with oxprenolol 80 mg . In the latter group , the eventual falls in blood pressure were 30.5 and 14.4 mmHg for lying systolic and diastolic , respectively ; and 32.1 and 20.0 mmHg for the st and ing systolic and diastolic pressures . The drug was well tolerated ; major side effects ( heart failure and bronchospasm ) occurred in three patients The effect of atenolol , a new beta-1-adrenergic receptor blocking agent , was studied in a double-blind cross-over trial in 24 carefully selected hypertensive out patients . After a four-week run-in period on matching placebo each patient received atenolol 200 mg/day , atenolol 400 mg/day , a combination of atenolol 200/mg day with bendrofluazide 5 mg/day , and bendrofluazide 5 mg/day alone , according to a r and om sequence . Atenolol at either dose produced a significantly greater reduction in all blood pressure levels except st and ing systolic pressure than bendrofluazide alone . There was no statistically significant difference between the effects of the two atenolol doses on either blood pressure or pulse rate . The addition of bendrofluazide to atenolol result ed in a further significant lowering of the blood pressure . A significant effect of thiazide on weight was noted . The study shows that atenolol , a cardioselective beta-blocker of similar potency to propranolol in animals but without membrane-stabilizing or partial agonist acitivity , is an effective and well-tolerated hypotensive agent This r and omised , double-blind study was design ed to investigate the efficacy of a once-daily ( OD ) combination of the AT1 receptor blocker , eprosartan 600 mg , and the thiazide diuretic , hydrochlorothiazide ( HCTZ ) 12.5 mg , in patients with mild to moderate hypertension ( sitting diastolic blood pressure ( sitDBP ) ⩾98 mm Hg and ⩽114 mm Hg ) not adequately controlled with eprosartan 600 mg OD . A total of 494 patients entered the open-label monotherapy run-in phase , which consisted of eprosartan 600 mg OD for 3 weeks . Patients who responded to monotherapy were not eligible to enter the r and omised phase of the study and were withdrawn . The remaining 309 patients were then r and omised to either eprosartan 600 mg plus HCTZ 12.5 mg OD or to continue on eprosartan 600 mg OD . In the eprosartan plus HCTZ combination group , both sitDBP and sitting systolic blood pressure ( sitSBP ) were significantly reduced compared with the eprosartan monotherapy group . In addition , the response rate was higher in the combination group compared with the monotherapy group . There were no significant effects on reduction of sitDBP due to gender , prior use of antihypertensives or baseline severity of hypertension . The tolerability profile for the combination group was similar to that for the monotherapy group . Headache was the most frequent adverse event in both treatment groups . The majority of adverse events were mild to moderate in intensity . In this study of patients who were unresponsive to eprosartan monotherapy for 3 weeks , a combination product of eprosartan 600 mg and HCTZ 12.5 mg was shown to be an effective and well tolerated treatment Fixed-dose combination therapy has received increased interest since publication of JNC-VI report and WHO/ISH guidelines 1999 . We compared in a r and omized , double-blind study the efficacy and tolerability of valsartan 80 mg combined with hydrochlorothiazide ( HCTZ ) 12.5 mg to monotherapy with either HCTZ 12.5 mg or 25 mg in patients with essential hypertension inadequately controlled by previous HCTZ 12.5 mg monotherapy . Two hundred and seventeen patients whose blood pressure ( BP ) control remained poor ( 95 mmHg h sitting diastolic BP < 115 mmHg ) after a 4-week single-blind period with HCTZ 12.5 mg were r and omized to receive either combination therapy with valsartan 80 mg plus HCTZ 12.5 mg ( V/HCTZ ) or monotherapy with HCTZ 12.5 mg or HCTZ 25 mg for 8 weeks . Reduction of sitting trough diastolic BP between baseline and week 8 as well as tolerability was evaluated . Reduction in trough diastolic BP was most pronounced in the V/HCTZ group ( –11.3 mmHg ) and significantly greater than in the HCTZ 12.5 mg group ( –2.9 mmHg , p < 0.001 ) and the HCTZ 25 mg group ( –5.7 mmHg , p < 0.001 ) . Tolerability of study medication was comparable between all three groups . In conclusion , switching to V/HCTZ combination therapy provides an additional lowering of BP compared to dosage increase of the thiazide in patients with BP insufficiently controlled by HCTZ 12.5 mg monotherapy In this double-blind , r and omised , three-way crossover ( latin square design ) , multicentre study , the aim was to compare the efficacy and tolerability of the fixed combination of felodipine and metoprolol with the individual components as monotherapy . A total of 58 patients with supine diastolic blood pressure of 100 - 115 mmHg were treated with ( 1 ) a fixed combination of felodipine plus metoprolol 5/50 - 10/100 mg ( FM ) , ( 2 ) felodipine 5 - 10 mg ( F ) or ( 3 ) metoprolol 50 - 100 mg ( M ) , for 12 weeks each . All treatments were extended-release formulations administered once daily and blood pressure was measured 24 h after dosing . Dose titration was performed after 6 weeks if diastolic blood pressure was > 90 mmHg . After 12 weeks of active treatment , the mean supine blood pressures were 153/89 , 159/93 and 163/94 mmHg with FM , F and M , respectively . The mean differences in systolic/diastolic blood pressure were -5.6/-3.1 mmHg ( p = 0.007/p = 0.002 ) , -10.2/-4.4 mmHg ( p < 0.0001/p < 0.0001 ) and -4.6/-1.4 mmHg ( p = 0.03/p = 0.15 ) for FM vs F , FM vs M , and F vs M , respectively . Blood pressure control ( supine diastolic blood pressure < or = 90 mmHg ) after 12 weeks was achieved in a significantly greater proportion of patients during treatment with FM than with F or M ; 71 % , 45 % and 40 % were controlled with the respective treatments . With FM , 45 % of the patients were taking the higher dose after 12 weeks of treatment . The corresponding figures for F and M were 60 % and 67 % , respectively . Thirteen of the 58 patients ( 22 % ) were controlled only with FM . ( ABSTRACT TRUNCATED AT 250 WORDS In 15 patients with mild to moderate essential hypertension , the effects of diltiazem ( 120 mg twice daily ) were compared with those of atenolol ( 50 mg once daily ) , the two drugs in combination , and placebo in a r and omized double-blind cross-over study with treatment phases of 4 weeks duration . Blood pressure was reduced in the active treatment phases ( supine blood pressure : diltiazem , 172/92 mmHg ; atenolol , 172/92 mmHg ; diltiazem plus atenolol , 164/88 mmHg ; pooled estimate of s.e.m . by analysis of variance = 3/1 ) compared with placebo ( 180/101 mmHg ) . Factorial analysis confirmed fully additive antihypertensive effects of the drugs in combination . The time interval from the beginning of the P wave to the beginning of the QRS complex ( P-R interval ) was longer during combination therapy ( 0.184s ) compared with either diltiazem ( 0.175s ) or atenolol ( 0.174s ) alone , or placebo ( 0.164s ) ; s.e.m . by analysis of variance = 0.003 . No clinical ly significant conduction disturbances occurred . Plasma atrial natriuretic peptide was elevated by atenolol but not diltiazem . Thus , in subjects with uncomplicated essential hypertension , diltiazem and atenolol had equal antihypertensive efficacy when used alone , and fully additive effects in combination , on both blood pressure and cardiac conduction Summary Sixteen patients with essential hypertension completed a double blind factorial trial comparing the effects of indapamide ( 2.5 mg daily ) and pindolol ( 10 mg daily ) on blood pressure , heart rate , plasma renin activity and plasma aldosterone concentration . There were four r and omised test phases of eight weeks each during which patients received indapamide alone , pindolol alone , indapamide plus pindolol and no active treatment ( placebo ) .  Blood pressure and heart rate were measured every two weeks . Supine mean arterial pressure fell from 117 mm Hg in the placebo phase to 111 mm Hg in the indapamide phase , 106 mm Hg in the pindolol phase and 103 mm Hg in the combined indapamide plus pindolol phase . Factorial analysis confirmed that the hypotensive effects of the two drugs were additive , without evidence of potentiation or antagonism . Indapamide caused significant reductions in plasma potassium and chloride , and increases in plasma bicarbonate and urate concentrations ; it also caused increases in plasma renin activity and aldosterone concentration . These changes are similar to those observed with thiazide diuretics Context Hypertension is a recognized risk factor for the development of congestive heart failure ( CHF ) . By measuring blood pressure , however , we have not yet been able to underst and the significance of pulse pressure as a contributor to CHF in middle-aged men and women . Contribution Using data from the Framingham Heart Study , the authors found that although elevations of systolic , diastolic , and pulse pressure were all related to the risk for CHF , the relation was strongest for systolic and pulse pressure . Caution s Underst and ing the relationships between systolic , diastolic , and pulse pressure and risk for CHF is helpful ; however , they do not help determine the increased risk faced by a person with systolic hypertension who also has increased pulse pressure . The Editors Hypertension is the most common risk factor for congestive heart failure ( CHF ) . It confers a twofold risk for the occurrence of CHF and also carries the highest population attributable risk among all risk factors for CHF ( 1 , 2 ) . Placebo-controlled clinical trials in patients with hypertension have demonstrated a consistent reduction in risk for CHF attributable to the lowering of elevated blood pressure ( 3 - 6 ) . The causal role of hypertension in the pathogenesis of CHF underscores the need to identify high-risk patients because early treatment may prevent or delay the occurrence of CHF ( 2 , 7 ) . The prognostic significance of systolic and diastolic blood pressure in CHF has been reported . However , blood pressure may also be divided into two other components : steady ( mean arterial pressure ) and pulsatile ( pulse arterial pressure ) ( 8 - 10 ) . Pulse pressure , a simple correlate of conduit vessel stiffness , is associated with left ventricular hypertrophy ( 11 ) . Increased pulse pressure has also been implicated in the development and progression of large-vessel atherosclerosis and small-vessel disease ( 12 - 14 ) . Accumulating evidence indicates that pulse pressure ( defined as the difference between systolic and diastolic blood pressure ) may be an important predictor of cardiovascular events ( 15 - 18 ) . Pulse pressure predicts the risk for CHF in elderly persons ( 19 , 20 ) ; however , the association of pulse pressure with CHF in middle-aged men and women has not been examined . The Framingham Heart Study provides an opportunity to examine the long-term associations of systolic , diastolic , and pulse pressure with the new onset of  CHF in middle-aged and elderly men and women .  Blood pressure and traditional risk factors have been measured repeatedly at serial examinations in this community-based cohort with long-term follow-up . We examined systolic blood pressure , diastolic blood pressure , and pulse pressure as predictors of risk for CHF in the Framingham Heart Study . Methods The Framingham Heart Study , which began in 1948 , has followed 5209 participants ( 28 to 62 years of age at entry to the study ) as part of a prospect i ve epidemiologic study of cardiovascular disease . Enrollment criteria and study design have been published previously ( 21 ) . Biennial follow-up visits included a medical history , physical examination , blood pressure measurements , 12-lead electrocardiography , and laboratory tests . Eligibility requirements for inclusion in our study were as follows : Participants had to be free of coronary heart disease and CHF and not be receiving antihypertensive therapy at Framingham Heart Study clinic baseline examinations 10 , 11 , or 12 ( 1968 to 1973 ) . Participants were followed for onset of CHF through mid-1994 . We obtained data for selected risk factors from the baseline examination . Methods for assessing risk factors have been published previously ( 21 , 22 ) . Risk factors , including age , sex , cigarette smoking , heart rate , antihypertensive medication use , and total and high-density lipoprotein cholesterol levels , were assessed .  Sitting systolic and diastolic blood pressure were measured twice by the examining physician ( using a mercury column sphygmomanometer ) and averaged . We used body mass index ( kg/m2 ) as a measure of obesity . Participants were categorized as smokers if they smoked cigarettes regularly within the 1-year period before the baseline examination . Electrocardiography revealed left ventricular hypertrophy when increased voltage was associated with major ST-T repolarization changes ( strain pattern ) ( 22 ) . Diabetes mellitus was defined on the basis of a fasting blood glucose level greater than 7.77 mmol/L ( > 140 mg/dL ) , two r and om nonfasting blood glucose levels greater than 11.10 mmol/L ( > 200 mg/dL ) , or the use of insulin or an oral hypoglycemic agent . Diagnostic criteria for CHF have been described previously ( 21 , 22 ) . At each clinic examination , a history of interim hospitalizations and symptoms of CHF were obtained . Outside medical records of participants who did not attend an examination were evaluated for incident CHF . All suspected interim events were review ed by a panel of three physicians who evaluated relevant Framingham Heart Study clinic notes , outside physician reports , and hospitalization records . Congestive heart failure was diagnosed when at least two major or one major and two minor criteria were present . Minor criteria were considered only if their presence could not be attributed to another disease process . Major criteria were paroxysmal nocturnal dyspnea , pulmonary rales , distended jugular veins , enlarging heart size on chest radiography , acute pulmonary edema , hepatojugular reflux , third heart sound , jugular venous pressure of 16 cm or greater , and weight loss of 4.5 kg or greater in response to diuresis . Major criteria also included pulmonary edema , visceral congestion , or cardiomegaly on autopsy . Minor criteria were bilateral ankle edema , nocturnal cough , shortness of breath on ordinary exertion , hepatomegaly , pleural effusion , decrease in vital capacity by one third from the previous maximum recorded value , and heart rate of 120 beats/min or more . Statistical Analysis We used multivariable Cox proportional-hazards regression models to examine the relations of systolic , diastolic , and pulse pressure with CHF . After accounting for age and sex and using a P value less than 0.15 as the selection criterion , we determined covariates by stepwise selection from the following list : body mass index , diabetes , smoking status , total cholesterol level , high-density lipoprotein ( HDL ) cholesterol level , totalHDL cholesterol ratio , left ventricular hypertrophy , and heart rate . Only total cholesterol level and totalHDL cholesterol ratio did not enter the model . After accounting for relevant covariates , we used Cox proportional-hazards models to obtain hazard ratio estimates with 95 % CIs for st and ardized values of systolic , diastolic , and pulse pressure . These estimates were obtained individually and pairwise by using SAS software ( SAS Institute , Inc. , Cary , North Carolina ) ( 23 ) . We repeated analyses for participants stratified according to hypertension status and sex . Because blood pressure and age are correlated , we conducted separate analyses for participants younger than 60 years of age and 60 years of age and older . To examine constancy of effects over time , follow-up was divided into early and late periods ( < 10 years , 10 years ) , and hazard ratios were calculated separately for early and late follow-up . In addition , we analyzed blood pressure as a time-varying covariate and assessed the effect of antihypertensive treatment after the baseline blood pressure measurements . We used the KaplanMeier method to plot age- and sex-st and ardized cumulative incidence rates for CHF as a function of pulse pressure tertile at baseline . Descriptive data are presented as percentages or means ( SD ) . A P value less than 0.05 was considered statistically significant . Role of the Funding Sources The funding sources had no role in the design , conduct , analyses , and reporting of the study or in the decision to su bmi t the manuscript for publication . Results A total of 894 men and 1146 women , age 50 to 79 years , fulfilled criteria for inclusion in our study . Table 1 presents baseline clinical characteristics for these persons . During 35 497 person-years of follow-up ( mean , 17.4 years [ range , 0.06 to 24 years ] ) , CHF developed in 234 ( 11.8 % ) persons . Myocardial infa rct ion preceded CHF in 59 ( 25 % ) persons . Table 1 . Baseline Clinical Characteristics of the Study Participants Increments of 1 SD in systolic pressure , pulse pressure , and diastolic pressure were associated with hazard ratios for congestive failure of 1.56 , 1.55 , and 1.24 , respectively , after adjustment for age , sex , smoking , left ventricular hypertrophy , body mass index , diabetes mellitus , HDL cholesterol level , and heart rate ( Table 2 ) . When blood pressure tertiles were used , similar associations were observed among various components of blood pressure and CHF . No threshold effect or J-shaped association was documented ( Table 2 ) . The cumulative incidence of CHF according to tertiles of baseline pulse pressure is plotted in the Figure . Table 2 . Risk FactorAdjusted Association of Blood Pressure with Congestive Heart Failure Figure . Cumulative incidence of congestive heart failure according to pulse pressure tertiles at the baseline examination . The joint influences of different blood pressure components were also examined , with adjustment for the covariates mentioned previously . Of note , correlations among the blood pressure variables ranged from modest to very high ( r = 0.20 for diastolic and pulse pressure , r = 0.65 for diastolic and systolic pressure , and r = 0.88 for systolic and pulse pressure ) . Diastolic pressure was not significant ( hazard ratio , 1.12 [ CI , 0.98 to 1.29 ] ) in conjunction with pulse pressure ( hazard ratio , 1.51 [ CI , 1.33 to 1.72 ] ) . Likewise , diastolic pressure was not significant ( hazard ratio , 0.86 [ CI , 0.72 to 1.03 ] ) in conjunction with systolic pressure ( hazard ratio , 1.71 [ CI , 1.45 to 2.01 ] ) , but joint estimates were less stable than those obtained for individual pressure variables . Finally Abstract Objective : To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes . Design : R and omised controlled trial comparing tight control of blood pressure aim ing at a blood pressure of < 150/85 mm Hg ( with the use of an angiotensin converting enzyme inhibitor captopril or a β blocker atenolol as main treatment ) with less tight control aim ing at a blood pressure of < 180/105 mm Hg . Setting : 20 hospital based clinics in Engl and , Scotl and , and Northern Irel and . Subjects : 1148 hypertensive patients with type 2 diabetes ( mean age 56 , mean blood pressure at entry 160/94 mm Hg ) ; 758 patients were allocated to tight control of blood pressure  and 390 patients to less tight control  with a median follow up of 8.4 years . Main outcome measures : Predefined clinical end points , fatal and non-fatal , related to diabetes , deaths related to diabetes , and all cause mortality . Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography . Results : Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control ( 144/82 mm Hg ) compared with the group assigned to less tight control ( 154/87 mm Hg ) ( P<0.0001 ) . Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24 % in diabetes related end points ( 95 % confidence interval 8 % to 38 % ) ( P=0.0046 ) , 32 % in deaths related to diabetes ( 6 % to 51 % ) ( P=0.019 ) , 44 % in strokes ( 11 % to 65 % ) ( P=0.013 ) , and 37 % in microvascular end points ( 11 % to 56 % ) ( P=0.0092 ) , predominantly owing to a reduced risk of retinal photocoagulation . There was a non-significant reduction in all cause mortality . After nine years of follow up the group assigned to tight blood pressure control also had a 34 % reduction in risk in the proportion of patients with deterioration of retinopathy by two steps ( 99 % confidence interval 11 % to 50 % ) ( P=0.0004 ) and a 47 % reduced risk ( 7 % to 70 % ) ( P=0.004 ) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study ( ETDRS ) chart . After nine years of follow up 29 % of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures . Conclusion : Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinical ly important reduction in the risk of deaths related to diabetes , complications related to diabetes , progression of diabetic retinopathy , and deterioration in visual acuity BACKGROUND The safety and effectiveness of different dosages and combinations of antihypertensive agents can be efficiently studied using a multifactorial trial design . In consultation with the Cardio-Renal Division of the Food and Drug Administration , we conducted a r and omized , double-blind , placebo-controlled , 3 x 4 factorial trial of bisoprolol , a beta 1-selective adrenergic blocking agent , and hydrochlorothiazide . METHODS A total of 512 patients with mild to moderate essential hypertension were r and omized to once-daily treatment with bisoprolol ( 0 , 2.5 , 10 , or 40 mg ) , hydrochlorothiazide ( 0 , 6.25 , or 25 mg ) , and all possible combinations .  Diastolic and systolic blood pressures were monitored during this 12-week trial . RESULTS The effects of bisoprolol and hydrochlorothiazide were additive with respect to reductions in diastolic and systolic blood pressures over the dosage ranges studied . The addition of hydrochlorothiazide ( or bisoprolol ) to therapy with bisoprolol ( or hydrochlorothiazide ) produced an incremental reduction in blood pressure . Dosages of hydrochlorothiazide as low as 6.25 mg/d contributed a significant antihypertensive effect . A hydrochlorothiazide dosage of 6.25 mg/d produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg/d . The low-dose combination of bisoprolol , 2.5 mg/d , and hydrochlorothiazide , 6.25 mg/d , reduced diastolic blood pressure to lower than 90 mm Hg in 61 % of patients and demonstrated a safety profile that compared favorably with that of placebo . CONCLUSIONS The utility of factorial design trials to characterize dose-response relationships and to test the potential interactions between various antihypertensive agents has been demonstrated . The combination of low dosages of bisoprolol and hydrochlorothiazide may be a rational alternative to conventional stepped-care therapy for the initial treatment of patients with mild to moderate hypertension In a r and omised , crossover study of patients with moderate to severe essential hypertension , the effects of the calcium entry antagonist nifedipine and the beta-receptor blocking drug acebutolol were studied on their own , and in combination . After 4 weeks of nifedipine tablets 20 mg twice daily ( Adalat , Bayer ) , mean supine blood pressure ( BP ) fell by 20 mmHg and after 4 weeks of acebutolol 200 mg twice a day ( Sectral , May & Baker ) by 11 mmHg . When nifedipine and acebutolol were given in combination in the above doses for 4 weeks , there was a significantly greater fall in BP than with either agent alone , supine mean arterial pressure falling by 27 mmHg . The above BPs were measured 2 h after the last dose of tablets . Measurements 12 h after the last dose showed smaller falls in BP , with a significantly greater fall with combination treatment than with acebutolol alone . The fall in BP 12 h after the last dose of the combination was greater than with nifedipine alone but this difference was not statistically significant . This r and omised , controlled study showed that nifedipine and acebutolol have a marked additive effect on BP which is sustained for at least 12 h after treatment Summary In this r and omised , double-blind , crossover trial , the efficacy in hypertension of atenolol and nifedipine as single agents or in combination was compared . 81 patients with mild to moderate essential hypertension ( sitting diastolic blood pressure 100–120 mm Hg , aged 20–70 years ) from 6 outpatient clinics entered the study . By use of a Latin-square design , patients received , in r and omised fashion , sustained release nifedipine 20 mg twice daily , atenolol 50 mg in the morning and then placebo in the evening , or sustained release nifedipine 20 mg plus atenolol 50 mg in the morning and then placebo in the evening . Each schedule was followed for 4 weeks . All treatments lowered systolic and diastolic blood pressure in the supine and st and ing positions compared with pretreatment values . The combination regimen significantly reduced supine and st and ing systolic ( p < 0.01 and p < 0.001 , respectively ) and diastolic ( p < 0.001 ) blood pressure compared with nifedipine alone , and it also significantly reduced supine and st and ing systolic ( p < 0.01 and p < 0.03 , respectively ) and diastolic ( p < 0.01 ) blood pressure compared with atenolol  alone . Heart rate was significantly decreased by atenolol and the combination compared with nifedipine alone.15 patients withdrew because of side effects : 9 during nifedipine treatment , 2 during atenolol treatment and 4 during combination treatment . Side effects were typical of those associated with nifedipine or atenolol . Flushes and hot sweats , which were frequent with nifedipine , were significantly less ( p < 0.001 ) with atenolol or the combination . For selected patients who do not respond to monotherapy with nifedipine or atenolol , the combination regimen seems an appropriate and useful alternative to β-blocker/diuretic combinations , especially where ischaemic heart disease may co-exist BACKGROUND Despite treatment , there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals . Inadequate reduction of their blood pressure is a likely cause , but the optimum target blood pressure is not known . The impact of acetylsalicylic acid ( aspirin ) has never been investigated in patients with hypertension . We aim ed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension . METHODS 18790 patients , from 26 countries , aged 50 - 80 years ( mean 61.5 years ) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg ( mean 105 mm Hg ) were r and omly assigned a target diastolic blood pressure . 6264 patients were allocated to the target pressure < or = 90 mm Hg , 6264 to < or = 85 mm Hg , and 6262 to < or = 80 mm Hg . Felodipine was given as baseline therapy with the addition of other agents , according to a five-step regimen . In addition , 9399 patients were r and omly assigned 75 mg/day acetylsalicylic acid ( Bamycor , Astra ) and 9391 patients were assigned  placebo . FINDINGS Diastolic blood pressure was reduced by 20.3 mm Hg , 22.3 mm Hg , and 24.3 mm Hg , in the < or = 90 mm Hg , < or = 85 mm Hg , and < or = 80 mm Hg target groups , respectively . The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg ; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg . Further reduction below these blood pressures was safe .  In patients with diabetes mellitus there was a 51 % reduction in major cardiovascular events in target group < or = 80 mm Hg compared with target group < or = 90 mm Hg ( p for trend=0.005 ) . Acetylsalicylic acid reduced major cardiovascular events by 15 % ( p=0.03 ) and all myocardial infa rct ion by 36 % ( p=0.002 ) , with no effect on stroke . There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group , and 129 versus 70 non-fatal major bleeds in the two groups , respectively ( p<0.001 ) . INTERPRETATION Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events . The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg . Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infa rct ion . There was no effect on the incidence of stroke or fatal bleeds , but non-fatal major bleeds were twice as common Summary In a multicentre , double-blind , crossover , placebo-controlled study , the antihypertensive effect of labetalol 100 mg and chlorthalidone 10 mg , given alone or in combination , has been assessed in 32 hypertensive patients . The combination had a greater effect in reducing blood pressure than did its separate components . This was particularly evident after exercise . Heart rate increased during chlorthalidone therapy , decreased during labetalol therapy , and a summation effect was observed during treatment with the combination . In most cases additivity was observed , as no interaction between the single components was observed , except for heart rate after exercise , and for diastolic blood pressure in the upright position . No interaction was observed either in the biochemical indices or in the clinical side-effects Summary : In this double-blind , r and omized , parallel-group study , the aim was to compare the efficacy and tolerability of a new fixed combination of felodipine and metoprolol with the individual components in monotherapy . After a placebo period of 4 weeks , 159 patients with mild to moderate essential hypertension were r and omized to extended-release formulations of either felodipine plus metoprolol 10 + 100 mg ( FM ) , felodipine 10 mg ( F ) , or metoprolol 100 mg ( M ) once daily if supine diastolic blood pressure > 95 mm Hg . After 12 weeks of active treatment , the reductions in supine blood pressure ( 24 h after dosing ) were 20/14 , 13/10 , and 11/8 mm Hg for FM , F , and M , respectively . The difference in change was 7/4 mm Hg ( p = 0.004/p = 0.006 ) and 8/5 mm Hg ( p = 0.0002/p < 0.0001 ) for the fixed combination and F or M , respectively . Blood pressure control ( diastolic blood pressure < 90 mm Hg after 12 weeks ) was significantly better for the combination than for F and M , i.e. , 71 % , 49 % ( p = 0.008 ) , and 34 % ( p = 0.004 ) , respectively . Adverse experiences were those to be expected from previous studies with felodipine and metoprolol and did not differ in frequency between groups . It can be concluded that a fixed combination of metoprolol and felodipine has a clinical ly relevant and significantly better blood pressure reduction 24 h postdose than the individual substances in monotherapy , without decreased tolerability In 16 patients with essential hypertension the effects of enalapril 20 mg once daily were compared with those of atenolol 50 mg once daily , with the two drugs in combination and with placebo using a double-blind cross-over design with allocation of treatment order by r and omised Latin squares . For each patient there were four treatment phases , each of four weeks duration , which together comprised a 2 x 2 factorial experiment . All blood pressure parameters were reduced in the three active treatment phases compared to placebo ( p less than 0.001 ) . Supine blood pressures ( group means ) were 171/97 ( placebo ) , 147/85 ( enalapril ) , 154/84 ( atenolol ) and 144/78 ( enalapril plus atenolol ) ( S.E.M. + /- 2/+/- 1-ANOVA ) , and st and ing blood pressures were 170/105 ( placebo ) , 146/92 ( enalapril ) , 154/92 ( atenolol ) and 147/86 ( enalapril plus atenolol ) ( S.E.M. + /- 3/+/- 1 ) . In the combination phase there was an additional hypotensive response but the potential fully additive effects of the two agents were attenuated by 30 - 50 % . The mechanism of the attenuated hypotensive effect of the combined agents has not been determined . Plasma atrial natriuretic peptide ( ANP ) concentration was doubled in the presence of atenolol ( P less than 0.01 ) suggesting that ANP may contribute to the hypotensive effect of the beta-blocker Fifteen out- patients with moderate hypertension were r and omly and sequentially treated with atenolol , indapamide and a combination of the two drugs after a wash-out period of at least 1 week and a 2-week placebo run-in period . The duration of treatment was 4 weeks in each case . The dosage was 2.5 mg indapamide and 100 mg atenolol , in single tablets which were taken at 11.00 hours . All the treatment regimens produced a highly significant ( p less than 0.001 ) reduction in systolic and diastolic , supine and st and ing blood pressure ; these reductions were not significantly different for the single drugs but were significantly greater for the combined therapy . The number of patients reaching the end-point of a diastolic blood pressure of 95 mmHg or less was the same with either atenolol or indapamide , i.e. 7 ( 46.6 % ) , but was greater with the combined therapy , i.e. 10 ( 66.6 % ) . A significant ( p less than 0.001 ) reduction in pulse rate was observed with the treatments involving atenolol .  Acceptability of the treatments was very good ; the number of volunteered and elicited complaints during the different treatments being less compared to the placebo period , particularly for the combined treatment . No significant difference was observed in the blood biochemistry tests . The results are discussed in light of the mechanisms of action of the two drugs , which seem well integrated with each other , and the duration of the antihypertensive effect , which allows a single administration with consequent good treatment compliance Two hundred thirty-four patients with supine diastolic blood pressure of between 95 and 114 mm Hg were enrolled into a double-blind , r and omized , parallel , multicenter trial . The patients were r and omized to either nicardipine 30 mg tid , propranolol 40 mg tid , or nicardipine 30 mg tid and propranolol 40 mg tid for six weeks . Two hundred six patients yielded data for analyses . Of the 28 not included , seven had missing data , whereas the remaining 21 were excluded because they either failed to meet inclusion criteria or were noncompliant at endpoint . Both nicardipine and propranolol as monotherapies and in combination achieved statistically significant , ( P less than .01 ) , supine diastolic blood pressure reduction relative to baseline . The combination of nicardipine and propranolol showed a greater reduction in supine diastolic and systolic measurements than either of the monotherapies . Nicardipine produced greater blood pressure reductions one hour after dosing , whereas the propranolol treatment tended to produce slightly greater blood pressure decreases eight hours after dose . The combination always result ed in the greatest blood pressure reduction , independent of time after dose . Adverse experiences were reported by 26 % of patients in the nicardipine-treated group , most often transient vasodilatory effects , by 17 % of the propranolol-treated patients , and by 18 % of the combination-treated group . This study demonstrated at the doses studied that nicardipine alone produced equivalent blood pressure reductions to those obtained by propranolol alone , but that the combination of these two drugs produced greater reductions in blood pressures than either of the monotherapies BACKGROUND To attain goal blood pressure ( BP ) , many hypertensive patients require combination antihypertensive therapy . Thiazide diuretic/beta-blocker regimens lower BP , and clinical studies indicate that they reduce the risk for cardiovascular consequences of hypertension . Fixed-dose combination tablets can simplify multidrug treatment regimens . METHODS This multicenter , r and omized , double-blind , placebo-controlled , unbalanced factorial study ( N = 1571 ) was design ed to determine whether hydrochlorothiazide ( HCT ) and extended release ( ER ) metoprolol both contribute to an antihypertensive effect .  Hypertensive adults with sitting diastolic BP ( SiDBP ) 95 to 114 mm Hg and systolic BP ( SiSBP ) < 180 mm Hg received one of three hydrochlorothiazide doses ( 6.25 mg , 12.5 mg , or 25 mg ) , one of four ER-metoprolol doses ( 25 mg , 50 mg , 100 mg , 200 mg ) , or one of nine of the combinations or placebo for 8 weeks . RESULTS Blood pressure decreased with all combinations ( P < .001 v placebo ) ; reductions were dose related , ranging from 8.7 to 15.7 mm Hg ( SiDBP ) and 9.7 to 18.9 mm Hg ( SiSBP ) ( model-derived values ) . Reductions with placebo were 5.3 ( SiDBP ) and 4.2 mm Hg ( SiSBP ) . Both active agents contributed to the combination effect ( P = .0015 for SiDBP ; P = .0006 for SiSBP ) . Several low-dose combinations were approximately as effective as high doses of the individual agents ( differences within 1 to 2.5 mm Hg ) . The adverse event discontinuation rate was 2.9 % . Serum potassium decreased and uric acid increased with increasing doses of HCT . CONCLUSIONS Extended-release metoprolol/hydrochlorothiazide is an effective antihypertensive combination that offers additive antihypertensive contributions from both components In a double-blind trial , 545 out- patients with essential hypertension received 25 mg/day chlorthalidone alone ( 274 patients ) or in fixed combination with 200 mg/day slow-release metoprolol ( 271 patients ) for 8 weeks . Both treatments significantly ( P<0.001 ) decreased systolic and diastolic blood pressure ; 45.6 % of patients receiving chlorthalidone and 82.5 % receiving combined therapy had a diastolic blood pressure of less than 95 mmHg . Patients not controlled by chlorthalidone or chlorthalidone plus metoprolol subsequently received chlorthalidone plus metoprolol ( 137 patients ) or chlorthalidone plus metoprolol plus a third drug ( 34 patients ) , respectively , for 8 weeks . A total of 79.5 % of patients receiving chlorthalidone plus metoprolol and 61.8 % receiving chlorthalidone plus metoprolol plus a third drug had a diastolic blood pressure of less than 95 mmHg . Only 5.9 % of patients experienced mild to modérate side-effects . Plasma potassium leveis significantly ( P<0.01 ) decreased during the first 8 weeks only . It is concluded that a diuretic alone or in fixed combination with a β-blocker is effective in the long-term treatment of arterial hypertension The tolerance and antihypertensive action of acebutolol , as a sole drug and in combination with a diuretic , were studied in a population of 34 female subjects aged over 65 years , with a mean of 81 years , suffering from well tolerated essential hypertension . The study was carried out in the form of double blind permutations , each subject receiving successively in an order determined by r and om selection each of three therapeutic phases : acebutolol , acebutolol in combination with a diuretic and a placebo . The results showed that in the elderly acebutolol had a moderate diuretic action which was remarkably potentialised by diuretics . The tolerance of this beta-blocker was excellent : no cases of cardiac failure , and no disturbances in atrioventricular conduction developed during the phases with active treatment In a double-blind , crossover study , five white men with mild-to-moderate hypertension received placebo and fixed doses of atenolol , metoprolol , chlorthalidone , verapamil , and the combination of atenolol and chlorthalidone in a quasi-r and om order . Daily dosages were : atenolol , 100 mg ; metoprolol , 200 mg ; chlorthalidone , 50 mg ; verapamil , 240 mg ; and the same doses of atenolol and chlorthalidone in combination .  St and ard office and daytime ambulatory blood pressures were assessed at the end of each month-long trial . Atenolol , metoprolol , chlorthalidone , and verapamil  controlled office blood pressure with similar reductions . Verapamil did not lower ambulatory blood pressure at this dose ( which is lower than is now commonly used ) , but reductions in ambulatory blood pressure were similar for atenolol , metoprolol , and chlorthalidone . The combination of atenolol and chlorthalidone maintained blood pressure control more effectively than the single drug treatments in both office and ambulatory setting s , and the combined hypotensive effects were additive . However , reductions in the office due to the combination appeared to overestimate hypotensive effectiveness in the ambulatory setting . This study suggests that the effectiveness of commonly prescribed antihypertensive regimens varies according to setting as well as drug , and that assessment of treatment effectiveness can be improved by automated ambulatory blood pressure monitoring 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 1 . The aim of the study was to compare the efficacy and the tolerability of treatment with atenolol ( 50 - 100 mg once daily ) , nitrendipine ( 20 - 40 mg once daily ) and their combination ( atenolol 50 mg + nitrendipine 20 mg ) once daily in patients with mild to moderate essential hypertension . 2 . The study was a r and omised , double-blind , placebo controlled parallel groups design : blood pressures were measured at ' trough ' effect ( i.e. 24 h after dosing ) to assess the adequacy of once-daily treatment . 3 . Mean blood pressures ( mm Hg ) recorded on four occasions over 12 weeks of treatment were significantly lower both with atenolol ( 155/97 sitting : 155/104 st and ing ) and with the combination of atenolol plus nitrendipine ( 153/96 sitting : 152/104 st and ing ) than with placebo ( 169/108 sitting : 169/114 st and ing ) . Nitrendipine alone had no significant effect on blood pressure 24 h after dosing ( 165/104 sitting : 165/110 st and ing ) . 4 . Withdrawals due to adverse effects were more common during treatment with nitrendipine : 7/32 of the patients experienced adverse effects attributable to intense systemic vasodilatation ( e.g. , flushing , erythema , headache ) . 2/37 patients taking atenolol  were withdrawn : one because he developed a psoriatic rash and the other because of impaired peripheral circulation . Of the 35 patients taking combination treatment , two were withdrawn : one developed headaches and dyspnoea , and the other asthma . 5 . The results suggest that once daily dosing with nitrendipine does not control blood pressure throughout the 24 h period in the majority of patients , and is associated with a considerable burden of adverse effects . Combination treatment was better tolerated but appeared to offer no advantages over atenolol alone in terms either of blood pressure control or adverse effects In 101 hypertensive patients , the effects of a combination of propranolol and bendrofluazide were compared with those of each drug alone . After an introductory period with a placebo , the patients received , in a double-blind r and omized trial , propranolol 80 mg twice a day , bendrofluazide 2.5 mg twice a day , or both drugs together twice daily . The combination produced significantly greater reductions in lying , st and ing , and post-exercise systolic and diastolic blood pressure than either drug separately . Side-effects were minimal and the combination was well accepted by patients 1 The hypotensive effect of single daily dosing with atenolol 100 mg and chlorthalidone 25 mg given alone or in combination has been assessed in a double-blind , crossover , placebo controlled trial in fifteen hypertensive patients . 2 Average lying blood pressures were : Placebo 155.4/103.9 mm Hg , atenolol 134.6/85.8 mm Hg , chlorthalidone 139.5/90.1 mm Hg , combination 127.7/82.5 mm Hg . 3 The effect of the combination therapy in reducing lying diastolic pressure compared with placebo ( a fall of 21.4 mm Hg ) was significantly less than the 31.9 mm Hg fall predicted from the sum of the individual effects ( P = 0.01 ) . 4 Observations on blood pressure at rest and under mental , isometric and bicycle ergometer stress were made pre-dose and post-dose for a 12 h period at the end of the last treatment period . 5 Lying blood pressure declined from the zero hour ( pre-dose ) reading on all treatments to a low at 15.00 - -18.00 h and then rose again . 6 The rise in systolic blood pressure after isometric exercise and mental stress was of a similar magnitude with all four treatment regimes . 7 Atenolol , alone and in combination with chlorthalidone , reduced the blood pressure and the pulse rate increase on exercise 2 h post-dose when compared with readings 24 h post-dose . 8 Once daily dosing with a combination of atenolol and chlorthalidone produced a fall in supine blood pressure over a 24 h period but the effect on exercise induced changes was not uniform over this period 1 . The effects of timolol alone and in combination with a fixed dose of hydrochlorothiazide and amiloride have been studied in a double-blind , controlled study in fifty-four patients with mild to moderate essential hypertension . 2 . After a 4 weeks placebo period patients were r and omly assigned to enter groups receiving timolol alone ( group A ) , hydrochlorothiazide + amiloride ( group B ) or timolol + hydrochlorothiazide + amiloride ( group C ) . Each treatment was carried out for 6 weeks . 3 . The use of timolol ( 10 mg ) , hydrochlorothiazide ( 25 mg ) and amiloride ( 2 - 5 mg ) in a combination tablet given twice daily gave better control of blood pressure in patients with mild to moderate essential hypertension than did equivalent dosages of timolol alone or of hydrochlorothiazide and amiloride . 4 . Clinical and laboratory side effects were minimal In a r and omized , double-blind , within-patient study , 28 out- patients with mild to moderate hypertension were given , at the end of a 3-week placebo wash-out period , four different antihypertensive treatments for 3 weeks each . the treatments were 50 mg atenolol , 100 mg atenolol , 12.5 mg chlorthalidone and a fixed combination of 50 mg atenolol and 12.5 mg chlorthalidone . All treatments were given once daily . Visits were scheduled for the last day of each treatment period , 24 - 26 hours after the last dose , and there was an intermediary wash-out period between each pair of active treatments . Supine systolic/diastolic blood pressure was 165/102 on placebo , 153/93 mmHg on 50 mg atenolol , 155/91 mmHg on 100 mg atenolol , 148/93 mmHg on 12.5 mg chlorthalidone and 144/89 mmHg on the combination . All the changes in pressure were significant ( p less than 0.01 ) versus placebo .  Supine systolic blood pressure was lower on the combination than on 100 mg atenolol alone ( p less than 0.05 ) and upright systolic pressure was lower on the combination than on 100 mg atenolol ( p less than 0.05 ) or 50 mg atenolol ( p less than 0.05 ) alone . The heart rate was lowered by atenolol alone or combined with chlorthalidone but did not fall below 56 bpm in any patient . Serum potassium levels were lower on 12.5 mg chlorthalidone than on placebo ( 3.88 mEq/l vs 4.09 mEq/l -- p less than 0.05 ) but the difference was trivial ; on the combination of atenolol-chlorthalidone there was no significant difference versus placebo ( 3.97 mEq/l vs 4.09 mEq/l -- NS ) . ( ABSTRACT TRUNCATED AT 250 WORDS Ninety four patients with mild hypertension ( average supine diastolic blood pressure ( phase V ) 95 - 110 mm Hg ) were allocated at r and om to receive restriction of dietary sodium ( maximum allowed 70 mmol(mEq)/24 h ) or a normal diet . In addition , they received in r and om order 25 mg chlorthalidone , 200 mg metoprolol ( slow release ) , and a fixed combination of these two drugs . Each drug treatment was given for four weeks and alternated with four weeks of placebo . Forty four patients were allocated to sodium restriction ( group 1 ) and 50 to normal diet ( group 2 ) . The mean 24 hour urinary sodium excretion in group 1 was 74 ( SD 31 ) mmol(mEq)/24 h , and in group 2 132 ( 51 ) mmol/24 h. Compared with the screening blood pressure the average decrement of the supine blood pressure in group 1 was 16.0/8.6 mm Hg with placebo , 21.7/11.5 mm Hg with the diuretic , 28.5/17.8 mm Hg with the beta blocker , and 28.9/18.4 mm Hg with the combined agent ; in group 2 these values were 13.3/6.1 , 20.3/9.7 , 21.3/12.9 , and 29.4/16.8 mm Hg , respectively . There was a sharp decrease of the average potassium concentration during chlorthalidone and combination treatment periods ( average value 3.3 mmol(mEq)/1 ) . These results suggest that moderate salt restriction used as sole treatment has a limited though demonstrable blood pressure lowering effect but that when it is used as an adjuvant to beta blocker treatment its value is greatly enhanced The antihypertensive effect of a fixed dosage combination of the cardioselective beta-adrenoceptor blocker , atenolol , and the oral thiazide-like diuretic , chlorthalidone ( Tenoretic ) was studied in 24 hypertensive Nigerians in a double-blind , cross-over comparison with three other treatments . These were atenolol alone , 100 mg daily , chlorthalidone alone , 25 mg daily , and atenolol ( 100 mg ) plus chlorthalidone ( 25 mg ) daily taken as separate formulations . Tenoretic was taken as a once-daily tablet containing 100 mg atenolol plus 25 mg chlorthalidone . The order of administration of the drugs was r and omized . Each drug was taken for 4 weeks . The results showed that atenolol and chlorthalidone lowered blood pressure to the same extent . Combination of the two drugs whether taken separately or in fixed-dosage combination was better than either product singly . The drugs were well tolerated The efficacy and safety of verapamil and propranolol were examined in 14 hypertensive patients ( mean age 51.2 , range 30 to 65 ) in a double-blind , r and omized , crossover study of verapamil , 360 mg , propranolol , 240 mg , these 2 formulations in combination and placebo , each given for 4 weeks . Supine blood pressure , heart rate , atrioventricular conduction ( PR interval ) and left ventricular function were measured . All treatments reduced diastolic blood pressure ( mean + /- st and ard deviation ) ( p less than 0.001 ) : placebo to 106.6 + /- 8.1 mm Hg ; propranolol to 93.8 + /- 7.7 ; verapamil to 89.8 + /- 7.8 ; the combination to 84.1 + /- 6.1 , but the effect of the combination was significantly greater than that of either drug alone ( p less than 0.05 ) . Heart rate at rest ( placebo , 80.2 + /- 12.2 beats/min ) was reduced by propranolol ( 63.3 + /- 9.4 , p less than 0.001 ) , but not by verapamil ( 79.0 + /- 8.9 ) . However , the addition of verapamil to propranolol led to a further reduction in heart rate ( 56.9 + /- 8.4 , p less than 0.005 ) . PR interval was prolonged significantly by the combination ( 185.5 + /- 35.3 ms ) when compared with placebo ( 154.0 + /- 22.7 ) ; propranolol ( 159.1 + /- 21.2 ) and verapamil ( 165.5 + /- 32.4 ) ( p less than 0.005 for each ) . The active drugs increased end-diastolic dimension and end-systolic dimension . For each variable , the effect of the combination was statistically significant ( p less than 0.01 ) . Fractional shortening was not altered significantly by any of the treatments . Thus verapamil plus propranolol is a very effective antihypertensive combination but heart rate , atrioventricular conduction and left ventricular function may be affected adversely , necessitating careful monitoring of therapy This study compared with placebo the efficacy and tolerability of optimised doses of felodipine 5 - 20 mg daily , metoprolol 50 - 200 mg daily and their combination in subjects 60 years or over with isolated systolic hypertension . The study employed a r and omised double-blind crossover design with allocation of treatment order within subjects by Latin squares . For each subject , after a single-blind run-in placebo phase , there were four r and omised treatment phases each of six weeks duration , with a dose titration step at three weeks if necessary . Twenty-eight subjects entered the r and omised phases of the study and twenty-one completed all four phases--13 male , 8 female ( ages : median 71 , range 59 - 85 years ) . At the end of both the felodipine and metoprolol phases systolic and diastolic pressure were reduced at 2 hours postdose compared with the placebo phase ( p < 0.001 ) , the blood pressure reduction with felodipine ( -40/-20 mmHg ) being greater than that with metoprolol ( -15/-9 mmHg ) ( p < 0.01 ) . Immediately predose ( 12 hours postdose ) there was a persisting reduction of supine systolic blood pressure ( -17 mmHg ) with felodipine ( p < 0.001 ) , but there was no significant effect of metoprolol . At both measurement times the two drugs when in combination had an additive effect on blood pressure . There was a 20 % increase in reported symptoms during each of the active treatment phases . Four subjects withdrew during the r and omised phases because of probable drug-related adverse events and six subjects required dosage reductions during the felodipine or combination phases . ( ABSTRACT TRUNCATED AT 250 WORDS The effects of nebivolol , a new beta-blocker with vasodilating properties , and hydrochlorothiazide ( HCTZ ) as monotherapies and in combination on BP and plasma lipids , lipoproteins and apolipoproteins were compared with placebo in a parallel 3 x 4 factorial design study . After an eight week wash-out period , 240 patients with primary hypertension were r and omised to receive either placebo , nebivolol 1 , 5 or 10 mg , HCTZ 12.5 or 25 mg or one of the six possible combinations of nebivolol and HCTZ .  Twenty patients were assigned to each of the 12 parallel groups . After 12 weeks of treatment , there was a significant dose-related reduction in BP among all active treatment groups . Apart from a slight and isolated increase in triglycerides with HCTZ 12.5 mg , lipid , lipoprotein and apolipoprotein levels as well as lipoprotein and apolipoprotein ratios were not significantly modified by 12 week active treatments when compared with placebo treatment . The results of this multifactorial study with 12 small sample size groups , suggest that nebivolol as monotherapy and in combination with HCTZ does not cause deleterious effects on the lipid profile The antihypertensive effect of Inderectic , a new combination capsule of propranolol 80 mg and bendrofluazide 2.5 mg , given twice daily was investigated in 21 hypertensive patients using a double-blind r and omized crossover method . Inderectic was compared with either agent used alone and with the same combination given as separate tablets . It gave a greater fall in mean lying and st and ing systolic and diastolic blood pressure than either agent alone . There was no statistically significant difference for the effect on these variables between the free combination and combined formulation . Only minor side-effects were recorded , no patient having to be withdrawn from the study and no biochemical changes were observed
target: When the blood pressure lowering effect of beta-blockers from this review was compared to that of thiazide diuretics from our previous review ( Chen 2009 ) , second-line beta-blockers reduce systolic BP to the same extent as second-line thiazide diuretics , but reduce diastolic BP to a greater degree .
  The different effect on diastolic BP means that beta-blockers have little or no effect on pulse pressure whereas thiazides cause a significant dose-related decrease in pulse pressure .
  This difference in the pattern of BP lowering with beta-blockers as compared to thiazides might be the explanation for the fact that beta-blockers appear to be less effective at reducing adverse cardiovascular outcomes than thiazide diuretics , particularly in older individuals
background: BACKGROUND Beta-blockers are one of the more commonly prescribed classes of anti-hypertensive drugs , both as first-line and second-line .
  OBJECTIVES To quantify the effect on systolic blood pressure ( SBP ) , diastolic blood pressure ( DBP ) , heart rate and withdrawals due to adverse effects of beta-blocker therapy when given as a second-line drug in adult patients with primary hypertension .