title: Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP). Statistical considerations in monitoring the Systolic Hypertension in the Elderly Program (SHEP). Relation of low body mass to death and stroke in the systolic hypertension in the elderly program. The SHEP Cooperative Research Group. Age, race, and gender variation in the utilization of coronary artery bypass surgery and angioplasty in SHEP. SHEP Cooperative Research Group. Systolic Hypertension in the Elderly Program. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol Coronary heart disease and treatment of hypertension. Some Oslo Study data. The Systolic Hypertension in the Elderly Program (SHEP): an intervention trial on isolated systolic hypertension. SHEP Cooperative Research Group. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients Medical Research Council's Treatment Trial for mild hypertension: an interim report. Comparison of the antihypertensive efficacy and adverse reactions to two doses of bendrofluazide and hydrochlorothiazide and the effect of potassium supplementation on the hypotensive action of bendrofluazide: substudies of the Medical Research Council's trials of treatment of mild hypertension: Med Prevalence of postural hypotension at baseline in the Systolic Hypertension in the Elderly Program (SHEP) cohort. Correlates of blood pressure change in middle-aged male mild hypertensives: results from the untreated control group in the Oslo hypertension trial. The Oslo Study. Oslo Hypertension Study Effect of stepped care treatment on the incidence of myocardial infarction and angina pectoris. 5-Year findings of the hypertension detection and follow-up program. Blinded subjective rankings as a method of assessing treatment effect: a large sample example from the Systolic Hypertension in the Elderly Program (SHEP). Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial Serum lipids and incidence of coronary heart disease. Findings from the Systolic Hypertension in the Elderly Program (SHEP). Correlates of ventricular ectopic activity in isolated systolic hypertension. SHEP Cooperative Research Group. Randomised trial of treatment of hypertension in elderly patients in primary care. Treatment of mild hypertension: a five year controlled drug trial. The Oslo study. Mortality over four years in SHEP participants with a low ankle-arm index. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous? Cardiovascular morbidity and mortality in mild hypertension: the Australian Trial. Results of MRC (UK) trial of drug therapy for mild hypertension. The effect of treatment on mortality in "mild" hypertension: results of the hypertension detection and follow-up program. Change in depression as a precursor of cardiovascular events. SHEP Cooperative Research Group (Systoloc Hypertension in the elderly). Effects of intensive blood-pressure control in type 2 diabetes mellitus. Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP) The need to treat mild hypertension. Misinterpretation of results from the Australian trial. Serum glucose levels during long-term observation of treated and untreated men with mild hypertension. The Oslo study. Evaluation of drug treatment in mild hypertension: VA-NHLBI feasibility trial. Plan and preliminary results of a two-year feasibility trial for a multicenter intervention study to evaluate the benefits versus the disadvantages of treating mild hypertension. Prepared for the Veterans Administration-N The effect of chlorthalidone on ventricular ectopic activity in patients with isolated systolic hypertension. The SHEP Study Group.
abstract: CONTEXT The Systolic Hypertension in the Elderly Program ( SHEP ) demonstrated that treating isolated systolic hypertension in older patients decreased incidence of total stroke , but whether all types of stroke were reduced was not evaluated . OBJECTIVE To investigate antihypertensive drug treatment effects on incidence of stroke by type and subtype , timing of strokes , case-fatality rates , stroke residual effects , and relationship of attained systolic blood pressure to stroke incidence . DESIGN The SHEP study , a r and omized , double-blind , placebo-controlled trial began March 1 , 1985 , and had an average follow-up of 4.5 years . SETTING AND PARTICIPANTS A total of 4736 men and women aged 60 years or older with isolated systolic hypertension at 16 clinical centers in the United States . INTERVENTIONS Patients were r and omly assigned to receive treatment with 12.5 mg/d of chlorthalidone ( step 1 ) ; either 25 mg/d of atenolol or 0.05 mg/d of reserpine ( step 2 ) could be added ( n = 2365 ) ; or placebo ( n = 2371 ) . MAIN OUTCOME MEASURES Occurrence , type and subtype , and timing of first strokes and stroke fatalities ; and change in stroke incidence for participants ( whether in active treatment or placebo groups ) reaching study -specific systolic blood pressure goal ( decrease of at least 20 mm Hg from baseline to below 160 mm Hg ) compared with participants not reaching goal . RESULTS A total of 85 and 132 participants in the active treatment and placebo groups , respectively , had ischemic strokes ( adjusted relative risk [ RR ] , 0.63 ; 95 % confidence interval [ CI ] , 0.48 - 0.82 ) ; 9 and 19 had hemorrhagic strokes ( adjusted RR , 0.46 ; 95 % CI , 0.21 - 1.02 ) ; and 9 and 8 had strokes of unknown type ( adjusted RR , 1.05 ; 95 % CI , 0.40 - 2 . 73 ) , respectively . Four subtypes of ischemic stroke were observed in active treatment and placebo group participants , respectively , as follows : for lacunar , n = 23 and n = 43 ( adjusted RR , 0.53 ; 95 % CI , 0.32 - 0.88 ) ; for embolic , n = 9 and n = 16 ( adjusted RR , 0.56 ; 95 % CI , 0.25 - 1.27 ) ; for atherosclerotic , n = 13 and n = 13 ( adjusted RR , 0 . 99 ; 95 % CI , 0.46 - 2.15 ) ; and for unknown subtype , n = 40 and n = 60 ( adjusted RR , 0.64 ; 95 % CI , 0.43 - 0.96 ) . Treatment effect was observed within 1 year for hemorrhagic strokes but was not seen until the second year for ischemic strokes . Stroke incidence significantly decreased in participants attaining study -specific systolic blood pressure goals . CONCLUSIONS In this study , antihypertensive drug treatment reduced the incidence of both hemorrhagic and ischemic ( including lacunar ) strokes . Reduction in stroke incidence occurred when specific systolic blood pressure goals were attained . JAMA . 2000;284:465 - The Systolic Hypertension in the Elderly Program ( SHEP ) , a r and omized , double-masked , placebo-controlled trial of 4736 persons , was design ed to assess the efficacy of antihypertensive drug treatment to reduce the risk of fatal and nonfatal strokes among people age 60 and over with isolated systolic hypertension . The statistical method used in interim monitoring of results was conditional power ( or stochastic curtailment ) . The findings did not become conclusive until near the completion of the trial , and therefore SHEP was continued to its scheduled closing date . The trial demonstrated a 36 % reduction in the incidence of stroke in the active treatment group ( P = .0003 ) . In addition to evaluating overall efficacy of treatment , the monitoring process considered such other issues as nonstroke outcomes , lag time between first report of stroke and final confirmation of stroke diagnosis , consistency of results across subgroups , and completeness of follow-up . The purpose of this article is to review these factors with primary emphasis on the statistical aspects BACKGROUND There are scant data on the effect of body mass index ( BMI ) ( calculated as weight in kilograms divided by the square of height in meters ) on cardiovascular events and death in older patients with hypertension . OBJECTIVE To determine if low body mass in older patients with hypertension confers an increased risk of death or stroke . PATIENTS Participants were 3975 men and women ( mean age , 71 years ) enrolled in 17 US centers in the Systolic Hypertension in the Elderly Program trial , a r and omized , double-blind , placebo-controlled clinical trial of lowdose antihypertensive therapy  , with follow-up for 5 years . MAIN OUTCOME MEASURES Five-year adjusted mortality and stroke rates from Cox proportional hazards analyses . RESULTS There was no statistically significant relation of death or stroke with BMI in the placebo group ( P = .47 ) , and there was a U- or J-shaped relation in the treatment group . The J-shaped relation of death with BMI in the treated group ( P = .03 ) showed that the lowest probability of death for men was associated with a BMI of 26.0 and for women with a BMI of 29.6 ; the curve was quite flat for women across a wide range of BMI s. For stroke , men and women did not differ , and the BMI nadir for both sexes combined was 29 , with risk increasing steeply at BMI s below 24 . Those in active treatment , however , had lower death and stroke rates compared with those taking placebo . CONCLUSIONS Among older patients with hypertension , a wide range of BMI s was associated with a similar risk of death and stroke ; a low BMI was associated with increased risk . Lean , older patients with hypertension in treatment should be monitored carefully for additional risk factors OBJECTIVE To assess variability in the use of coronary artery bypass grafting ( CABG ) and percutaneous transluminal angioplasty ( PTCA ) in the Systolic Hypertension in the Elderly Program ( SHEP ) cohort with incident coronary heart disease ( CHD ) by age , sex , and race . DESIGN Retrospective analysis of a multicenter prospect i ve cohort study . SETTING Community-based ambulatory population in academic centers . PATIENTS Among 4736 subjects initially enrolled in SHEP , there were 432 incident cases of CHD , excluding those patients who experienced rapid or sudden cardiac death . MAIN OUTCOME MEASURE Incident cases of CHD who underwent CABG or PTCA .  RESULTS Of those participants > or = 60 and < 75 years of age , 7.3 % underwent PTCA , compared with 3.9 % of those > or = 75 years ( P = 0.14 ) . 15.4 % of those < 75 underwent CABG surgery  , compared with 7.8 % of those 75 and older ( P = 0.018 ) . When both of these endpoints , CABG and PTCA , were combined , 22.4 % of those < 75 underwent a procedure , while only 11.7 % of the older cohort did ( P = 0.005 ) . Twenty-six percent of men underwent either CABG or PTCA , while only 9.1 % of women did ( P < 0.001 ) . Of those < 75 years of age , 31.1 % of men and 12.3 % of women underwent CABG or PTCA ( P < 0.001 ) . In the 75 and older age category , 19.5 % of men underwent these interventions , compared with 5.9 % of women ( P = 0.005 ) . Active treatment group was significantly associated with decreased use of procedures in participants < 75 year old with CHD . Race , activity limitations , number of comorbid conditions , education level , marital status , employment status , and social support were not significantly associated with CABG or PTCA use . When the variables studied were entered into a logistic regression model , increased age and female sex remained independently associated with decreased  CABG and PTCA use . CONCLUSION In the SHEP trial older patients and women , regardless of comorbid conditions , socioeconomic status , and social support , underwent less intensive cardiovascular interventions than did younger patients and men when they developed CHD BACKGROUND Blood pressure reduction achieved with beta-blockers and diuretics is the best recorded intervention to date for prevention of cardiovascular morbidity and death in patients with hypertension . Left ventricular hypertrophy ( LVH ) is a strong independent indicator of risk of cardiovascular morbidity and death . We aim ed to establish whether selective blocking of angiotensin II improves LVH beyond reducing blood pressure and , consequently , reduces cardiovascular morbidity and death . METHODS We did a double-masked , r and omised , parallel-group trial in 9193 participants aged 55 - 80 years with essential hypertension ( sitting blood pressure 160 - 200/95 - 115 mm Hg ) and LVH ascertained by electrocardiography ( ECG ) . We assigned participants once daily losartan-based or atenolol-based antihypertensive treatment for at least 4 years and until 1040 patients had a primary cardiovascular event ( death , myocardial infa rct ion , or stroke ) . We used Cox regression analysis to compare regimens . FINDINGS Blood pressure fell by 30.2/16.6 ( SD 18.5/10.1 ) and 29.1/16.8 mm Hg ( 19.2/10.1 ) in the losartan and atenolol groups , respectively . The primary composite endpoint occurred in 508 losartan ( 23.8 per 1000 patient-years ) and 588 atenolol patients ( 27.9 per 1000 patient-years ; relative risk 0.87 , 95 % CI 0.77 - 0.98 , p=0.021 ) . 204 losartan and 234 atenolol patients died from cardiovascular disease ( 0.89 , 0.73 - 1.07 , p=0.206 ) ; 232 and 309 , respectively , had fatal or non-fatal stroke ( 0.75 , 0.63 - 0.89 , p=0.001 ) ; and myocardial infa rct ion ( non-fatal and fatal ) occurred in 198 and 188 , respectively ( 1.07 , 0.88 - 1.31 , p=0.491 ) . New-onset diabetes was less frequent with losartan . Interpretation Losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure and is better tolerated . Losartan seems to confer benefits beyond reduction in blood pressure The Oslo Hypertension Study began in 1972 ; patients were followed for an average of 66 months ( range : 60 to 78 ) . A total of 785 healthy men , aged 40 to 49 , with mild hypertension was r and omly assigned to either a drug-treated group or to an untreated control group . Hydrochlorothiazide was used alone in 36 percent of patients , in combination with propranolol in 26 percent , and with methyldopa in 20 percent . Other drugs , including combinations with hydrochlorothiazide , were used in 18 percent . A total of 95 percent of patients in the drug-treated group received hydrochlorothiazide .  Complications of hypertension such as stroke and aneurysm occurred only in the control group . Coronary events were more numerous in the drug-treated group ; thus , the total incidence of cardiovascular complications did not significantly differ between the treated and untreated groups . After five and 10 years , total mortality was the same in both groups . However , the coronary heart disease mortality rate at 10 years was significantly greater in the drug-treated group than in the untreated control group ( 14 versus three , p less than 0.01 ) . This article presents possible reasons for the failure of antihypertensive drug therapy to prevent coronary heart disease . The adverse effect of diuretics and beta-adrenergic blockers , both on lipid and carbohydrate metabolism , is contrasted with the effect of the alpha-adrenergic blocker prazosin , which has been shown to have no adverse effect on the blood lipid profile . In a short-term trial that was part of the Oslo Study , prazosin was found to reduce total serum cholesterol by 9 percent , low-density lipoprotein and very-low-density lipoprotein cholesterol by 10 percent , and total triglycerides by 16 percent . All these changes are statistically significant The Systolic Hypertension in the Elderly Program ( SHEP ) is a r and omized double-blind placebo-controlled trial to determine if antihypertensive treatment of isolated systolic hypertension ( ISH ) [ systolic blood pressure ( SBP ) greater than or equal to 160 mmHg , diastolic blood pressure ( DBP ) less than 90 mmHg ] reduces the 5 year incidence of fatal and nonfatal stroke . Between March 1 , 1985 and January 15 , 1988 , 4736 persons ( target 4800 ) with ISH , age 60 years and over , were enrolled . Potential participants met blood pressure ( BP ) and age criteria . Those on antihypertensive medication prior to enrollment without documented diastolic hypertension had their medication tapered and discontinued , and then met BP criteria ( 33 % of cohort ) . Stepped-care therapy with chlorthalidone and atenolol ( alternative , reserpine ) or matching placebos was initiated as first and second steps . At baseline the trial population was 43.1 % male , 56.9 % female ; 13.9 % black , 86.1 % non-black . Also , the mean age was 71.6 years ; the mean SBP was 170.3 mmHg and the mean DBP was 76.6 mmHg ; 59.8 % had codeable resting electrocardiographic abnormalities .  The trial is now in follow-up phase with scheduled termination in 1991 Objective To compare the incidence of stroke and other cardiovascular events in hypertensive patients receiving a low-dose diuretic and low-dose calcium antagonist combination with those receiving low-dose diuretic monotherapy  , and assess the effects of a small blood pressure difference at achieved levels lower than those achieved in previous placebo-controlled trials . Methods The Felodipine Event Reduction ( FEVER ) trial was an investigator- design ed , prospect i ve , multicentre , double-blind , r and omized , placebo-controlled , parallel group trial . It enrolled 9800 Chinese patients , of either sex , aged 50–79 years , with one or two additional cardiovascular risk factors or disease , whose blood pressure , 6 weeks after switching from previous antihypertensive therapy to low-dose ( 12.5 mg a day ) hydrochlorothiazide , was in the range 140–180 mmHg ( systolic ) or 90–100 mmHg ( diastolic ) . These patients were r and omly assigned either to low-dose felodipine extended release or placebo , and followed at 3-month intervals for an average of 40 months . Results The intention-to-treat analysis included 9711 r and omly selected patients with only 30 ( 0.3 % ) lost to follow-up . A total of 31 842 patient-years of follow-up were accumulated , with 85.9 % of patients remaining on blinded r and omized treatment . Add-on therapy was given to 33.9 % of the hydrochlorothiazide – felodipine patients and to 42.3 % of the hydrochlorothiazide – placebo patients . In the felodipine  group , systolic blood pressure (SBP)/diastolic blood pressure ( DBP ) decreased ( from r and omization to study end ) from 154.2/91.0 to 137.3/82.5 mmHg , and in the placebo group from 154.4/91.3 to 142.5/85.0 mmHg , with an average difference throughout the trial of 4.2/2.1 mmHg . In the felodipine group , the primary endpoint ( fatal and non-fatal stroke ) was reduced by 27 % ( P = 0.001 ) . Among secondary endpoints , all cardiovascular events were reduced by 27 % ( P < 0.001 ) , all cardiac events by 35 % ( P = 0.012 ) , death by any cause by 31 % ( P = 0.006 ) , coronary events by 32 % ( P = 0.024 ) , heart failure by 30 % ( P = 0.239 ) , cardiovascular death by 33 % ( P = 0.019 ) , cancer by 36 % ( P = 0.017 ) in the felodipine group . No significant differences were found in new-onset diabetes . Both treatments were very well tolerated . Conclusions In moderately complicated hypertensive patients from China even a difference in SBP/DBP as small as 4/2 mmHg , such as that induced by adding low-dose felodipine to low-dose hydrochlorothiazide , is associated with very substantial reductions in the incidence of most types of cardiovascular events . As the SBP achieved in the felodipine group was below the recommended goal of less than 140 mmHg , and SBP in the placebo group was slightly above that level , FEVER provides the required evidence in support of the guidelines recommended goal , even for a hypertensive population not entirely consisting of patients with diabetes or previous cardiovascular events The pilot phase of the British multicentre r and omized controlled trial of treatment for mild hypertension has shown : ( 1 ) that unselected subjects , aged 35 - 64 years , with mild hypertension are willing to enter and remain in a long-term trial even though asymptomatic ; ( 2 ) that the differences of mean systolic and mean diastolic pressure achieved between treated and control subjects is sufficient to produce the expected difference in terminating events with the 18000 patients calculated as needed for the full-scale trial ; ( 3 ) that side effects with the two selected active primary regimens ( bendrofluazide and propranolol ) are common but mild ( no serious side effects or toxic reactions have been reported ) ; ( 4 ) that the work load imposed by the trial , though considerable during screening and the initiation of patients into the trial , can largely be taken by specially trained nursing staff , and when screening is completed the trial does not impose a heavy burden of follow-up examinations ; ( 5 ) that there are no adverse psychological effects caused by alerting asymptomatic people to their raised pressure and enrolling them into a prolonged programme of clinical attendance ; ( 6 ) that the total costs of carrying out a full-scale trial -- estimated at about lb.2 m ( $ U.S. 4m)--are commensurate with the potential annual savings in health service expenditure whether the trial shows treatment to be effective or unwarranted As sub studies of the Medical Research Council 's trials of treatment of mild hypertension and of hypertension in the elderly , two studies were carried out comparing the effects of different doses of two diuretics on blood pressure , concentrations of some biochemical variables , and the incidence of subjective adverse reactions . In one study , in which 484 patients with mild hypertension participated , daily doses of bendrofluazide 5 mg and 10 mg , with and without oral potassium supplements , were compared . In the second , involving 701 elderly patients with hypertension , daily doses of hydrochlorothiazide 25 mg together with amiloride 2.5 mg were compared with hydrochlorothiazide 50 mg together with amiloride 5 mg . The mean ( + /- SD ) duration s of treatment were 35 + /- 17 months in the first study and 10 + /- 7 months in the second . Neither study showed any significant difference in blood pressure response to the two doses of diuretic , whereas biochemical changes and the reported incidence of subjective adverse reactions were dose-related . In the first study , potassium supplementation with potassium chloride 16.8 or 33.6 mmol did not have a significant effect on the fall in serum potassium level , which was only slightly reduced , and did not have any significant effect on the antihypertensive effect of either dose of bendrofluazide OBJECTIVE The objective of this study was to examine the prevalence and correlates of postural hypotension ( defined as a drop in systolic blood pressure of greater than or equal to 20 mm Hg ) in a cohort of elderly persons with isolated systolic hypertension ( ISH ) . DESIGN Baseline cross-sectional analysis of the 4,736 persons r and omized in the Systolic Hypertension in the Elderly Program ( SHEP ) . SETTING A r and omized multi-center double-blind outpatient clinical trial of the impact of treating ISH . PARTICIPANTS Men and women age greater than or equal to 60 years with the systolic blood pressure ( SBP ) greater than or equal to 160 mm Hg and diastolic blood pressure ( DBP ) less than 90 mm Hg . MEASURES Medical histories were obtained using interviewer-administered , st and ardized clinical history forms . At entry into the study ,  seated and st and ing BP was measured by certified BP technicians using a r and om zero sphygmomanometer . Postural hypotension ( PH ) was assessed at 1 and 3 minutes after the participant arose from a seated position . MAIN RESULTS PH was found in 10.4 % of participants at 1 minute and in 12.0 % of participants at 3 minutes . 5.3 % of participants demonstrated PH at both time intervals while 17.3 % demonstrated PH at either or both of the time intervals . Factors significantly ( P less than 0.05 ) associated with the presence of PH were higher mean SBP and a lower mean body mass index . CONCLUSIONS Somewhat different persons were defined as having PH based upon the 1 minute and 3 minute st and ing measures of BP , and prevalence estimates of PH can vary depending on whether one or more intervals of measurement are used . Cross-sectional data analysis indicated that PH , in healthy community-dwelling older persons with ISH , may not be associated with a history of disorders or problems usually thought to be related to PH . However , prospect i ve data are needed to determine the prognostic significance of PH , and whether one or multiple measurements carry more significance The  never-treated control group  in the Oslo Study hypertension trial of middle-aged men 40 - 49 years old at entry ( n = 379 ) was studied with respect to five-year change in blood pressure and its correlates . The study began in 1972 and ended in 1979 , and each patient was followed for five years . Both baseline and rate of change of correlates were analyzed as independent variables versus rate of change in blood pressure as the dependent variable . Rate of change in serum triglycerides were found to be the strongest correlate of rate of change in blood pressure in this population of healthy mild hypertensives . In addition , rate of change in serum cholesterol and body weight made significant contributions in some analyses , but to a lower degree than did rate of change in triglycerides . The model predicts a substantial decrease in blood pressure if lipids and body weight are reduced . Rate of change in sodium , uric acid , and chloride concentrations were also associated with blood pressure change , but total degree of explanation of all explaining variables only accounted for 11 - 15 % of total variation in annual blood pressure change Summary The Oslo Hypertension Study started in 1972 and lasted for 66 ( range 60–78 ) months . A total of 785 healthy men , aged 40 to 49 years , with mild hypertension were r and omised to a drug-treated group and to an untreated , control group . The drugs used for treatment were hydrochlorothiazide alone in 36 % , hydrochlorothiazide and propranolol in 26 % , hydrochlorothiazide and methyldopa in 20 % , and other drugs in 18%.A total of 95 % in the drug-treated group received hydrochlorothiazide . Pressure complications , such as stroke and aneurysms , only occurred in the control group . Coronary events were more numerous in the drug-treated group , so that the total incidence of cardiovascular complications did not significantly differ between the treated and untreated groups . After 5 and 10 years , total mortality was found to be the same in both groups . However , the 10-year coronary heart disease mortality was significantly higher in the drug-treated group than in the untreated controls ( 14 vs 3 , p < 0.01 ) . Possible reasons for the failing effect of drug treatment of hypertension on coronary heart disease is discussed , and attention is drawn to the adverse effect of diuretics and β-adrenergic blockers , both on lipid and carbohydrate metabolism . This is in contrast to the α-adrenergic blocker , prazosin , which has been shown to improve the blood lipid profile Information on indices of coronary heart disease ( CHD ) and myocardial infa rct ion ( MI ) ( angina pectoris by Rose Question naire , MI by Rose Question naire , history , and electrocardiogram ) was obtained in the Hypertension Detection and Follow-Up Program ( U.S. National Institutes of Health ) at baseline , Year 2 , and Year 5 of follow-up . The presence of any of these findings at baseline markedly increased all-cause mortality during the 5 years of observation . In individuals with negative findings at baseline , the 5-year incidence of MI and angina pectoris by these indices was less in the Stepped Care than Referred Care cohort . These results are compatible with the conclusion that antihypertensive therapy reduces the incidence of symptomatic CHD Because many r and omized clinical trials study more than one important outcome variable , evaluation of efficacy is often difficult and not completely satisfactory . This paper considers the use of a procedure for endpoint determination described by Follmann et al. , that allows raters to integrate subjectively all relevant information about an individual 's clinical course into a single univariate assessment . To explore the method 's feasibility , we tested the procedure with data from a completed clinical trial , the Systolic Hypertension in the Elderly Program ( SHEP ) . We provided raters blinded to treatment assignment with cards that schematically represent the clinical trajectories of SHEP study participants . The raters independently ranked these trajectories . The method combined ranks across raters to determine a single rank for each study participant ; we used a rank procedure to test treatment effect . The major findings were : ( i ) the raters showed a high level of concordance of rankings ; ( ii ) tests of treatment effect were highly statistically significant ; ( iii ) three statistical methods were effective for implementing the ranking in the large study size case . These methods were use of : ( a ) scoring rules ; ( b ) incomplete block design s , and ( c ) categorical ranking 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 BACKGROUND The association of serum lipids with coronary heart disease has been studied extensively in middle-aged men and , to a lesser extent , in similar women . Less well defined are lipid variables predictive of CHD in individuals of age > or = 60 years . METHODS AND RESULTS The  Systolic Hypertension in the Elderly Program recruited 4736 persons ( mean age , 72 years ; 14 % were black ; and 43 % were men ) . Mean systolic and diastolic blood pressures were 170 and 77 mm Hg , respectively . Baseline mean total cholesterol was 6.11 mmol/L ( 236 mg/dL ) ; HDL cholesterol , 1.39 mmol/L ( 54 mg/dL ) ; and non-HDL cholesterol , 4.72 mmol/L ( 182 mg/dL ) . Triglyceride levels  were 1.62 mmol/L ( 144 mg/dL ) for fasting participants and 1.78 mmol/L for the total group . LDL cholesterol , estimated in fasting sample s with triglycerides of < 4.52 mmol/L , averaged 3.98 mmol/L ( 154 mg/dL ) . Mean follow-up was 4.5 years . In multivariate Cox regression analyses , baseline total , non-HDL , and LDL cholesterol levels and the ratios of total , non-HDL , and LDL to HDL cholesterol were significantly related to CHD incidence . HDL cholesterol and triglycerides were not significant in these analyses . In fasting participants with triglyceride levels of < 4.52 mmol/L , a 1.03 mmol/L ( 40 mg/dL ) higher baseline total , non-HDL , or LDL cholesterol was associated with a 30 % to 35 % higher CHD event rate . CONCLUSIONS The results of this study support the concept that serum lipids are CHD risk factors in older Americans Ventricular ectopic activity was recorded at baseline in 5.6 % of the 12-lead electrocardiograms and 8.2 % of the 2-minute rhythm strips of 4674 subjects with isolated systolic hypertension ( systolic blood pressure 160 to 219 mm Hg , diastolic blood pressure < 90 mm Hg ) participating in the Systolic Hypertension in the Elderly Program ( SHEP ) . In this study 1.3 % had 6 to 10 ventricular premature beats ( VPB ) , and 0.7 % had > 10 VPB on the 2-minute rhythm strip . Correlates of VPB presence on the 12-lead ECG were older-age male sex , presence of Q/QS pattern and higher heart rate . Participants with serum potassium < 3.5 mmol/L had a higher prevalence of VPB . Similarly , the number of VPB on the 2-minute rhythm strip was associated with male sex , increasing age , with lower serum potassium , history of palpitations , and presence of Q/QS patterns A r and omised trial of the treatment of hypertension in 884 patients aged 60 to 79 years at the onset showed a reduction of 18/11 mm Hg in blood pressure over a mean follow up period of 4.4 years . The principal antihypertensive agents were atenolol and bendrofluazide . There was a reduction in the rate of fatal stroke in the treatment group to 30 % of that in the control group ( 95 % confidence interval 11 - 84 % , p less than 0.025 ) . The rate of all strokes ( fatal and non-fatal ) in the treatment group was 58 % of that in the control group ( 95 % confidence interval 35 - 96 % , p less than 0.03 ) . The incidence of myocardial infa rct ion and total mortality was unaffected by treatment . Question naires completed by the patients and their relatives failed to identify any differences in symptoms that were likely to be due to treatment In 1972 - -1973 , 785 symptom-free men , aged 40 to 49 years , without target organ damage , with systolic blood pressures between 150 and 179 mm Hg and diastolic blood pressure below 110 mm Hg , were assigned at r and om to one of two groups : ( 406 to a drug treatment group and 379 to a control group ) for a five-year controlled drug treatment trial to evaluate the effect of therapy on cardiovascular complications . Drug treatment started with hydrochlorothiazide . If systolic blood pressure remained above 140 mm Hg and /or diastolic blood pressure above 90 mm Hg , alphamethyldopa was added . If there were side effects , methyldopa was replaced with propranolol . The control group was not given a placebo . The mean observation time was 66 months ( range 60 to 78 months ) . A difference in blood pressure between groups of about 17 mm Hg systolic and 10 mm Hg diastolic was maintained throughout the study . The study protocol had a rather low " ethical " blood pressure roof , 180 mm Hg systolic and /or 110 mm Hg diastolic . Seventeen percent of the control group had an increase in blood pressure above this level during the trial , and drug treatment was started . There was no effect on major cardiovascular morbidity comparing groups as established by r and omization , with 18 events in the treatment group and 20 events in the control group . There was no difference between the groups in total mortality and mortality from cardiovascular events . However , in the subgroups with diastolic blood pressure greater than or equal to 100 mm Hg before r and omization , there was a probable reduction in total morbidity from cardiovascular events in favor or the group receiving drug therapy , 7.6 and 16.4 percent events in the treated and control groups , respectively . Cerebrovascular events occurred only in the control group , 7 versus 0 . Two cases of fatal aortic aneurysms also occurred in the control group . Other " pressure " complications , such as marked left ventricular hypertrophy in the electrocardiogram and left ventricular failure , occurred only in the control group . However , regarding coronary heart disease , including sudden death , the incidence tended to be higher in the treated group , although it was not statistically significant . Only 13 men ( 1.7 percent ) failed to meet for regular examinations . At the end of the study these men were also followed up with regard to possible cardiovascular events OBJECTIVES To assess the risk of total and cardiovascular mortality in older adults with systolic hypertension and with a low ankle-arm index ( AAI ) as a marker of sub clinical peripheral arterial disease ( PAD ) . DESIGN Prospect i ve observational study PARTICIPANTS A subgroup of 1537 participants in the Systolic Hypertension in the Elderly Program ( SHEP ) were screened for lower extremity arterial disease using the AAI . Participants were evaluated at 4 years to determine vital status and cause of death . Total and cardiovascular disease ( CVD ) mortality rates were assessed in relationship to clinical CVD at baseline , cardiovascular risk factors and the presence of a low AAI ( sub clinical PAD ) . RESULTS Total mortality rates increased as the AAI decreased in those with and without clinical CVD at baseline . In those without clinical CVD at baseline , the presence of an AAI < or = .9 was associated with an age-adjusted relative risk ( RR ) of 3.00 for total mortality in men and 2.67 in women . Results were similar for CVD mortality and persisted after adjustment for cardiovascular risk factors including the presence of an abnormal electrocardiogram . CONCLUSIONS A low ankle arm-index predicted a two to three-fold increase in total and cardiovascular mortality in older adults with systolic hypertension of risk for incident cardiovascular disease . In this study of older adults with systolic hypertension , 19.7 % of the participants had sub clinical PAD . Risk factor modification could be targeted to older adults based on markers of asymptomatic atherosclerosis BACKGROUND The optimal combination drug therapy for hypertension is not established , although current U.S. guidelines recommend inclusion of a diuretic . We hypothesized that treatment with the combination of an angiotensin-converting-enzyme ( ACE ) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic . METHODS In a r and omized , double-blind trial , we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide . The primary end point was the composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , hospitalization for angina , resuscitation after sudden cardiac arrest , and coronary revascularization . RESULTS The baseline characteristics of the two groups were similar . The trial was terminated early after a mean follow-up of 36 months , when the boundary of the prespecified stopping rule was exceeded . Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-hydrochlorothiazide group . There were 552 primary - outcome events in the benazepril-amlodipine group ( 9.6 % ) and 679 in the benazepril-hydrochlorothiazide group ( 11.8 % ) , representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2 % and a relative risk reduction of 19.6 % ( hazard ratio , 0.80 , 95 % confidence interval [ CI ] , 0.72 to 0.90 ; P<0.001 ) . For the secondary end point of death from cardiovascular causes , nonfatal myocardial infa rct ion , and nonfatal stroke , the hazard ratio was 0.79 ( 95 % CI , 0.67 to 0.92 ; P=0.002 ) . Rates of adverse events were consistent with those observed from clinical experience with the study drugs . CONCLUSIONS The benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events . ( Clinical Trials.gov number , NCT00170950 . Context Experts debate the consequences of excessive lowering of diastolic pressure in patients with hypertension and coronary artery disease . Contribution This report is a secondary analysis of data from a large trial of 2 antihypertensive drug regimens in patients with known coronary artery disease . The authors found a J-shaped relationship between diastolic blood pressure and all-cause death and myocardial infa rct ion , with the increased risk occurring at diastolic blood pressures below 70 to 80 mm Hg , that is , the lower the diastolic pressure , the higher the risk . Caution s The study examined associations between blood pressure and outcomes ; it could not prove that the antihypertensive therapy that lowered diastolic pressure too much caused the adverse outcomes . The Editors For 2 decades , the hypertension literature has been haunted by the phenomenon of a paradoxical increase in morbidity and mortality with an excessive decrease in blood pressure ( J-curve ) . Indeed , several reports have shown that low diastolic pressure is associated with an increased risk for coronary heart disease and related mortality in older adults and in patients taking antihypertensive medications ( 1 - 13 ) . After doing a review and meta- analysis of pertinent studies , Farnett and colleagues ( 14 ) concluded that although there was no consistent J-shaped relationship between stroke and systolic or diastolic pressure , there was a consistent J-shaped relationship for cardiac events and diastolic pressure . These authors stated that this dichotomy in the relationship between diastolic pressure and target organ disease may leave a clinician with the uncomfortable choice of whether to prevent stroke or renal disease at the expense of coronary heart disease . These findings were at variance with the generally accepted dogma formulated by the sixth report of the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure ( JNC VI ) ( 15 ) , which stated that the relationship between pressure and risk was strong , continuous , independent , predictive and etiologically significant . Within the past decade , the phenomenon of a J-curve has been studied in several large trials of normotensive and hypertensive patients ( 16 - 30 ) . Not surprisingly , arguments regarding whether a J-curve could be clinical ly significant have become somewhat contentious . That is , some rely on evidence that on-treatment diastolic pressure below 70 mm Hg does not increase risk for cardiovascular disease and thus deny an impairment of vital organ perfusion within the usual values achievable by antihypertensive treatment . Others , however , consider the J-curve a more real possibility , particularly for the heart . In contrast to other organs , the heart is perfused mostly during diastole and thus could be more vulnerable to diastolic pressure reduction . If a J-curve did exist , it should be most evident in patients with limited coronary perfusion , in other words , in those with manifest coronary artery disease ( CAD ) . Optimal blood pressure in patients with hypertension and CAD remains controversial because few r and omized clinical trials have been done in this population ( 31 , 32 ) . The International Verapamil-Tr and olapril Study ( INVEST ) ( 33 ) , a r and omized trial , evaluated more than 22000 patients with CAD and hypertension . This patient profile , together with unprecedented levels of blood pressure control , provided a unique opportunity to critically investigate the hypothesis that the risk for CAD would increase with an excessive decrease in diastolic pressure . Methods Study Design and Intervention The INVEST design , methods , and principal results have been previously published ( 33 ) . The trial used an open design with blinded end point assessment . In brief , clinical ly stable patients with CAD and hypertension were r and omly assigned to a verapamil sustained-releasebased or atenolol-based strategy .  Patients with previous myocardial infa rct ion ( MI ) within 3 months of enrollment or class IV or V congestive heart failure were excluded .  Blood pressure goals were based on JNC VI ( systolic pressure < 140 mm Hg and diastolic pressure < 90 mm Hg or systolic pressure < 130 mm Hg and diastolic pressure < 85 mm Hg in patients with diabetes or renal impairment ) ( 15 ) . The addition of tr and olapril or hydrochlorothiazide was recommended when necessary to achieve blood pressure goals . Tr and olapril was also recommended for patients with heart failure , diabetes , or renal impairment . Documented CAD was defined as any of the following : remote ( 3 months before enrollment ) confirmed MI , coronary angiography showing more than 50 % narrowing of at least 1 major coronary artery , diagnosis of classic angina pectoris , or concordant abnormalities on 2 different signals ( electrocardiography , echocardiography , or radionuclide scans ) from stress test findings concordant for ischemia ( for example , ST-segment depression or perfusion defects on radionuclide scanning or wall-motion abnormalities on echocardiography or radionuclide scanning ) . Patient Monitoring and Follow-up Protocol visits were scheduled every 6 weeks for the first 6 months and then biannually until 2 years after the last patient was enrolled . Patients were assessed for response to treatment , symptoms , treatment adherence , and adverse effects at each visit and at the end of the study as detailed elsewhere ( 33 ) . Patient follow-up was complete when we received a final assessment form through the online data system or a death report . The Internet-based electronic data collection method used in INVEST did not accept the entry until all required fields were complete . Blood pressure  was measured by using a st and ard mercury sphygmomanometer with an appropriately sized cuff applied to the upper nondominant arm at heart level . By auscultation at the brachial artery , systolic pressure was recorded at the first Korotkoff sound and diastolic pressure was recorded at the disappearance of the fifth Korotkoff sound . Blood pressure was measured twice , at least 2 minutes apart , and the measurements were averaged . Study Outcomes The primary outcome was the first occurrence of all-cause death , nonfatal MI , or nonfatal stroke by intention-to-treat analysis . The MI and stroke definitions are detailed elsewhere ( 34 ) . These 3 components individually were the main secondary outcomes . For this analysis , additional outcomes included fatal and nonfatal MI , fatal and nonfatal stroke , and average on-treatment blood pressure before outcome or censoring . Ascertainment and blinded adjudication of outcomes were described previously ( 32 ) . Follow-up data were available for 22008 ( 97.5 % ) patients . Statistical Analysis The main conclusions of INVEST were that the 2 treatment strategies were equivalent with respect to the primary outcome , main secondary outcomes , and on-treatment systolic and diastolic pressures . Thus , data for all enrolled patients were combined and included in these analyses following the intention-to-treat principle . A P value of 0.05 or less was considered statistically significant . Patients without a primary outcome event were censored at their latest follow-up visit . Average follow-up systolic and diastolic pressures were calculated for each patient by using all post-baseline results , up to the date of primary outcome or censoring . The baseline value was substituted for patients with no post-baseline data ( n= 1154 ) . In this exploratory analysis , the proportions of patients were pooled by 10 mm Hg strata of average follow-up systolic pressure , and the distribution of primary outcome event rate was evaluated to determine whether the relationship was linear . A similar presentation was prepared for diastolic pressure . Because the frequency distributions seemed consistent with a quadratic curve , a quadratic Cox proportional hazards model was formed for the time to primary outcome for each blood pressure variable , with factors for blood pressure and blood pressure squared . Similarly , the relationship between each 10 mm Hg stratum of average systolic pressure and diastolic pressure and all-cause death , fatal and nonfatal MI , and fatal and nonfatal stroke was evaluated . For the time to primary outcome , a second model was fitted , adjusting for the following baseline covariates : age ( 10-year increments ) , sex , race and ethnicity ( white , Asian , black , Hispanic , multiracial , or other ) , previous MI , heart failure ( classes I to III ) , body mass index in increments of 5 kg/m2 , U.S. residency , renal impairment , peripheral vascular disease , left ventricular hypertrophy , smoking history , coronary revascularization , dyslipidemia , stroke or transient ischemic attack , angina pectoris , arrhythmia , diabetes , cancer , aspirin use , and average systolic pressure or diastolic pressure and systolic pressure squared or diastolic pressure squared . To identify clinical ly relevant interactions between the J-shaped curve and baseline diastolic pressure , demographic characteristics , and comorbid conditions for the primary outcome , a 2-step procedure was used . First , baseline covariates were tested individually by adding the variable and 2 interaction terms ( variablediastolic pressure and variable[diastolic pressure squared ] ) to the Cox proportional hazards model . Variables included were age older than 70 years , sex , previous MI , heart failure ( classes I to III ) , previous stroke or transient ischemic attack , diabetes , cancer , renal impairment , hypercholesterolemia , peripheral vascular disease , smoking history , U.S. residency , body mass index greater than 29 kg/m2 ( mean baseline body mass index ) , and diastolic pressure greater than 86 mm Hg ( mean baseline diastolic pressure ) . The change in log likelihood was used to assess the significance of simultaneously adding the 2 interaction terms . The second step in identifying clinical ly relevant interactions between the J-shaped curve and baseline covariates was to plot the hazard ratios for the primary outcome versus diastolic pressure in the The Australian Therapeutic Trial in Mild Hypertension was a controlled trial in which mildly hypertensive patients , aged between 35 and 65 years ( diastolic blood pressure 95 - 109 ) were r and omly assigned to take antihypertensive drugs or matched placebos  for periods of up to 6 years . The overall data showed that the treated group had a lower incidence of both death and of nonfatal cardiovascular events . The differences in the incidence of noncardiovascular deaths did not differ significantly between the two groups . Univariate analysis of possible prognostic factors at the time of entry into the study showed a higher incidence of trial endpoints -- mostly events due to ischemic heart disease and cerebrovascular disease -- in older subjects , men , cigarette smokers and those with higher systolic blood pressures , and in thinner subjects than in others . There was a lower incidence of these events in actively treated persons than in control subjects at each level of incidence of each covariate measured . Treatment benefit was greatest in persons with lower systolic blood pressures and lower serum cholesterol levels . Multivariate regression analyses confirmed that the incidence of trial endpoints increased with age and with systolic blood pressures . There was a higher incidence in smokers than in nonsmokers , especially in those with low body weights . Treatment benefited thin smokers most , and the effects of treatment seemed to be reduced in those with higher serum cholesterol levels . There was a substantial fall in blood pressure in many of the placebo group The main aim of the trial was to determine whether drug treatment of mild hypertension ( phase V diastolic pressure 90 - 109 mm Hg ) reduced the rates of stroke , of death due to hypertension , and of coronary events , in men and women aged 35 - 64 years . A total of 17,354 patients was recruited , and 85,572 patient-years of observation accrued . Patients were r and omly allocated at entry to take bendrofluazide or placebo , or propranolol or placebo . The stroke rate was reduced with treatment ( 60 strokes , vs 109 in the placebo groups ) , being 1.4 and 2.6 per 1,000 patient-years of observation , respectively ( p less than 0.01 ) , but overall rates of coronary events were not different ( 222 with treatment and 234 with placebos ) . The incidence of all cardiovascular events was reduced with treatment ( 286 events , vs 352 with placebos ; p less than 0.05 ) . For rates of mortality from all causes , treatment made no difference . Several post hoc analyses of subgroup results were performed . The all-cause mortality was reduced in men on treatment ( 157 deaths , vs 181 in placebo groups ) but increased in women on treatment ( 91 deaths , vs 72 with placebos ) ; this difference between the sexes was significant ( p = 0.05 ) . The reduction in stroke rate was greater with bendrofluazide than with propranolol ( p = 0.002 ) . The rate of strokes was reduced in both smokers and non-smokers taking bendrofluazide , but only in non-smokers taking propranolol ; this difference between the drugs was significant ( p = 0.03 ) . The coronary-event rate was not reduced by bendrofluazide , whatever the smoking habit , nor in smokers taking propranolol , but it was reduced in non-smokers taking propranolol . ( ABSTRACT TRUNCATED AT 250 WORDS In the Hypertension Detection and Follow-up Program , 7825 ( 71.5 per cent ) of the 10,940 participants had diastolic blood pressures averaging between 90 and 104 mm Hg on entry into the study and were design ated Stratum 1 . Half were referred to their usual source of care in the community ( the referred-care group ) , and half were treated intensively in special clinics ( the stepped-care group ) . Five-year mortality in the Stratum 1 patients given stepped care was 20.3 per cent lower than in those given referred care ( P less than 0.01 ) . Particularly noteworthy was the beneficial effect of stepped-care treatment on persons with diastolic pressures of 90 to 104 mm Hg who had no evidence of end-organ damage and were not receiving antihypertensive medication when they entered the study . This subgroup had 28.6 per cent fewer deaths at five years among those treated with stepped care than among those treated with referred care ( P less than 0.01 ) . These findings support a recommendation that in patients with mild hypertension , treatment should be considered early , before damage to end organs occurs OBJECTIVE To determine the relationship between increasing depressive symptoms and  cardiovascular events or mortality . DESIGN Cohort analytic study of data from r and omized  placebo-controlled  double-blind clinical trial of antihypertensive therapy . Depressive symptoms were assessed semi-annually with the Center for Epidemiological Studies -Depression ( CES-D ) scale during an average follow-up of 4.5 years . SETTING Ambulatory patients in 16 clinical centers of the Systolic Hypertension in the Elderly Program . PATIENTS Generally healthy men and women aged 60 years or older r and omized to active antihypertensive drug therapy or placebo who were 70 % white and 53 % women and had follow-up CES-D scores and no outcome events during the first 6 months ( N=4367 ) . MAIN OUTCOME MEASURES All-cause mortality , fatal or nonfatal stroke , or myocardial infa rct ion . RESULTS Baseline depressive symptoms were not related to subsequent events ; however , an increase in depression was prognostic . Cox proportional hazards regression analyses with the CES-D scale as a time-dependent variable , controlling for multiple covariates , indicated a 25 % increased risk of death per 5-unit increase in the CES-D score ( relative risk [ RR ] , 1.25;95 % confidence interval [ CI ] , 1.15 to 1.36 ) . The RR for stroke or myocardial infa rct ion was 1.18(95%CI,1.08 to 1.30 ) . Increase in CES-D score was an independent predictor in both placebo and active drug groups , and it was strongest as a risk factor for stroke among women ( RR,1.29;95%CI,1.07 to 1.34 ) . CONCLUSIONS Among elderly persons , a significant and substantial excess risk of death and stroke or myocardial infa rct ion was associated with an increase in depressive symptoms over time , which may be a marker for subsequent major disease events and warrants the attention of physicians to such mood changes . However , further studies of casual pathways are needed before wide-spread screening for depression in clinical practice is to be recommended BACKGROUND There is no evidence from r and omized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus . We investigated whether therapy targeting normal systolic pressure ( i.e. , < 120 mm Hg ) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events . METHODS A total of 4733 participants with type 2 diabetes were r and omly assigned to intensive therapy , targeting a systolic pressure of less than 120 mm Hg , or st and ard therapy , targeting a systolic pressure of less than 140 mm Hg . The primary composite outcome was nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The mean follow-up was 4.7 years . RESULTS After 1 year , the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the st and ard-therapy group . The annual rate of the primary outcome was 1.87 % in the intensive-therapy group and 2.09 % in the st and ard-therapy group ( hazard ratio with intensive therapy , 0.88 ; 95 % confidence interval [ CI ] , 0.73 to 1.06 ; P=0.20 ) . The annual rates of death from any cause were 1.28 % and 1.19 % in the two groups , respectively ( hazard ratio , 1.07 ; 95 % CI , 0.85 to 1.35 ; P=0.55 ) . The annual rates of stroke , a prespecified secondary outcome , were 0.32 % and 0.53 % in the two groups , respectively ( hazard ratio , 0.59 ; 95 % CI , 0.39 to 0.89 ; P=0.01 ) . Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group ( 3.3 % ) and 30 of the 2371 participants in the st and ard-therapy group ( 1.3 % ) ( P<0.001 ) . CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events , targeting a systolic blood pressure of less than 120 mm Hg , as compared with less than 140 mm Hg , did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events . ( Clinical Trials.gov number , NCT00000620 . Objective To assess longitudinally the association of serum uric acid and its change due to diuretic treatment with  cardiovascular events in hypertensive patients . Design Cohort study in a r and omized trial . Setting Cohort of hypertensive patients . Participants A total of 4327 men and women , aged ≥ 60 years , with isolated systolic hypertension , r and omized to placebo or chlorthalidone  , with the addition of atenolol or reserpine if needed , were observed for 5 years . Main outcome measures Major cardiovascular events , coronary events , stroke and all-cause mortality . Results Cardiovascular event rates for quartiles of baseline serum uric acid were : I , 32.7 per 1000 person-years ; II , 34.5 per 1000 person-years ; III , 38.1 per 1000 person-years ; and IV , 41.4 per 1000 person-years ( P for trend = 0.02 ) . The adjusted hazard ratio ( HR ) , of cardiovascular events for the highest quartile of serum uric acid versus the lowest quartile was 1.32 ( 95 % CI , 1.03–1.69 ) . The benefit of active treatment was not affected by baseline serum uric acid . After r and omization , an increase of serum uric acid < 0.06 mmol/l ( median change ) in the active treatment group was associated with a HR of 0.58 ( 0.37–0.92 ) for coronary events compared with those with a serum uric acid increase ≥ 0.06 mmol/l . This difference was not explained by blood pressure effects . Those with a serum uric acid increase ≥ 0.06 mmol/l in the active treatment group had a similar risk of coronary events as the placebo group . Conclusions Serum uric acid independently predicts cardiovascular events in older persons with isolated systolic hypertension . Monitoring serum uric acid change during diuretic treatment may help to identify patients who will most benefit from treatment Despite the clear-cut result of the Australian Therapeutic Trial in Mild Hypertension , which demonstrated prospect ively the benefit of treatment of diastolic blood pressure in the range of 95 to 109 mm Hg , a retrospective analysis that classified subjects by the average diastolic pressure level attained during the trial purported to show an absence of treatment benefit at lower average diastolic pressures and a negative treatment effect at higher levels . However , the method of classification by average attained diastolic pressure introduced substantial selection bias , invalidating the retrospective analysis and rendering as spurious both the deleterious treatment effect and its lack of efficacy at lower diastolic levels Serum glucose levels , triglyceride levels , and body weight are reported from a controlled drug trial in men , aged 40 to 49 , with uncomplicated mild hypertension . The drug treatment started with hydrochlorothiazide alone , and methyldopa was added when necessary . If side effects occurred , methyldopa was replaced by propranolol . No detailed advice about diet , smoking , or weight reduction was given to any group . The untreated control subjects had a small increase in serum glucose levels during five years , from 6.08 to 6.21 mmol/liter . Those treated with hydrochlorothiazide alone and those treated with hydrochlorothiazide plus methyldopa had a small increase in serum glucose levels of the same order as that in the control subjects . However , those receiving the thiazide/propranolol combination experienced a sizeable increase in glucose levels , from 5.96 to 6.53 mmol/liter ( p less than 0.001 ) . This increase was significantly greater than the increase in the other groups ( p less than 0.001 ) . The thiazide/propranolol group also showed a significant increase in serum triglyceride levels ( p less than 0.05 ) . There was no difference in serum potassium levels in the different drug groups . The results indicate that moderate thiazide doses do not have significant effects on serum glucose levels in this age group . Propranolol in combination with thiazide seems to increase the level of serum glucose A feasibility trial to investigate the practicality of determining the advantages and disadvantages of prompt pharmacologic treatment for mild hypertension was jointly funded by the Veterans Administration and the National Heart , Lung and Blood Institute . Its clinical phase has been completed , and it demonstrated 1 . that the required relatively young asymptomatic population could be enrolled in the study and 2 . that it could be persuaded to adhere to the protocol for 2 years ; however , it was evident that intensive efforts would be required in both areas . The feasibility trial screened almost 120,000 potential subjects over a period of 16 months to r and omize about 1,000 subjects at four clinical centers . These men and women were 21 to 50 years old , had diastolic pressures from 85 to 105 mm Hg as out patients , and had no evidence of cardiovascular renal abnormalities . They were r and omized in double-blind fashion into active drug therapy and placebo groups . Stepped care therapy involved 50 mg chlorthalidone ( Step 1 ) , 100 mg chlorthalidone ( Step 2 ) and 100 chlorthalidone plus 0.25 mg reserpine ( Step 3 ) . Death , myocardial infa rct ion , stroke , angina pectoris , and congestive heart failure were the " major " morbid events that were looked for ; also recorded were " minor " morbid events consisting primarily of electrocardiographic arrhythmias . The development of significant hypertension was considered a treatment failure . Side effects were carefully tabulated in both active drug and placebo groups . The study revealed an average drop in diastolic pressure of almost 12 mm Hg for active drug group and less than half of that for the placebo group ; once established 6 months after r and omization , the new pressure levels persisted almost without change throughout the study . Although the feasibility trial was not design ed to answer the primary question regarding the benefits of treatment , the events were tabulated for each group . A total of 12 placebo-treated subjects developed significant hypertension and were put on active drug . There was not a significant difference between the two groups in the incidence of " major " morbid events ; a total of eight active and five placebo patients developed myocardial infa rct ion or died suddenly . There , however , was an excess of arrhythmias among the active drug subjects ( 17 in the active group versus 8 in the placebo group on the basis of preliminary data ) . Finally , there were twice as many side effects and 20 times as many chemical abnormalities among the active as among the placebo subjects . A protocol for a full scale study of the benefits of pharmacologic therapy in mild hypertensives has been prepared and is ready for implementation as needed ; it involves relatively minor modifications of the protocol tested in the feasibility trial In an ancillary study of the Systolic Hypertension in the Elderly Program ( SHEP ) , the effects of diuretics on ventricular ectopic activity were investigated in 186 patients with isolated systolic hypertension .  Ventricular premature complexes ( VPCs ) were examined as the number of VPCs/24 hours , presence of > or = 1 VPC , presence of > or = 10 VPCs/24 hours , and presence of VPC pairs or ventricular tachycardia . Significant changes in VPCs were not observed either in the 92 patients r and omized to chlorthalidone stepped-care ( 12.5 and 25 mg/day ) or in the 94  placebo-treated patients ( p > 0.1 for all VPC definitions and both groups ) . Serum potassium decreased from 4.4 + /- 0.5 to 4.1 + /- 0.5 mEq/liter ( p = 0.002 ) in the chlorthalidone group and did not change ( 4.4 + /- 0.5 to 4.5 + /- 0.4 mEq/liter ) in the placebo group . Potassium was prescribed routinely for confirmed hypokalemia < 3.5 mEq/liter . A relation between serum potassium and VPC or change in serum potassium and change in VPC was not observed in the chlorthalidone group . In summary , in patients with isolated systolic hypertension , chlorthalidone in doses that are effective in decreasing stroke and cardiovascular event rates ( 12.5 or 25 mg/day ) , did not increase VPCs
target: Antihypertensive drugs used in the treatment of adults ( primary prevention ) with mild hypertension ( systolic BP 140 - 159 mmHg and /or diastolic BP 90 - 99 mmHg ) have not been shown to reduce mortality or morbidity in RCTs .
  More RCTs are needed in this prevalent population to know whether the benefits of treatment exceed the harms
background: BACKGROUND People with no previous cardiovascular events or cardiovascular disease represent a primary prevention population .
  The benefits and harms of treating mild hypertension in primary prevention patients are not known at present .
  This review examines the existing r and omised controlled trial ( RCT ) evidence .
  OBJECTIVES PRIMARY OBJECTIVE To quantify the effects of antihypertensive drug therapy on mortality and morbidity in adults with mild hypertension ( systolic blood pressure ( BP ) 140 - 159 mmHg and /or diastolic BP 90 - 99 mmHg ) and without cardiovascular disease .