title: Apparent effect on blood pressure is only partly responsible for the risk reduction due to antihypertensive treatments. 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). Effects of Angiotensin-Converting Enzyme Inhibition in Low-Risk Patients Early After Coronary Artery Bypass Surgery Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) Lifestyle intervention: results of the Treatment of Mild Hypertension Study (TOMHS). Relation between mortality and treated blood pressure in elderly patients with hypertension: report of the European Working Party on High Blood Pressure in the Elderly. Long-Term Antihypertensive Efficacy and Safety of the Oral Direct Renin Inhibitor Aliskiren: A 12-Month Randomized, Double-Blind Comparator Trial With Hydrochlorothiazide Statistical considerations in monitoring the Systolic Hypertension in the Elderly Program (SHEP). Risks and benefits in the trial of the European Working Party on High Blood Pressure in the Elderly. Relation of low body mass to death and stroke in the systolic hypertension in the elderly program. The SHEP Cooperative Research Group. Results of the pilot study for the Hypertension in the Very Elderly Trial Nonpharmacologic intervention to reduce blood pressure in older patients with mild hypertension. A 12-month comparison of ACE inhibitor and CA antagonist therapy in mild to moderate essential hypertension--The GLANT Study. Study Group on Long-term Antihypertensive Therapy. Irbesartan in patients with atrial fibrillation. Syst‐Eur—A Multicenter Trial on the Treatment of Isolated Systolic Hypertension in the Elderly: First Interim Report 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. Randomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: Objectives, protocol, and organization Effect of ramipril on the incidence of diabetes. Preventing microalbuminuria in type 2 diabetes. Hypotensive therapy in stroke survivors. Blood pressure reduction in elderly: a randomised controlled trial of methyldopa. Prevention of hypertension in patients with pre-hypertension: protocol for the PREVER-prevention trial Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39 A prospective, double-blind, randomized controlled trial of the angiotensin-converting enzyme inhibitor Ramipril In Aortic Stenosis (RIAS trial) Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study) Treatment of hypertension in patients 80 years of age or older. Morbidity and mortality in the Systolic Hypertension in the Elderly Program (SHEP) pilot study. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. Is a systolic blood pressure target <140 mmHg indicated in all hypertensives? Subgroup analyses of findings from the randomized FEVER trial. Effect of valsartan on the incidence of diabetes and cardiovascular events. Compliance to treatment for hypertension in elderly patients: the SHEP pilot study. Systolic Hypertension in the Elderly Program. The Systolic Hypertension in the Elderly Program (SHEP): an intervention trial on isolated systolic hypertension. SHEP Cooperative Research Group. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. PART-2 Collaborative Research Group. Prevention of Atherosclerosis with Ramipril. The effects of blood pressure reduction in older patients: an overview of five randomized controlled trials in elderly hypertensives. Early prediction of severity in acute pancreatitis by urinary trypsinogen activation peptide: a multicentre study Prevalence of postural hypotension at baseline in the Systolic Hypertension in the Elderly Program (SHEP) cohort. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial Effects of Blood Pressure Lowering in Patients with Acute Ischemic Stroke and Carotid Artery Stenosis Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. STOP-Hypertension 2: a prospective intervention trial of "newer" versus "older" treatment alternatives in old patients with hypertension. Swedish Trial in Old Patients with Hypertension. Telmisartan to prevent recurrent stroke and cardiovascular events. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial Oslo Hypertension Study Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. Clinical trials with ambulatory blood pressure monitoring: fewer patients needed? Impact of the treatment of isolated systolic hypertension on behavioral variables. Results from the systolic hypertension in the elderly program. Adverse treatment effects in the trial of the European Working Party on High Blood Pressure in the Elderly. The effect of antihypertensive treatment on electrocardiogram voltages in the EWPHE trial. Long-term mortality after 5-year multifactorial primary prevention of cardiovascular diseases in middle-aged men. Ambulatory monitoring uncorrected for placebo overestimates long-term antihypertensive action. Systolic Hypertension in Europe (SYST-EUR) Trial Investigators. Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial of Patients with Type 2 Diabetes and Overt Nephropathy Blinded subjective rankings as a method of assessing treatment effect: a large sample example from the Systolic Hypertension in the Elderly Program (SHEP). Prospective study on the treatment of mild hypertension in the aged. The Hypertension in the Very Elderly Trial (HYVET) Long term effects of nisoldipine on the progression of coronary atherosclerosis and the occurrence of clinical events: the NICOLE study EFFICACY OF ANTIHYPERTENSIVE DRUG TREATMENT ACCORDING TO AGE, SEX, BLOOD PRESSURE, AND PREVIOUS CARDIOVASCULAR DISEASE IN PATIENTS OVER THE AGE OF 60 Nitrendipine in older patients with isolated systolic hypertension: second progress report on the SYST-EUR trial. Serum cholesterol levels and survival in elderly hypertensive patients: analysis of data from the European Working Party on High Blood Pressure in the Elderly. The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Serum lipids and incidence of coronary heart disease. Findings from the Systolic Hypertension in the Elderly Program (SHEP). Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Correlates of ventricular ectopic activity in isolated systolic hypertension. SHEP Cooperative Research Group. The systolic hypertension in the elderly pilot program: methodological issues. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. Long-term safety and efficacy of moexipril alone and in combination with hydrochlorothiazide in elderly patients with hypertension. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. [SYST-EUR: a multicenter trial of treatment of systolic hypertension in aged subjects. An initial report]. Mortality and treated blood pressure in patients of the European Working Party on High Blood Pressure in the Elderly. Effect of two different therapeutic approaches on total and cardiovascular mortality in a Cardiovascular Study in the Elderly (CASTEL). Orthostatic fall in blood pressure in the very elderly hypertensive: results from the Hypertension in the Very Elderly Trial (HYVET) — pilot Randomised trial of treatment of hypertension in elderly patients in primary care. 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. Subgroup and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly. Glucose intolerance during diuretic therapy in elderly hypertensive patients. A second report from the European Working Party on high blood pressure in the elderly (EWPHE). Mortality over four years in SHEP participants with a low ankle-arm index. Ambulatory pressure decreases on long‐term placebo treatment in older patients with isolated systolic hypertension Cardiovascular morbidity and mortality in mild hypertension: the Australian Trial. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. Effects of treatment in hypertension. Results of a controlled study. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study Effects of low-dose angiotensin II receptor blocker candesartan on cardiovascular events in patients with coronary artery disease. Results of MRC (UK) trial of drug therapy for mild hypertension. Systolic Hypertension in the Elderly: Long‐Term Lacidipine Treatment: Objective, Protocol, and Organization Comparison of valsartan/hydrochlorothiazide combination therapy at doses up to 320/25 mg versus monotherapy: a double-blind, placebo-controlled study followed by long-term combination therapy in hypertensive adults. Antihypertensive therapy in patients above age 60 years (Fourth Interim report of the European Working Party on High Blood pressure in Elderly: EWPHE). Trial of Secondary Prevention With Atenolol After Transient Ischemic Attack or Nondisabling Ischemic Stroke RETRACTED: Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study Change in depression as a precursor of cardiovascular events. SHEP Cooperative Research Group (Systoloc Hypertension in the elderly). Relation of life events to blood pressure control in the SHEP pilot trial. Long-Term Effects of Cholesterol Lowering and Angiotensin-Converting Enzyme Inhibition on Coronary Atherosclerosis: The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT) Primary prevention with metoprolol in patients with hypertension. Mortality results from the MAPHY study. The Hypertension Optimal Treatment (HOT) Study: 12-month data on blood pressure and tolerability. With special reference to age and gender. 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. 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 Antihypertensive therapy in older patients with isolated systolic hypertension: the Syst-Eur experience in general practice Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. The effect of chlorthalidone on ventricular ectopic activity in patients with isolated systolic hypertension. The SHEP Study Group. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. Body mass index and prognosis in elderly hypertensive patients: a report from the European Working Party on High Blood Pressure in the Elderly. Systolic Hypertension in the Elderly Program (SHEP): antihypertensive efficacy of chlorthalidone. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. Antihypertensive therapy in elderly patients. Pilot trial of the European Working Party on High Blood Pressure in the Elderly. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease.
abstract: The mechanism of risk reduction obtained by blood pressure-lowering pharmacological treatment remains unclear . We explored the amount of risk reduction attributable to the apparent effect of antihypertensive medicines on blood pressure by using the capture approach . Five r and omized , placebo or nil controlled trials with a total of 28,997 subjects and 1,935 cardiovascular fatal or non-fatal events from the INDANA data base met the eligibility criteria . Computations were performed on the original individual records using multiple Cox 's proportional hazard regression models design ed for meeting the assumed treatment mode of action and comparing relevant assumptions . For coronary event , the results are inconclusive essentially because the risk reduction is mild . However , for stroke the risk reduction adjusted for baseline risk factors is 34 % ( P<0.0001 ) . The part explained by the effect of treatment on systolic blood pressure is 49 % of this reduction , with 95 % confidence interval not including 100 % . This result suggests that the apparent effect on blood pressure is not the only cause of stroke risk reduction in hypertensive subjects su bmi tted to an antihypertensive medicine 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 - Background — Early after  coronary artery bypass surgery ( CABG ) , activation of numerous neurohumoral and endogenous vasodilator systems occurs that could be influenced favorably by angiotensin-converting enzyme inhibitors . Methods and Results — The Ischemia Management with Accupril post – bypass Graft via Inhibition of the coNverting Enzyme ( IMAGINE ) trial tested whether early initiation ( ≤7 days ) of an angiotensin-converting enzyme inhibitor after CABG reduced cardiovascular events in stable patients with left ventricular ejection fraction ≥40 % . The trial was a double-blind , placebo-controlled study of 2553 patients r and omly assigned to quinapril , target dose 40 mg/d , or placebo , who were followed up to a maximum of 43 months . The mean ( SD ) age was 61 ( 10 ) years . The incidence of the primary composite end point ( cardiovascular death , resuscitated cardiac arrest , nonfatal myocardial infa rct ion , coronary revascularization , unstable angina or heart failure requiring hospitalization , documented angina , and stroke ) was 13.7 % in the quinapril group and 12.2 % in the placebo group ( hazard ratio 1.15 , 95 % confidence interval 0.92 to 1.42 , P=0.212 ) over a median follow-up of 2.95 years . The incidence of the primary composite end point increased significantly in the first 3 months after CABG in the quinapril group ( hazard ratio 1.52 , 95 % confidence interval 1.03 to 2.26 , P=0.0356 ) . Adverse events also increased in the quinapril group , particularly during the first 3 months after CABG . Conclusions — In patients at low risk of cardiovascular events after CABG , routine early initiation of angiotensin-converting enzyme inhibitor therapy does not appear to improve clinical outcome up to 3 years after CABG ; however , it increases the incidence of adverse events , particularly early after CABG . Thus , early after CABG , initiation of angiotensin-converting enzyme inhibitor therapy should be individualized and continually reassessed over time according to risk Although the benefits of antihypertensive treatment in " young " elderly ( under 70 years ) hypertensive patients are well established , the value of treatment in older patients ( 70 - 84 years ) is less clear . The Swedish Trial in Old Patients with Hypertension ( STOP-Hypertension ) was a prospect i ve , r and omised , double-blind , intervention study set up to compare the effects of active antihypertensive therapy ( three beta-blockers and one diuretic ) and placebo on the frequency of fatal and non-fatal stroke and myocardial infa rct ion and other cardiovascular death in hypertensive Swedish men and women aged 70 - 84 years . We recruited 1627 patients at 116 health centres throughout Sweden , who were willing to participate , and who met the entry criteria of three separate recordings during a 1-month placebo run-in period of systolic blood pressure between 180 and 230 mm Hg with a diastolic pressure of at least 90 mm Hg , or a diastolic pressure between 105 and 120 mm Hg irrespective of the systolic pressure . The total duration of the study was 65 months and the average time in the study was 25 months . 812 patients were r and omly allocated active treatment and 815 placebo . The mean difference in supine blood pressure between the active treatment and placebo groups at the last follow-up before an endpoint , death , or study termination was 19.5/8.1 mm Hg . Compared with placebo , active treatment significantly reduced the number of primary endpoints ( 94 vs 58 ; p = 0.0031 ) and stroke morbidity and mortality ( 53 vs 29 ; p = 0.0081 ) . Although we did not set out to study an effect on total mortality , we also noted a significantly reduced number of deaths in the active treatment group ( 63 vs 36 ; p = 0.0079 ) . The benefits of treatment were discernible up to age 84 years . We conclude that antihypertensive treatment in hypertensive men and women aged 70 - 84 confers highly significant and clinical ly relevant reductions in cardiovascular morbidity and mortality as well as in total mortality BACKGROUND Questions regarding the efficacy of nonpharmacologic approaches for the treatment of stage 1 hypertension were addressed as part of the Treatment of Mild Hypertension Study ( TOMHS ) , a 4-year , r and omized clinical trial ( N = 902 ) . This report describes the lifestyle intervention program used in TOMHS , presents data on the lifestyle changes observed , and focuses on the effect of weight loss on blood pressure and blood lipid levels . METHODS Participants were r and omly assigned to receive either placebo or one of five different antihypertensive medications . All took part in a lifestyle intervention program to reduce weight and sodium and alcohol intake  and to increase physical activity .  RESULTS Substantial changes from baseline levels were achieved for all lifestyle intervention variables . Mean weight change was -10.5 lb ( -5.6 % ) at 1 year , -8.5 lb ( -4.5 % ) at 2 years , -7.4 lb ( -4.0 % ) at 3 years , and -5.7 lb ( -3.0 % ) at 4 years . At 4 years , 70 % of participants remained below baseline weight and 34 % maintained a weight loss of 10 lb or greater . Mean change in urinary sodium excretion was -12.5 mmol/8 hr ( -23 % ) at 1 year , -10.7 mmol/8 hr ( -20 % ) at 2 years , -8.4 mmol/8 hr ( -16 % ) at 3 years , and -4.6 mmol/8 hr ( -9 % ) at 4 years . Alcohol intake declined by 1.6 drinks/week among drinkers at 4 years . Reported leisure physical activity increased by 86 % at 1 year and remained 50 % above baseline at 4 years . Beneficial changes in blood pressure and serum lipids were associated with these changes . CONCLUSIONS These results support a role for lifestyle interventions as the initial treatment for stage 1 hypertension and demonstrate that such interventions can be successfully implemented in the clinical setting OBJECTIVE --To investigate the relation between mortality and treated systolic and diastolic blood pressures . DESIGN --R and omised double blind placebo controlled trial . Mortality in the two treatment groups was examined in thirds of treated systolic and diastolic blood pressures . PATIENTS --339 And 352 patients allocated to placebo and active treatment , respectively .  The groups were similar at r and omisation in sex ratio ( 70 % women ) , mean age ( 71.5 years ) , blood pressure ( 182/101 mm Hg ) , and proportion of patients with cardiovascular complications ( 35 % ) . MEASUREMENTS AND MAIN RESULTS --In the placebo group total mortality rose with increasing systolic pressure whereas it had a U shaped relation with diastolic pressure , the total lowest mortality being in patients in the middle third of the distribution of diastolic pressure . In the group given active treatment  total mortality showed a U shaped relation with systolic pressure and an inverse association with treated diastolic pressure . In both groups cardiovascular and non-cardiovascular mortality followed the same trends as total mortality . The increased mortality in the lowest thirds of pressure was not associated with an increased proportion of patients with cardiovascular complications at r and omisation or with a fall in diastolic pressure exceeding the median fall in pressure in each group . In contrast , patients in the lowest thirds of pressure showed greater decreases in body weight and haemoglobin concentration than those in the middle and upper thirds of pressure . CONCLUSIONS --In patients taking active treatment  total mortality was increased in the lowest thirds of treated systolic and diastolic blood pressures . This increased mortality is not necessarily explained by an exaggerated reduction in pressure induced by drugs as for diastolic pressure a U shaped relation also existed during treatment with placebo . In addition , patients in the lowest thirds of systolic and diastolic pressures were characterised by decreases in body weight and haemoglobin concentration , and the patients in the lowest thirds of diastolic pressure taking active treatment also by an increased non-cardiovascular mortality , suggesting some deterioration of general health Background — Diuretics are recommended as first-line agents for the treatment of hypertension . This r and omized , double-blind , multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension . Methods and Results — After a 2- to 4-week placebo run-in , 1124 patients ( mean sitting diastolic blood pressure [ BP ] 95 to 109 mm Hg ) were r and omized to aliskiren 150 mg ( n=459 ) , hydrochlorothiazide 12.5 mg ( n=444 ) , or placebo ( n=221 ) once daily . Forced titration ( to aliskiren 300 mg or hydrochlorothiazide 25 mg ) occurred at week 3 ; at week 6 , patients receiving placebo were reassigned ( 1:1 ratio ) to aliskiren 300 mg or hydrochlorothiazide 25 mg . From week 12 , amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled . Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method . BP reductions ( mean sitting systolic BP/mean sitting diastolic BP ) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 ( −20.3/−14.2 versus −18.6/−13.0 mm Hg ; P<0.05 ) and were also greater at week 52 ( −22.1/−16.0 versus −21.2/−15.0 mm Hg ; P<0.05 for mean sitting diastolic BP ) . At the end of the monotherapy period ( week 12 ) , aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP ( −17.4/−12.2 versus −14.7/−10.3 mm H ; P<0.001 ) . Adverse event rates were similar with aliskiren- ( 65.2 % ) and hydrochlorothiazide-based therapy ( 61.5 % ) . Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy ( 17.9 % versus 0.9 % ; P<0.0001 ) . Conclusions — Aliskiren treatment , both as monotherapy and with optional addition of amlodipine , provided significantly greater BP reductions than the respective hydrochlorothiazide regimens . Aliskiren-based therapy was well tolerated . Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension 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 Hypertensive patients over the age of 60 years were admitted to a double-blind placebo-controlled trial . Patients in the actively treated group received a combined potassium-losing and -sparing diuretic ( triamterene 50 mg plus hydrochlorothiazide 25 mg ; n = 416 ) ; this dose could be doubled and methyldopa ( up to 2 g , daily ) was added in 35 % of patients when blood pressure remained high . The placebo group ( n = 424 ) received matching capsules and tablets . Adverse effects were assessed in the double-blind period of the trial by calculating the incidence of abnormal biochemical results , investigator reports of diseases and prescriptions of concomitant therapy and a self-administered symptom question naire completed by patients . In 1000 hypertensive subjects over 60 years of age , 1 year of active treatment would prevent 11 fatal cardiac events , 6 fatal and 11 non-fatal strokes and 8 cases of severe congestive heart failure . No unexpected adverse treatment effects were observed . A significant excess incidence rate ( per 1000 person years ) was found in the active group compared with placebo for : ( 1 ) impaired renal function , a serum creatinine greater than 180 mumol/l ( 2.0 mg/dl ) ; ( 2 ) mild hypokalaemia , a serum potassium less than 3.5 mmol/l ; ( 3 ) reports of gout ; and ( 4 ) an elevated serum uric acid greater than 0.52 mmol/l in men or greater than 0.46 in women . Elevated blood sugar and prescriptions for hypoglycaemic drugs tended to be more frequent in the actively treated group , but this difference was not statistically significant . In both groups , there was a low incidence ( less than 7 per 1000 person years ) of anaemia and depression and diseases of the liver , gall bladder or pancreas . ( ABSTRACT TRUNCATED AT 250 WORDS 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 Background The risks and benefits of treating hypertension in individuals older than 80 years are uncertain . A meta- analysis has suggested that a reduction in stroke events of 36 % may have to be balanced against a 14 % increase in total mortality . Objectives To report the results of the pilot study of the Hypertension in the Very Elderly Trial ( HYVET ) , which is in progress to address these issues . Methods The HYVET-Pilot was a multicentre international open pilot trial . In 10 European countries , 1283 patients older than 80 years and with a sustained blood pressure of 160–219/90–109 mmHg were allocated r and omly to one of three treatments : a diuretic-based regimen ( usually bendroflumethiazide ; n = 426 ) , an angiotensin-converting enzyme inhibitor regimen ( usually lisinopril ; n = 431 ) or no treatment ( n = 426 ) . The procedure permitted doses of the drug to be titrated and diltiazem slow-release to be added to active treatment . Target blood pressure was < 150/80 mmHg and mean follow-up was 13 months . Results In the combined actively treated groups , the reduction in stroke events relative hazard rate ( RHR ) was 0.47 [ 95 % confidence interval ( CI ) 0.24 to 0.93 ] and the reduction in stroke mortality RHR was 0.57 ( 95 % CI 0.25 to 1.32 ) . However , the estimate of total mortality supported the possibility of excess deaths with active treatment ( RHR 1.23 , 95 % CI 0.75 to 2.01 ) . Conclusions The preliminary results support the need for the continuing main HYVET trial . It is possible that treatment of 1000 patients for 1 year may reduce stroke events by 19 ( nine non-fatal ) , but may be associated with 20 extra non-stroke deaths BACKGROUND Although nonpharmacologic interventions are widely recommended in the therapy of high blood pressure in older adults , surprisingly little data exist to confirm the efficacy of these interventions in older persons . METHODS We conducted a r and omized , controlled clinical trial in persons aged 60 to 85 years with a diastolic blood pressure of 85 to 100 mm Hg . The experimental arm was a nonpharmacologic intervention combining weight reduction , sodium restriction , and increased physical activity . The nonpharmacologic intervention consisted of eight weekly group and two individual sessions during the intensive phase , followed by four monthly group sessions during the maintenance phase . The control group received no treatment during the study .  Blood pressure was assessed by certified technicians ( blinded to group assignment ) using r and om zero sphygmomanometers . RESULTS Of 56 participants r and omized , 47 completed the entire 6-month trial ( 21 in the intervention group and 26 in the control group ) . Attendance at the intervention sessions was excellent . The intervention group lost more weight ( -2.1 kg ) over 6 months than the control group ( + 0.3 kg ) . Trends for decreasing 24-hour urine sodium excretion in both the intervention and control groups , with greater trend in the intervention group , were not statistically significant . The intervention group experienced more reduction in systolic and diastolic blood pressure than did the control group ( mean differences between groups at 6 months , 4.2/4.9 mm Hg , respectively ) . CONCLUSIONS Our data indicate that a nonpharmacologic intervention will lower systolic and diastolic blood pressure levels in older people with borderline or mild elevations of diastolic blood pressure Patients with mild to moderate essential hypertension were treated mainly with an ACE inhibitor ( delapril , n = 980 ) or a Ca antagonist ( n = 956 ) for 12 months , and the incidence of cerebrovascular and cardiovascular events as well as drug-related side effects were compared between the two groups . There were no significant differences between the clinical background s of the two groups . In both groups , the blood pressure was decreased significantly from 1 month of treatment onwards , with the degree of reduction being greater in the Ca antagonist group throughout the study period ( p < 0.001 ) . Cerebrovascular or cardiovascular events occurred in 11 out of 980 patients in the delapril group and 18 out of 956 patients in the Ca antagonist group ( p = NS ) . Cerebrovascular disease developed in 5 delapril-treated patients and 11 Ca antagonist-treated patients , and heart disease developed in 5 and 7 patients , respectively ( both p = NS ) . Discontinuation of treatment due to side effects was significantly more common in the delapril group than in the Ca antagonist group ( p < 0.001 ) . There was no significant difference in the incidence of cerebrovascular and cardiovascular events between the two groups , and the results suggested that blood pressure reduction per se did not necessarily lead to a parallel decrease in cerebrovascular and cardiovascular complications BACKGROUND The risk of cardiovascular events among patients with atrial fibrillation is high . We evaluated whether irbesartan , an angiotensin-receptor blocker , would reduce this risk . METHODS We r and omly assigned patients with a history of risk factors for stroke and a systolic blood pressure of at least 110 mm Hg to receive either irbesartan at a target dose of 300 mg once daily or double-blind placebo . These patients were already enrolled in one of two trials ( of clopidogrel plus aspirin versus aspirin alone or versus oral anticoagulants ) . The first co primary outcome was stroke , myocardial infa rct ion , or death from vascular causes ; the second was this composite outcome plus hospitalization for heart failure . RESULTS A total of 9016 patients were enrolled and followed for a mean of 4.1 years . The mean reduction in systolic blood pressure was 2.9 mm Hg greater in the irbesartan group than in the placebo group , and the mean reduction in diastolic blood pressure was 1.9 mm Hg greater . The first co primary outcome occurred at a rate of 5.4 % per 100 person-years in both groups ( hazard ratio with irbesartan , 0.99 ; 95 % confidence interval [ CI ] , 0.91 to 1.08 ; P=0.85 ) . The second co primary outcome occurred at a rate of 7.3 % per 100 person-years among patients receiving irbesartan and 7.7 % per 100 person-years among patients receiving placebo ( hazard ratio , 0.94 ; 95 % CI , 0.87 to 1.02 ; P=0.12 ) . The rates of first hospitalization for heart failure ( a prespecified secondary outcome ) were 2.7 % per 100 person-years among patients receiving irbesartan and 3.2 % per 100 person-years among patients receiving placebo ( hazard ratio , 0.86 ; 95 % CI , 0.76 to 0.98 ) . Among patients who were in sinus rhythm at baseline , there was no benefit of irbesartan in preventing hospitalization for atrial fibrillation or atrial fibrillation recorded on 12-lead electrocardiography , nor was there a benefit in a subgroup that underwent transtelephonic monitoring . More patients in the irbesartan group than in the placebo group had symptomatic hypotension ( 127 vs. 64 ) and renal dysfunction ( 43 vs. 24 ) . CONCLUSIONS Irbesartan did not reduce cardiovascular events in patients with atrial fibrillation . ( Funded by Bristol-Myers Squibb and Sanofi-Aventis ; Clinical Trials.gov number , NCT00249795 . ) Syst-Eur is a multicenter placebo-controlled outcome trial design ed by the European Working Party on High Blood Pressure in the Elderly to investigate the effect of antihypertensive treatment on the incidence of stroke in elderly patients with isolated systolic hypertension ( ISH ) . Eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160 - 219 mm Hg with a diastolic blood pressure less than 95 mm Hg . The present paper is an interim report on the first 316 patients r and omized into this trial . The placebo ( n = 170 ) and active treatment ( n = 146 ) groups were similar at r and omization with respect to age ( 73 + /- 8 years ; mean + /- SD ) , sitting blood pressure ( 178 + /- 12 mm Hg systolic ; 85 + /- 7 mm Hg diastolic ) , percentage of men ( 34 % ) , and percentage of patients with cardiovascular complications ( 29 % ) . After r and omization blood pressure fell more ( p less than 0.001 ) in patients on active treatment than in those in the placebo group ( 19 + /- 20 mm Hg systolic ; 6 + /- 10 mm Hg diastolic vs. 7 + /- 19 and 1 + /- 10 mm Hg for sitting blood pressure ) . This first interim report on the Syst-Eur trial demonstrates that a multinational trial in elderly patients with ISH is feasible and that a significant blood pressure difference between the two treatment groups can be achieved and maintained . New centers are being recruited in order to r and omize a total of 3,000 patients 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 Calcium antagonists are a first-line treatment for hypertension . The effectiveness of diltiazem , a non-dihydropyridine calcium antagonist , in reducing cardiovascular morbidity or mortality is unclear . We compared the effects of diltiazem with that of diuretics , beta-blockers , or both on cardiovascular morbidity and mortality  in hypertensive patients . METHODS In a prospect i ve , r and omised , open , blinded endpoint study , we enrolled 10,881 patients , aged 50 - 74 years , at health centres in Norway and Sweden , who had diastolic blood pressure of 100 mm Hg or more . We r and omly assigned patients diltiazem , or diuretics , beta-blockers , or both . The combined primary endpoint was fatal and non-fatal stroke , myocardial infa rct ion , and other cardiovascular death . Analysis was done by intention to treat . FINDINGS Systolic and diastolic blood pressure were lowered effectively in the diltiazem and diuretic and beta-blocker groups ( reduction 20.3/18.7 vs 23.3/18.7 mm Hg ; difference in systolic reduction p<0.001 ) . A primary endpoint occurred in 403 patients in the diltiazem group and in 400 in the diuretic and beta-blocker group ( 16.6 vs 16.2 events per 1000 patient-years ; relative risk 1.00 [ 95 % CI 0.87 - 1.15 ] , p=0.97 ) . Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 in the diuretic and beta-blocker group ( 6.4 vs 7.9 events per 1000 patient-years ; 0.80 [ 0.65 - 0.99 ] , p=0.04 ) and fatal and non-fatal myocardial infa rct ion in 183 and 157 patients ( 7.4 vs 6.3 events per 1000 patient-years ; 1.16 [ 0.94 - 1.44 ] , p=0.17 ) . INTERPRETATION Diltiazem was as effective as treatment based on diuretics , beta-blockers , or both in preventing the combined primary endpoint of all stroke , myocardial infa rct ion , and other cardiovascular death BACKGROUND It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure . METHODS We r and omly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan ( 300 mg daily ) , amlodipine ( 10 mg daily ) , or  placebo .  The target blood pressure was 135/85 mm Hg or less in all groups . We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration , the development of end-stage renal disease , or death from any cause . We also compared them with regard to the time to a secondary , cardiovascular composite end point . RESULTS The mean duration of follow-up was 2.6 years . Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group ( P=0.02 ) and 23 percent lower than that in the amlodipine group ( P=0.006 ) . The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group ( P=0.003 ) and 37 percent lower in the irbesartan group than in the amlodipine group ( P<0.001 ) . Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups ( P=0.07 for both comparisons ) . These differences were not explained by differences in the blood pressures that were achieved . The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group ( P=0.008 ) and 21 percent more slowly than in the amlodipine group ( P=0.02 ) . There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point . CONCLUSIONS The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes . This protection is independent of the reduction in blood pressure it causes Summary The Syst-Eur Trial is a concerted action of the European Community ’s Medical and Health Research Programme . The trial is carried out in consultation with the World Health Organization , the International Society of Hypertension , the European Society of Hypertension and the World Hypertension League . This article describes the objectives and the protocol of Syst-Eur , a multicentre trial design ed by the European Working Party on High Blood . Pressure in the Elderly ( EWPHE ) , to test the hypothesis that antihypertensive treatment of elderly patients with isolated systolic hypertension results in a significant change in stroke morbidity and mortality . Secondary endpoints include cardiovascular events , such as myocardial infa rct ion and congestive heart failure .  To be eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160–219 mmHg with a diastolic pressure less than 95 mmHg . Patients must give their informed consent and be free of major cardiovascular and non-cardiovascular diseases at entry . The patients are r and omized to active treatment or placebo . Active treatment consists of nitrendipine ( 10–40 mg/day ) , combined with enalapril ( 5–20 mg/day ) and hydrochlorothiazide ( 12.5–25 mg/day ) , as necessary . The patients of the control group receive matching placebos . The drugs ( or matching placebos ) are stepwise titrated and combined in order to reduce systolic blood pressure by 20 mmHg at least to a level below 150 mmHg . Morbidity and mortality are monitored to enable an intention-to-treat and per protocol comparison of the outcome in the 2 treatment groups . A one-year pilot trial ( 1989 ) showed that the protocol is practicable . The Ethics Committee therefore decided to start the definite study ( 1990 ) , in which r and omized patients will be followed for 5 years . Recruitment of new centres and of the required 3,000 patients will last 3 years ( until 1993 ) BACKGROUND Previous studies have suggested that blockade of the renin-angiotensin system may prevent diabetes in people with cardiovascular disease or hypertension . METHODS In a double-blind , r and omized clinical trial with a 2-by-2 factorial design , we r and omly assigned 5269 participants without cardiovascular disease but with impaired fasting glucose levels ( after an 8-hour fast ) or impaired glucose tolerance to receive ramipril ( up to 15 mg per day ) or placebo ( and rosiglitazone or placebo ) and followed them for a median of 3 years . We studied the effects of ramipril on the development of diabetes or death , whichever came first ( the primary outcome ) , and on secondary outcomes , including regression to normoglycemia . RESULTS The incidence of the primary outcome did not differ significantly between the ramipril group ( 18.1 % ) and the placebo group ( 19.5 % ; hazard ratio for the ramipril group , 0.91 ; 95 % confidence interval [ CI ] , 0.81 to 1.03 ; P=0.15 ) . Participants receiving ramipril were more likely to have regression to normoglycemia than those receiving placebo ( hazard ratio , 1.16 ; 95 % CI , 1.07 to 1.27 ; P=0.001 ) . At the end of the study , the median fasting plasma glucose level was not significantly lower in the ramipril group ( 102.7 mg per deciliter [ 5.70 mmol per liter ] ) than in the placebo group ( 103.4 mg per deciliter [ 5.74 mmol per liter ] , P=0.07 ) , though plasma glucose levels 2 hours after an oral glucose load were significantly lower in the ramipril group ( 135.1 mg per deciliter [ 7.50 mmol per liter ] vs. 140.5 mg per deciliter [ 7.80 mmol per liter ] , P=0.01 ) . CONCLUSIONS Among persons with impaired fasting glucose levels or impaired glucose tolerance , the use of ramipril for 3 years does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycemia . ( Clinical Trials.gov number , NCT00095654 [ Clinical Trials.gov ] . ) BACKGROUND The multicenter double-blind , r and omized Bergamo Nephrologic Diabetes Complications Trial ( BENEDICT ) was design ed to assess whether angiotensin-converting-enzyme inhibitors and non-dihydropyridine calcium-channel blockers , alone or in combination , prevent microalbuminuria in subjects with hypertension , type 2 diabetes mellitus , and normal urinary albumin excretion . METHODS We studied 1204 subjects , who were r and omly assigned to receive at least three years of treatment with tr and olapril  ( at a dose of 2 mg per day ) plus verapamil ( sustained-release formulation , 180 mg per day ) , tr and olapril alone ( 2 mg per day ) , verapamil alone ( sustained-release formulation , 240 mg per day ) , or placebo .  The target blood pressure was 120/80 mm Hg . The primary end point was the development of persistent microalbuminuria ( overnight albumin excretion , > or = 20 microg per minute at two consecutive visits ) . RESULTS The primary outcome was reached in 5.7 percent of the subjects receiving tr and olapril plus verapamil , 6.0 percent of the subjects receiving tr and olapril , 11.9 percent of the subjects receiving verapamil , and 10.0 percent of control subjects receiving placebo . The estimated acceleration factor ( which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression ) adjusted for predefined baseline characteristics was 0.39 for the comparison between verapamil plus tr and olapril and placebo ( P=0.01 ) , 0.47 for the comparison between tr and olapril and placebo ( P=0.01 ) , and 0.83 for the comparison between verapamil and placebo ( P=0.54 ) . Tr and olapril plus verapamil and tr and olapril alone delayed the onset of microalbuminuria by factors of 2.6 and 2.1 , respectively . Serious adverse events were similar in all treatment groups . CONCLUSIONS In subjects with type 2 diabetes and hypertension but with normoalbuminuria , the use of tr and olapril plus verapamil and tr and olapril alone decreased the incidence of microalbuminuria to a similar extent . The effect of verapamil alone was similar to that of placebo Abstract A prospect i ve r and omised controlled trial of hypotensive therapy in 97 hypertensive patients surviving an ischaemic-type stroke was started in 1964 and terminated 4 years later . The patients were under 80 years of age , consecutively admitted to one hospital and the control and treated groups compared well for age , sex , and severity of hypertension . The drugs used were methyldopa , bethanidine or debrisoquine combined with restriction of salt intake , weight reduction , and thiazide diuretics , and the results were analysed with regard to survival and recurrence rates . Hypertension was defined as diastolic if this pressure was 110 mm . Hg or above , and as systolic if this pressure was over 160 mm . Hg with the diastolic below 110 mm . Hg . The mortality-rate at the end of a 2 to 5 year followup was 26 % in the treated group and 46 % in the untreated , and the non-fatal recurrence-rate 14 % in the treated and 23 % in the controls . Good smooth control was essential to success , untreated patients doing better than those whose control was unsatisfactory . In patients aged over 65 treatment of systolic hypertension was of no benefit , although the diastolic hypertensives improved marginally with treatment . As age increased this effect was progressively less apparent but the figures are probably too small to mean anything . In this series significant improvement occurred in treated hypertensive patients who had survived a stroke if they were aged 65 or below , but not if they were older A total of 123 out of 549 elderly residents of local authority welfare homes in Nottinghamshire were found at screening to have a st and ing or lying diastolic blood pressure of 100 mm Hg or more . These 123 subjects were r and omly allocated to simple observation or to treatment with methyldopa . The cumulative mortality was similar in the observed and treated groups and in the normotensive group from which the subjects had been separated . Thus moderate hypertension , whether treated or not , was not a major risk predictor in the elderly population studied Background Blood pressure ( BP ) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension , which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age . Non-drug interventions to prevent hypertension have had low effectiveness . In individuals with previous cardiovascular disease or diabetes , the use of BP-lowering agents reduces the incidence of major cardiovascular events . In the absence of higher baseline risk , the use of BP agents reduces the incidence of hypertension . The PREVER-prevention trial aims to investigate the efficacy , safety and feasibility of a population -based intervention to prevent the incidence of hypertension and the development of target-organ damage . Methods This is a r and omized , double-blind , placebo-controlled clinical trial , with participants aged 30 to 70 years , with pre-hypertension . The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo . The primary outcomes will be the incidence of hypertension , adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG . The secondary outcomes will be fatal or non-fatal cardiovascular events : myocardial infa rct ion , stroke , heart failure , evidence of new sub- clinical atherosclerosis , and sudden death . The study will last 18 months . The sample size was calculated on the basis of an incidence of hypertension of 14 % in the control group , a size effect of 40 % , power of 85 % and P alpha of 5 % , result ing in 625 participants per group . The project was approved by the Ethics committee of each participating institution . Discussion The early use of blood pressure-lowering drugs , particularly diuretics , which act on the main mechanism of blood pressure rising with age , may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension . If this intervention shows to be effective and safe in a population -based perspective , it could be the basis for an innovative public health program to prevent hypertension in Brazil . Trial Registration Clinical Trials NCT00970931 Abstract Objective : To determine whether tight control of blood pressure with either a β blocker or an angiotensin converting enzyme inhibitor has a specific advantage or disadvantage in preventing the macrovascular and microvascular complications of type 2 diabetes . Design : R and omised controlled trial comparing an angiotensin converting enzyme inhibitor ( captopril ) with a β blocker ( atenolol ) in patients with type 2 diabetes aim ing at a blood pressure of < 150/<85 mm Hg . Setting : 20 hospital based clinics in Engl and , Scotl and , and Northern Irel and . Subjects : 1148 hypertensive patients with type 2 diabetes ( mean age 56 years , mean blood pressure 160/94 mm Hg ) . Of the 758 patients allocated to tight control of blood pressure , 400 were allocated to captopril and 358 to atenolol . 390 patients were allocated to less tight control of blood pressure . Main outcome measures : Predefined clinical end points , fatal and non-fatal , related to diabetes , death related to diabetes , and all cause mortality . Surrogate measures of microvascular and macrovascular disease included urinary albumin excretion and retinopathy assessed by retinal photography . Results : Captopril and atenolol were equally effective in reducing blood pressure to a mean of 144/83 mm Hg and 143/81 mm Hg respectively , with a similar proportion of patients ( 27 % and 31 % ) requiring three or more antihypertensive treatments . More patients in the captopril group than the atenolol group took the allocated treatment : at their last clinic visit , 78 % of those allocated captopril and 65 % of those allocated atenolol were taking the drug ( P<0.0001 ) . Captopril and atenolol were equally effective in reducing the risk of macrovascular end points . Similar proportions of patients in the two groups showed deterioration in retinopathy by two grade s after nine years ( 31 % in the captopril group and 37 % in the atenolol group ) and developed clinical grade albuminuria ≥300 mg/l ( 5 % and 9 % ) . The proportion of patients with hypoglycaemic attacks was not different between groups , but mean weight gain in the atenolol group was greater ( 3.4 kg v 1.6 kg ) . Conclusion : Blood pressure lowering with captopril or atenolol was similarly effective in reducing the incidence of diabetic complications . This study provided no evidence that either drug has any specific beneficial or deleterious effect , suggesting that blood pressure reduction in itself may be more important than the treatment used Aims Angiotensin-converting enzyme ( ACE ) inhibitors improve left ventricular ( LV ) remodelling and outcome in heart failure and hypertensive heart disease . They may be similarly beneficial in patients with aortic stenosis ( AS ) , but historical safety concerns have limited their use , and no prospect i ve clinical trials exist . Methods and results We conducted a prospect i ve , r and omized , double-blind , placebo-controlled trial in 100 patients with moderate or severe asymptomatic AS to examine the physiological effects of ramipril , particularly LV mass ( LVM ) regression . Subjects were r and omized to ramipril 10 mg daily ( n = 50 ) or placebo ( n = 50 ) for 1 year , and underwent cardiac magnetic resonance , echocardiography , and exercise testing at 0 , 6 , and 12 months , with follow-up data available in 77 patients . There was a modest but progressive reduction in LVM ( the primary end point ) in the ramipril group vs. the placebo group ( mean change −3.9 vs. + 4.5 g , respectively , P = 0.0057 ) . There were also trends towards improvements in myocardial physiology : the ramipril group showed preserved tissue Doppler systolic velocity compared with placebo ( + 0.0 vs. −0.5 cm/s , P = 0.04 ) , and a slower rate of progression of the AS ( valve area 0.0 cm2 in the ramipril group vs. −0.2 cm2 in the placebo arm , P = 0.067 ) . There were no significant differences in major adverse cardiac events . Conclusion ACE inhibition leads to a modest , but progressive reduction in LVM in asymptomatic patients with moderate – severe AS compared with placebo , with trends towards improvements in myocardial physiology and slower progression of valvular stenosis . A larger clinical outcome trial to confirm these findings and explore their clinical relevance is required Abstract Objective To investigate whether a low dose of the angiotensin converting enzyme ( ACE ) inhibitor ramipril lowers cardiovascular and renal events in patients with type 2 diabetes who have microalbuminuria or proteinuria . Design R and omised , double blind , parallel group trial comparing ramipril ( 1.25 mg/day ) with placebo ( on top of usual treatment ) for cardiovascular and renal outcomes for at least three years . Setting Multicentre , primary care study conducted mostly by general practitioners in 16 European and north African countries . Participants 4912 patients with type 2 diabetes aged > 50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria ( urinary albumin excretion 20 mg/l in two consecutive sample s ) , and serum creatinine ≤ 150 μmol/l . Main outcome measures The primary outcome measure was the combined incidence of cardiovascular death , non-fatal myocardial infa rct ion , stroke , heart failure leading to hospital admission , and end stage renal failure . Results Participants were followed for 3 to 6 ( median 4 ) years . There were 362 primary events among the 2443 participants taking ramipril ( 37.8 per 1000 patient years ) and 377 events among the 2469 participants taking placebo ( 38.8 per 1000 patient years ; hazard ratio 1.03 ( 95 % confidence interval 0.89 to 1.20 , P = 0.65 ) ) . None of the components of the primary outcome was reduced . Ramipril  lowered systolic and diastolic blood pressures ( by 2.43 and 1.06 mm Hg respectively after two years ) and favoured regression from microalbuminuria ( 20 - 200 mg/l ) or proteinuria ( > 200mg/l ) to normal level ( < 20 mg/l ) or microalbuminuria ( P < 0.07 ) in 1868 participants who completed the study . Conclusions Low dose ( 1.25 mg ) ramipril once daily has no effect on cardiovascular and renal outcomes of patients with type 2 diabetes and albuminuria , despite a slight decrease in blood pressure and urinary albumin . The cardiovascular benefits of a daily higher dose ( 10 mg ) ramipril observed elsewhere are not found with an eightfold lower daily dose BACKGROUND Whether the treatment of patients with hypertension who are 80 years of age or older is beneficial is unclear . It has been suggested that antihypertensive therapy may reduce the risk of stroke , despite possibly increasing the risk of death . METHODS We r and omly assigned 3845 patients from Europe , China , Australasia , and Tunisia who were 80 years of age or older and had a sustained systolic blood pressure of 160 mm Hg or more to receive either the diuretic indapamide ( sustained release , 1.5 mg ) or matching placebo .  The angiotensin-converting-enzyme inhibitor perindopril ( 2 or 4 mg ) , or matching placebo , was added if necessary to achieve the target blood pressure of 150/80 mm Hg . The primary end point was fatal or nonfatal stroke . RESULTS The active-treatment group ( 1933 patients ) and the placebo group ( 1912 patients ) were well matched ( mean age , 83.6 years ; mean blood pressure while sitting , 173.0/90.8 mm Hg ) ; 11.8 % had a history of cardiovascular disease . Median follow-up was 1.8 years . At 2 years , the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group . In an intention-to-treat analysis , active treatment was associated with a 30 % reduction in the rate of fatal or nonfatal stroke ( 95 % confidence interval [ CI ] , -1 to 51 ; P=0.06 ) , a 39 % reduction in the rate of death from stroke ( 95 % CI , 1 to 62 ; P=0.05 ) , a 21 % reduction in the rate of death from any cause ( 95 % CI , 4 to 35 ; P=0.02 ) , a 23 % reduction in the rate of death from cardiovascular causes ( 95 % CI , -1 to 40 ; P=0.06 ) , and a 64 % reduction in the rate of heart failure ( 95 % CI , 42 to 78 ; P<0.001 ) . Fewer serious adverse events were reported in the active-treatment group ( 358 , vs. 448 in the placebo group ; P=0.001 ) . CONCLUSIONS The results provide evidence that antihypertensive treatment with indapamide ( sustained release ) , with or without perindopril , in persons 80 years of age or older is beneficial . ( Clinical Trials.gov number , NCT00122811 [ Clinical Trials.gov ] . ) The pilot study of the Systolic Hypertension in the Elderly Program was a r and omized , double-blind , placebo-controlled trial of drug therapy for isolated systolic hypertension . It followed 551 elderly participants with untreated blood pressures of greater than 160/less than 90 mm Hg for an average of 34 months . Mean age of the participants was 72 years ; 63 % were women , and 82 % were white . Pretreatment blood pressures averaged 172/75 mm Hg . Participants were r and omly assigned to treatment with chlorthalidone or placebo as Step I medication . Blood pressures at annual visits averaged 141/68 and 157/73 mm Hg for the drug-treated and placebo-treated groups , respectively , with 60 % and 33 % of the survivors on blinded medication having systolic blood pressures of less than 160 mm Hg at their last annual visit . All-cause mortality rates for the drug-treated and placebo-treated groups were 25.4 and 22.7 deaths per 1,000 participant-years of risk , and rates for definite " first stroke " were 8.3 and 12.8 per 1,000 years of risk . Differences between groups were significant for systolic and diastolic blood pressure but not for death or stroke rates . A full-scale study has begun to determine the effects of drug therapy for isolated systolic hypertension on stroke and mortality rates BACKGROUND Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease . We investigated whether treatment with an angiotensin-receptor blocker ( ARB ) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria . METHODS In a r and omized , double-blind , multicenter , controlled trial , we assigned 4447 patients with type 2 diabetes to receive olmesartan ( at a dose of 40 mg once daily ) or placebo for a median of 3.2 years . Additional antihypertensive drugs ( except angiotensin-converting-enzyme inhibitors or ARBs ) were used as needed to lower blood pressure to less than 130/80 mm Hg . The primary outcome was the time to the first onset of microalbuminuria . The times to the onset of renal and cardiovascular events were analyzed as secondary end points . RESULTS The target blood pressure ( < 130/80 mm Hg ) was achieved in nearly 80 % of the patients taking olmesartan and 71 % taking placebo ;  blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group . Microalbuminuria developed in 8.2 % of the patients in the olmesartan group ( 178 of 2160 patients who could be evaluated ) and 9.8 % in the placebo group ( 210 of 2139 ) ; the time to the onset of microalbuminuria was increased by 23 % with olmesartan ( hazard ratio for onset of microalbuminuria , 0.77 ; 95 % confidence interval , 0.63 to 0.94 ; P=0.01 ) . The serum creatinine level doubled in 1 % of the patients in each group . Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events--81 of 2232 patients ( 3.6 % ) as compared with 91 of 2215 patients ( 4.1 % ) (P=0.37)--but a greater number had fatal cardiovascular events--15 patients ( 0.7 % ) as compared with 3 patients ( 0.1 % ) ( P=0.01 ) , a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease ( 11 of 564 patients [ 2.0 % ] vs. 1 of 540 [ 0.2 % ] , P=0.02 ) . CONCLUSIONS Olmesartan was associated with a delayed onset of microalbuminuria , even though blood-pressure control in both groups was excellent according to current st and ards . The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern . ( Funded by Daiichi Sankyo ; Clinical Trials.gov number , NCT00185159 . ) AIMS Major guidelines recommend lowering systolic blood pressure ( SBP ) to < 140 mmHg in all hypertensives , but evidence is missing whether this is beneficial in ( i ) uncomplicated hypertensives , ( ii ) grade 1 hypertensives , and ( iii ) elderly hypertensives . Providing this missing evidence is important to justify efforts and costs of aggressive therapy in all hypertensives . METHODS AND RESULTS Felodipine Event Reduction ( FEVER ) was a double-blind , r and omized trial on 9711 Chinese hypertensives , in whom cardiovascular outcomes  were significantly reduced by more intense therapy ( low-dose hydrochlorothiazide and low-dose felodipine ) achieving a mean of 138 mmHg SBP compared with less-intense therapy ( low-dose hydrochlorothiazide and placebo ) achieving a mean of 142 mmHg . FEVER included older and younger patients , and patients with and without diabetes or cardiovascular disease . In the analyses here reported , Cox regression models assessed outcome differences between more and less-intense treatments in groups of patients with different baseline characteristics . Significant reductions in stroke were found in uncomplicated hypertensives ( -39 % , P = 0.002 ) , in hypertensives with r and omization SBP < 153 mmHg ( -29 % , P = 0.03 ) , and in elderly hypertensives ( -44 % , P < 0.001 ) , when their SBP was lowered by more intense treatment . Significant reductions ( between -29 and -47 % , P = 0.02 to < 0.001 ) were also found in all cardiovascular events and all deaths . Achieving mean SBP values < 140 mmHg by adding a small dose of a generic drug prevented 2.1 ( uncomplicated hypertensives ) and 5.2 ( elderly ) cardiovascular events every 100 patients treated for 3.3 years . CONCLUSIONS These analyses provide strong support , missing so far , to guidelines recommending goal SBP < 140 mmHg in uncomplicated hypertensives , individuals with moderately elevated BP and elderly hypertensives BACKGROUND It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance . METHODS In this double-blind , r and omized clinical trial with a 2-by-2 factorial design , we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan ( up to 160 mg daily ) or placebo ( and nateglinide or placebo ) in addition to lifestyle modification . We then followed the patients for a median of 5.0 years for the development of diabetes ( 6.5 years for vital status ) . We studied the effects of valsartan on the occurrence of three co primary outcomes : the development of diabetes ; an extended composite outcome of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , hospitalization for heart failure , arterial revascularization , or hospitalization for unstable angina ; and a core composite outcome that excluded unstable angina and revascularization . RESULTS The cumulative incidence of diabetes was 33.1 % in the valsartan group , as compared with 36.8 % in the placebo group ( hazard ratio in the valsartan group , 0.86 ; 95 % confidence interval [ CI ] , 0.80 to 0.92 ; P<0.001 ) . Valsartan , as compared with placebo , did not significantly reduce the incidence of either the extended cardiovascular outcome ( 14.5 % vs. 14.8 % ; hazard ratio , 0.96 ; 95 % CI , 0.86 to 1.07 ; P=0.43 ) or the core cardiovascular outcome ( 8.1 % vs. 8.1 % ; hazard ratio , 0.99 ; 95 % CI , 0.86 to 1.14 ; P=0.85 ) . CONCLUSIONS Among patients with impaired glucose tolerance and cardiovascular disease or risk factors , the use of valsartan for 5 years , along with lifestyle modification , led to a relative reduction of 14 % in the incidence of diabetes but did not reduce the rate of cardiovascular events . ( Clinical Trials.gov number , NCT00097786 . Assessing the compliance of people over 60 years of age and older with an antihypertensive treatment regimen was a major objective of the Systolic Hypertension in the Elderly Program ( SHEP ) pilot study . The study r and omized 551 men and women over the age of 60 ( mean age = 72 years ) to a stepped care treatment that included chlorthalidone or placebo in a double-blind trial . Three measures of compliance to treatment protocol --pill count , self-report , and a urine chlorthalidone assay -- all indicated high levels of compliance in 80 to 90 % of participants at 3 months and 1 year after r and omization . Pill-taking compliance was similar in the active and placebo groups , although the rate of discontinuance from study medications at 1 year was higher in the placebo than in the active group . Compliance was high in all age categories , including those over age 80 . These data suggest that elderly patients can achieve high levels of compliance with antihypertensive medications 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 OBJECTIVES The primary objective of this study was to investigate the effects of the angiotensin-converting enzyme ( ACE ) inhibitor , ramipril , on carotid atherosclerosis in patients with coronary , cerebrovascular or peripheral vascular disease . BACKGROUND Angiotensin-converting enzyme inhibitors have been shown to reduce the risk of coronary events in various patient groups and to prevent the development of atherosclerosis in animal models . It has been hypothesized that the clinical benefits of ACE inhibitors may , therefore , be mediated by effects on atherosclerosis . METHODS Six hundred seventeen patients were r and omized in equal proportions to ramipril ( 5 - 10 mg daily ) or placebo . At baseline , two years and four years , carotid atherosclerosis was assessed by B-mode ultrasound , and left ventricular mass was assessed by M-mode echocardiography . RESULTS Blood pressure ( BP ) was reduced by a mean of 6 mm Hg systolic and 4 mm Hg diastolic in the ramipril group compared with the placebo group ( p<0.001 ) . There was no difference between groups in the changes in common carotid artery wall thickness ( p = 0.58 ) or in carotid plaque ( p = 0.93 ) . Left ventricular mass index decreased by 3.8 g/m2 ( 4 % ) in the ramipril group compared with the placebo group ( 2p = 0.04 ) . CONCLUSIONS The results provide no support for the hypothesis that reduced atherosclerosis is responsible for the beneficial effects of ACE inhibitors on major coronary events . It is more likely that the benefits are due to lower BP , reduced left ventricular mass or other factors such as reversal of endothelial dysfunction Direct evidence about the effects of antihypertensive treatment on vascular disease in older patients is available from five r and omized trials conducted exclusively in patients over the age of 60 years . These trials involved a total of 12,483 individuals with systolic or diastolic hypertension ( mean age = 72 years , mean entry blood pressure = 181/88 mmHg ) . Over an average follow-up period of 4.7 years , a 15/6 mmHg difference in blood pressure between study and control groups was achieved . Among those patients assigned active treatment , stroke incidence was reduced by 34 % SD6 and coronary heart disease incidence was reduced by 19 % SD7 . These proportional reductions were of similar size to those observed in trials in predominantly younger patients . However , the absolute benefits observed in older patients were more than twice as great as those observed in younger patients . The results suggest that over 10 years , treatment would prevent at least one major vascular event among every 10 elderly patients at similar risk to those enrolled in the trials BACKGROUND There is a pressing clinical requirement for an early simple test of severity in acute pancreatitis . We investigated the use of an assay of trypsinogen activation peptide ( TAP ) . METHODS We undertook a multicentre study in 246 patients ( 172 with acute pancreatitis [ 35 with severe disease ] , 74 controls ) . We assessed the predictive value of urinary TAP concentrations measured by a vali date d competitive immunoassay . We compared the results with those for plasma C-reactive protein and three clinicobiochemical scoring systems . TAP and C-reactive protein concentrations were analysed at set times after symptom onset and compared with the clinicobiochemical systems scores at key times during hospital stay . FINDINGS At 24 h after symptom onset , the median urinary TAP concentration was 37 nmol/L ( IQR 17 - 110 ) for severe and 15 nmol/L ( 5 - 35 ) for mild disease ( p<0.001 ) . The respective values for plasma C-reactive protein were 24 mg/L ( 3 - 34 ) and 25 mg/L ( 6 - 75 ; p=0.208 ) . The sensitivity , specificity , positive predictive , and negative predictive values of the test to show severe acute pancreatitis compared with mild acute pancreatitis at 24 h were : for TAP ( > 35 nmol/L ) , 58 % , 73 % , 39 % , and 86 % , respectively , and for C-reactive protein ( > 150 mg/L ) , 0 % , 90 % , 0 % , and 75 % . 48 h after admission the values for the clinicobiochemical scoring systems were : APACHE II ( > or = 8) , 56 % , 64 % , 30 % , and 85 % ; Ranson score ( > or = 3 ) , 89 % , 64 % , 38 % , and 96 % ; and Glasgow score ( > or = 3 ) , 77 % , 75 % , 44 % , and 93 % . At 48 h , the values for C-reactive protein were 86 % , 61 % , 37 % , and 94 % and for TAP were 83 % , 72 % , 44 % , and 94 % . Combined testing of C-reactive protein and TAP was not superior to TAP alone for accuracy . INTERPRETATION Urinary TAP provided accurate severity prediction 24 h after onset of symptoms . This single marker of severity in acute pancreatitis deserves routine clinical application 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 BACKGROUND Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes , and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension . We assessed the effects of the routine administration of an angiotensin converting enzyme ( ACE ) inhibitor-diuretic combination on serious vascular events in patients with diabetes , irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs . METHODS The trial was done by 215 collaborating centres in 20 countries . After a 6-week active run-in period , 11 140 patients with type 2 diabetes were r and omised to treatment with a fixed combination of perindopril and indapamide or matching placebo , in addition to current therapy . The primary endpoints were composites of major macrovascular and microvascular events , defined as death from cardiovascular disease , non-fatal stroke or non-fatal myocardial infa rct ion , and new or worsening renal or diabetic eye disease , and analysis was by intention-to-treat . The macrovascular and microvascular composites were analysed jointly and separately . This trial is registered with Clinical Trials.gov , number NCT00145925 . FINDINGS After a mean of 4.3 years of follow-up , 73 % of those assigned active treatment and 74 % of those assigned control remained on r and omised treatment . Compared with patients assigned placebo , those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg . The relative risk of a major macrovascular or microvascular event was reduced by 9 % ( 861 [ 15.5 % ] active vs 938 [ 16.8 % ] placebo ; hazard ratio 0.91 , 95 % CI 0.83 - 1.00 , p=0.04 ) . The separate reductions in macrovascular and microvascular events were similar but were not independently significant ( macrovascular 0.92 ; 0.81 - 1.04 , p=0.16 ; microvascular 0.91 ; 0.80 - 1.04 , p=0.16 ) . The relative risk of death from cardiovascular disease was reduced by 18 % ( 211 [ 3.8 % ] active vs 257 [ 4.6 % ] placebo ; 0.82 , 0.68 - 0.98 , p=0.03 ) and death from any cause was reduced by 14 % ( 408 [ 7.3 % ] active vs 471 [ 8.5 % ] placebo ; 0.86 , 0.75 - 0.98 , p=0.03 ) . There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline . INTERPRETATION Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events , including death . Although the confidence limits were wide , the results suggest that over 5 years , one death due to any cause would be averted among every 79 patients assigned active therapy Background The Sc and inavian C and esartan Acute Stroke Trial ( SCAST ) showed no beneficial clinical effects of blood pressure lowering with the angiotensin receptor blocker c and esartan in the acute phase of stroke . In the present analysis we wanted to see if the effects of blood pressure lowering are harmful in the subgroup of patients with carotid artery stenosis . Methods SCAST was a r and omized- and placebo-controlled , double-masked trial of 2029 patients with acute stroke and high systolic blood pressure ( ≥140 mmHg ) . Of 1733 patients with ischemic stroke 993 underwent carotid artery imaging  , and the degree of stenosis was categorized as no/insignificant ( 0–49 % , n = 806 ) , moderate ( 50–69 % , n = 97 ) or severe ( = 70 % , n = 90 ) . The trial 's two co- primary effect variables were the composite end-point of vascular death , stroke or myocardial infa rct ion , and functional outcome at six-months , according to the modified Rankin Scale . Results Among patients with moderate or severe carotid artery  stenosis the vascular end-point occurred in 9 of 87 patients ( 10·3 % ) treated with c and esartan and in 17 of 100 controls ( 17·0 % ) , and there was no evidence of a different risk in patients with severe stenosis ( adjusted hazard ratio 0·74 , 95 % confidence interval 0·28–1·96 , P = 0·54 ) . For functional outcome there was also no clear difference , although in patients with severe stenosis the risk of a poor outcome was somewhat higher than in any of the other groups ( adjusted odds ratio 2·24 , 95 % confidence interval 0·71–7·09 , P = 0·16 ) . Progressive stroke also occurred more often in patients with carotid artery stenosis treated with c and esartan ( 10 of 87 patients ( 11·5 % ) vs. 4 of 100 patients ( 4·0 % ) ) , with a trend towards an increased risk with increasing severity of stenosis ( P-value for linear trend = 0·04 ) . Conclusions There is no clear evidence that the effect of c and esartan is qualitatively different in patients with carotid artery stenosis , but there are signals that patients with severe stenosis are at particularly high risk of stroke progression and poor functional outcome The Renoprotection of Optimal Antiproteinuric Doses ( ROAD ) study was performed to determine whether titration of benazepril or losartan to optimal antiproteinuric doses would safely improve the renal outcome in chronic renal insufficiency . A total of 360 patients who did not have diabetes and had proteinuria and chronic renal insufficiency were r and omly assigned to four groups . Patients received open-label treatment with a conventional dosage of benazepril ( 10 mg/d ) , individual uptitration of benazepril ( median 20 mg/d ; range 10 to 40 ) , a conventional dosage of losartan ( 50 mg/d ) , or individual uptitration of losartan ( median 100 mg/d ; range 50 to 200 ) . Uptitration was performed to optimal antiproteinuric and tolerated dosages , and then these dosages were maintained . Median follow-up was 3.7 yr . The primary end point was time to the composite of a doubling of the serum creatinine , ESRD , or death . Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease . Compared with the conventional dosages , optimal antiproteinuric dosages of benazepril and losartan that were achieved through uptitration were associated with a 51 and 53 % reduction in the risk for the primary end point ( P = 0.028 and 0.022 , respectively ) . Optimal antiproteinuric dosages of benazepril and losartan , at comparable BP control , achieved a greater reduction in both proteinuria and the rate of decline in renal function compared with their conventional dosages . There was no significant difference for the overall incidence of major adverse events between groups that were given conventional and optimal dosages in both arms . It is concluded that uptitration of benazepril or losartan against proteinuria conferred further benefit on renal outcome in patients who did not have diabetes and had proteinuria and renal insufficiency It is well established that hypertensive patients benefit from drug treatment of their disorder . In recent years three major out-come studies of antihypertensive treatment in elderly hypertensives have shown substantial benefits , i.e. a reduction in the risk of stroke and other cardiovascular mortality and morbidity . In all these studies beta-blockers and /or diuretics were used in comparison with placebo . Newer therapeutic alternatives have , however , at least theoretically , many advantages which could result in further improvements in prognosis . The initial Swedish Trial in Old Patients with Hypertension ( STOP-Hypertension 1 ) was conducted in men and women aged 70 - 84 years . STOP-Hypertension 2 will evaluate the therapy used in STOP-Hypertension 1 against therapy based on either ACE-inhibitors ( enalapril and lisinopril ) or on calcium antagonists ( isradipine and felodipine ) , using the PROBE design ( Prospect i ve , R and omised , Open , Blinded Endpoint evaluation ) . The primary aim will be to assess the effect on cardiovascular mortality . Statistical calculations indicate that 6,600 patients , followed for four years will be needed ( 2p < 0.05 , power 90 % ) to obtain significance if there is a 25 % difference between the new and the established therapy . Patients in primary health care ( 300 centres ) will be included if their supine blood pressure is > or = 180/105 mmHg ( and /or ) . Recruitment of patients started in September 1992 and so far more than 100 patients /week have been included BACKGROUND Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke . In addition , inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events , including stroke . However , the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established . We evaluated the effects of therapy with an angiotensin-receptor blocker , telmisartan , initiated early after a stroke . METHODS In a multicenter trial involving 20,332 patients who recently had an ischemic stroke , we r and omly assigned 10,146 to receive telmisartan  ( 80 mg daily ) and 10,186 to receive  placebo . The primary outcome was recurrent stroke . Secondary outcomes were major cardiovascular events ( death from cardiovascular causes , recurrent stroke , myocardial infa rct ion , or new or worsening heart failure ) and new-onset diabetes . RESULTS The median interval from stroke to r and omization was 15 days . During a mean follow-up of 2.5 years , the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group . A total of 880 patients ( 8.7 % ) in the telmisartan group and 934 patients ( 9.2 % ) in the placebo group had a subsequent stroke ( hazard ratio in the telmisartan group , 0.95 ; 95 % confidence interval [ CI ] , 0.86 to 1.04 ; P=0.23 ) . Major cardiovascular events occurred in 1367 patients ( 13.5 % ) in the telmisartan group and 1463 patients ( 14.4 % ) in the placebo group ( hazard ratio , 0.94 ; 95 % CI , 0.87 to 1.01 ; P=0.11 ) . New-onset diabetes occurred in 1.7 % of the telmisartan group and 2.1 % of the placebo group ( hazard ratio , 0.82 ; 95 % CI , 0.65 to 1.04 ; P=0.10 ) . CONCLUSIONS Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke , major cardiovascular events , or diabetes . ( Clinical Trials.gov number , NCT00153062 . Background The prognostic benefits of blood pressure lowering treatment in elderly hypertensive patients were established more than a decade ago , but are less clear in those with mildly to moderately elevated blood pressure . Objective To assess whether c and esartan-based antihypertensive treatment in elderly patients with mildly to moderately elevated blood pressure confers a reduction in cardiovascular events , cognitive decline and dementia . Design Prospect i ve , double-blind , r and omized , parallel-group study conducted in 1997–2002 . Setting and participants The study was of 4964 patients aged 70–89 years , with systolic blood pressure 160–179 mmHg , and /or diastolic blood pressure 90–99 mmHg , and a Mini Mental State Examination ( MMSE ) test score ⩾ 24 . A total of 527 centres in 15 countries participated in the study . Intervention Patients were assigned r and omly to receive the angiotensin receptor blocker c and esartan or placebo , with open-label active antihypertensive therapy added as needed . As a consequence , active antihypertensive therapy was extensively used in the control group ( 84 % of patients ) . Mean follow-up was 3.7 years . Main outcome measures The primary outcome measure was major cardiovascular events , a composite of cardiovascular death , non-fatal stroke and non-fatal myocardial infa rct ion . Secondary outcome measures included cardiovascular death , non-fatal and fatal stroke and myocardial infa rct ion , cognitive function measured by the MMSE and dementia . Results Blood pressure fell by 21.7/10.8 mmHg in the c and esartan group and by 18.5/9.2 mmHg in the control group . A first major cardiovascular event occurred in 242 c and esartan patients and in 268 control patients ; risk reduction with c and esartan was 10.9 % [ 95 % confidence interval ( CI ) , −6.0 to 25.1 , P = 0.19 ] . C and esartan-based treatment reduced non-fatal stroke by 27.8 % ( 95 % CI , 1.3 to 47.2 , P = 0.04 ) , and all stroke by 23.6 % ( 95 % CI , −0.7 to 42.1 , P = 0.056 ) . There were no significant differences in myocardial infa rct ion and cardiovascular mortality . Mean MMSE score fell from 28.5 to 28.0 in the c and esartan group and from 28.5 to 27.9 in the control group ( P = 0.20 ) . The proportions of patients who had a significant cognitive decline or developed dementia were not different in the two treatment groups . Conclusions In elderly hypertensive patients , a slightly more effective blood pressure reduction during c and esartan-based therapy , compared with control therapy , was associated with a modest , statistically non-significant , reduction in major cardiovascular events and with a marked reduction in non-fatal stroke . Cognitive function was well maintained in both treatment groups in the presence of substantial blood pressure reductions . Both treatment regimens were generally well tolerated 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 BACKGROUND Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction , whether or not they have heart failure . We assessed the role of an angiotensin-converting-enzyme inhibitor , ramipril , in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure . METHODS A total of 9297 high-risk patients ( 55 years of age or older ) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were r and omly assigned to receive ramipril ( 10 mg once per day orally ) or matching placebo for a mean of five years . The primary outcome was a composite of myocardial infa rct ion , stroke , or death from cardiovascular causes . The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper . RESULTS A total of 651 patients who were assigned to receive  ramipril ( 14.0 percent ) reached the primary end point , as compared with 826 patients who were assigned to receive placebo ( 17.8 percent ) ( relative risk , 0.78 ; 95 percent confidence interval , 0.70 to 0.86 ; P<0.001 ) . Treatment with ramipril reduced the rates of death from cardiovascular causes ( 6.1 percent , as compared with 8.1 percent in the placebo group ; relative risk , 0.74 ; P<0.001 ) , myocardial infa rct ion ( 9.9 percent vs. 12.3 percent ; relative risk , 0.80 ; P<0.001 ) , stroke ( 3.4 percent vs. 4.9 percent ; relative risk , 0.68 ; P<0.001 ) , death from any cause ( 10.4 percent vs. 12.2 percent ; relative risk , 0.84 ; P=0.005 ) , revascularization procedures ( 16.3 percent vs. 18.8 percent ; relative risk , 0.85 ; P<0.001 ) , cardiac arrest ( 0.8 percent vs. 1.3 percent ; relative risk , 0.62 ; P=0.02 ) , [ corrected ] heart failure ( 9.1 percent vs. 11.6 percent ; relative risk , 0.77 ; P<0.001 ) , and complications related to diabetes ( 6.4 percent vs. 7.6 percent ; relative risk , 0.84 ; P=0.03 ) . CONCLUSIONS Ramipril significantly reduces the rates of death , myocardial infa rct ion , and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure We have tested the concept that fewer patients are needed in trials of antihypertensive treatment if blood pressure is measured by ambulatory monitoring rather than by conventional sphygmomanometry .  233 patients ( > or = 60 years old ) with isolated systolic hypertension were r and omly allocated placebo ( n = 119 ) or active treatment ( n = 114 ) . Blood pressure measurements were compared by  Wilcoxon 's test  and blood pressure profiles by ANOVA . With either method of measurement , the same number of patients ( 40 in each treatment group ) was required to show a reduction after 1 year in clinic ( 13/8 mm Hg ) or average blood pressure over 24 h ( 9/5 mm Hg ) . To detect that the decrease in systolic pressure was not steadily maintained through the day , 40 patients in each treatment group were needed for blood pressure profiles made up of 4-hourly or 2-hourly means and 60 for profiles of 1-hourly means . For diastolic pressure , the corresponding numbers were 80 , 100 , and more than the number of available patients , respectively . We conclude that parallel-group trials focusing on the average blood pressure over 24 h , rather than on conventionally measured blood pressure , can not economise on sample size . Moreover , trials study ing the full course of blood pressure throughout the day , require more -- not fewer-- patients than studies of only the conventional or average 24 h blood pressure BACKGROUND Little information has been published on the impact of antihypertensive medications on quality of life in older persons . Particular concern has existed that lowering systolic blood pressure in older persons might have adverse consequences on cognition , mood , or leisure activities . METHODS A multicenter double-blind r and omized controlled trial was conducted over an average of 5 years ' followup involving 16 academic clinical trial clinics . Participants consisted of 4736 persons ( 1.06 % ) selected from 447,921 screenees aged 60 years and older . Systolic blood pressure at baseline ranged from 160 to 219 mm Hg , while diastolic blood pressure was less than 90 mm Hg . Participants were r and omized to active antihypertensive drug therapy  or matching placebo . Active treatment consisted of 12.5 to 25 mg of chlorthalidone for step 1 , while step 2 consisted of 25 to 50 mg of atenolol . If atenolol was contraindicated , 0.05 to 0.10 mg of reserpine could be used for the second-step drug . The impact of drug treatment on measures of cognitive , emotional , and physical function and leisure activities was assessed . RESULTS Our analyses demonstrate that active treatment of isolated systolic hypertension in the Systolic Hypertension in the Elderly Program cohort had no measured negative effects and , for some measures , a slight positive effect on cognitive , physical , and leisure function . The positive findings in favor of the treatment group were small . There was no effect on measures related to emotional state . Measures of cognitive and emotional function were stable in both groups for the duration of the study . Both treatment groups showed a modest trend toward deterioration of some measures of physical and leisure function over the study period . CONCLUSIONS The overall study cohort exhibited decline over time in activities of daily living , particularly the more strenuous ones , and some decline in certain leisure activities . However , mood , cognitive function , basic self-care , and moderate leisure activity were remarkably stable for both the active and the placebo groups throughout the entire study . Results of this study support the inference that medical treatment of isolated systolic hypertension does not cause deterioration in measures of cognition , emotional state , physical function , or leisure activities Adverse treatment effects were assessed in 840 elderly hypertensive patients r and omly assigned to active treatment  ( a combination of triamterene and hydrochlorothiazide ) or placebo ; methyldopa was added to the regimen in one third of the treated patients . Symptoms of dry mouth , nasal stuffiness , and diarrhea were reported by significantly more treated patients than placebo control subjects . More patients receiving diuretics plus methyldopa than diuretics alone reported dry mouth and diarrhea . Significantly more treated patients than control subjects showed evidence of a high serum creatinine level , mild hypokalemia , and gout . More treated patients tended to have diabetes . The benefits of treatment outweighed these adverse treatment effects Long-term effects of antihypertensive treatment on various electrocardiogram ( ECG ) voltages and the association between ECG findings at r and omization and subsequent mortality were evaluated in the double-blind , placebo-controlled trial of elderly hypertensive patients , conducted by the European Working Party on High Blood Pressure in the Elderly ( EWPHE ) . Patients were treated with a combination of hydrochlorothiazide and triamterene or matching placebo ; methyldopa or placebo was added if blood pressures remained high . RaVL and SV1 + RV5 at r and omization were related to systolic blood pressure ( SBP ) and RaVL was also related to diastolic blood pressure ( DBP ) , after adjustment for age , gender , and body mass index ( BMI ) . When adjusted for age and body mass index , the decreases in RaVL and SV1 + RV5 were not correlated with the changes in SBP after 1 year of active treatment but the decreases in SV1 + RV5 were positively related to the fall in DBP . After 4 years of active treatment , the fall in SBP was associated with decreases in RaVL and in SV1 + RV5 , after adjustment for age and changes in BMI OBJECTIVE To investigate the long-term effects of multifactorial primary prevention of cardiovascular diseases ( CVD ) . DESIGN The 5-year r and omized , controlled trial was performed between 1974 and 1980 . The subjects and their risk factors were reevaluated in 1985 . Posttrial mortality follow-up was continued up to December 31 , 1989 . SETTING Institute of Occupational Health , Helsinki , Finl and , and Second Department of Medicine , University of Helsinki . PARTICIPANTS In all , 3490 business executives born during 1919 through 1934 participated in health checkups in the late 1960s . In 1974 , 1222 of these men who were clinical ly healthy , but with CVD risk factors , were entered into the primary prevention trial ; 612 were r and omized to an intervention and 610 to a control group . INTERVENTIONS During the 5-year trial , the subjects of the intervention group visited the investigators every fourth month . They were treated with intensive dietetic-hygienic measures and frequently with hypolipidemic ( mainly clofibrate and /or probucol ) and antihypertensive ( mainly beta-blockers and /or diuretics ) drugs . The control group was not treated by the investigators . MAIN OUTCOME MEASURES Total mortality , cardiac mortality , mortality due to other causes . RESULTS Total coronary heart disease risk was reduced by 46 % in the intervention group as compared with the control group at end-trial . During 5 posttrial years , the risk factor and medication differences were largely leveled off between the groups . Between 1974 and 1989 the total number of deaths was 67 in the intervention group and 46 in the control group ( relative risk [ RR ] , 1.45 ; 95 % confidence interval [ CI ] , 1.01 to 2.08 ; P = .048 ) ; there were 34 and 14 cardiac deaths ( RR , 2.42 ; 95 % CI , 1.31 to 4.46 ; P = .001 ) , two and four deaths due to other CVD ( not significant ) , 13 and 21 deaths due to cancer ( RR , 0.62 ; 95 % CI , 0.31 to 1.22 ; P = .15 ) , and 13 and one deaths due to violence ( RR , 13.0 ; 95 % CI , 1.70 to 98.7 ; P = .002 ) , respectively . Multiple logistic regression analysis of treatments in the intervention group did not explain the 15-year excess cardiac mortality . CONCLUSION These unexpected results may not question multifactorial prevention as such but do support the need for research on the selection and interaction(s ) of methods used in the primary prevention of cardiovascular diseases This study compares blood pressure ( BP ) changes during active antihypertensive treatment and placebo as assessed by conventional and ambulatory BP measurement . Older patients ( > or = 60 years , n=337 ) with isolated systolic hypertension by conventional sphygmomanometry at the clinic were r and omized to placebo or active treatment consisting of nitrendipine ( 10 to 40 mg/d ) , with the possible addition of enalapril ( 5 to 20 mg/d ) and /or hydrochlorothiazide ( 12.5 to 25 mg/d ) . At baseline , clinic systolic/diastolic BP averaged 175/86 mm Hg and 24-hour and daytime ambulatory BPs averaged 148/80 and 154/85 mm Hg , respectively . After 13 months ( median ) of active treatment , clinic BP had dropped by 22.7/7.0 mm Hg and 24-hour and daytime BPs by 10.5/4.5 and 9.7/4.3 mm Hg , respectively ( P<.001 for all ) . However , clinic ( 9.8/1.6 mm Hg ) , 24-hour ( 2.1/1.1 mm Hg ) , and daytime ( 2.9/1.0 mm Hg ) BPs decreased also during placebo ( P<.05 , except for daytime diastolic BP ) ; these decreases represented 43%/23 % , 20%/24 % , and 30%/23 % of the corresponding BP fall during active treatment . After subtraction of placebo effects , the net BP reductions during active treatment averaged only 12.9/5.4 , 8.3/3.4 , and 6.8/3.2 mm Hg for clinic , 24-hour , and daytime BPs , respectively . The effect of active treatment was also subject to diurnal variation ( P<.05 ) . Changes during placebo in hourly systolic and diastolic BP means amounted to ( median ) 21 % ( range , -1 % to 42 % ) and 25 % ( -3 % to 72 % ) , respectively , of the corresponding changes during active treatment . In conclusion , expressed in millimeters of mercury , the effect of antihypertensive treatment on BP is larger with conventional than with ambulatory measurement . Regardless of whether BP is measured by conventional sphygmomanometry or ambulatory monitoring , a substantial proportion of the long-term BP changes observed during active treatment may be attributed to placebo effects . Thus , ambulatory monitoring uncorrected for placebo or control observations , like conventional sphygmomanometry , overestimates BP responses in clinical trials of long duration Context Previously published results of this r and omized , double-blind trial showed that high-risk patients with type 2 diabetic nephropathy had better renal protection if they were treated with irbesartan rather than amlodipine in addition to conventional antihypertensive therapy . Contribution These detailed analyses showed no differences in overall cardiovascular outcomes between patients given irbesartan or amlodipine .  Fewer patients given irbesartan had heart failure and fewer patients given amlodipine had heart attacks . Caution s The trial had limited power to detect important differences between groups in mortality or strokes , and most patients received several antihypertensive agents . The Editors Patients with diabetes have an increased risk for cardiovascular complications and death ( 1 ) . Studies that analyzed the effects of inhibition of the reninangiotensin system on the risk for cardiovascular complications included a substantial number of patients with diabetes ( 2 - 5 ) or were done exclusively in patients with diabetes ( 6 - 8 ) . The meta- analysis of these studies ( 9 ) , the analysis of the diabetic cohorts in the Heart Outcomes Prevention Evaluation ( HOPE ) study ( 2 ) , and the Losartan Intervention for Endpoint Reduction in Hypertension ( LIFE ) trial ( 5 ) demonstrated that angiotensin-converting enzyme ( ACE ) inhibitors ( 2 , 9 ) and angiotensin-receptor blockers ( 5 ) had a statistically significant advantage over placebo or alternative agents in decreasing the risk for several cardiovascular events . These studies r and omly assigned few patients with renal involvement and overt proteinuria . Overt proteinuria occurred in fewer than 20 % of the 470 patients in the Appropriate Blood Pressure Control in Diabetes ( ABCD ) trial ( 6 ) , and only 11 % of the 1195 patients in the LIFE trial ( 5 ) . The Captopril Prevention Project ( CAPP ) ( 3 ) and the Swedish Trial in Old Patients with Hypertension-2 ( STOP Hypertension-2 ) ( 4 ) did not state the number of patients with diabetes and overt proteinuria . There were no such patients in the Fosinopril versus Amlodipine Cardiovascular Events Trial ( FACET ) ( 7 ) , and patients with dipstick-positive albuminuria were excluded from the HOPE trial ( 2 ) . Since proteinuria is an independent risk factor for cardiovascular disease ( 10 , 11 ) , the data obtained in the aforementioned trials can not be extrapolated to patients with type 2 diabetes and overt nephropathy . Trials performed in such patients have reported a blood pressureindependent effect of two different angiotensin-receptor blocker agents to protect against nephropathy ( 12 , 13 ) without a change in all-cause mortality . Apart from studies in heart failure , few cardiovascular data exist for receptor blockers compared with either placebo or calcium-channel blockers . We report on the analysis of the cardiovascular end points that were monitored as secondary end points in the Irbesartan Diabetic Nephropathy Trial ( IDNT ) ( 12 ) and assess whether an angiotensin II receptor blocker or a calcium-channel blocker alters the risk for cardiovascular events beyond those observed by blood pressure reduction alone without such agents . Methods Patients The IDNT was a r and omized , double-blind study on the effect of treatment with irbesartan or amlodipine compared with placebo in patients with type 2 diabetic nephropathy . The protocol of this study has been published ( 12 , 14 ) . Entry criteria required that patients be between 30 and 70 years of age and have type 2 diabetes mellitus and overt nephropathy , as evidence d by current treatment for hypertension or by a protein excretion rate of 900 mg/d or greater , serum creatinine level of 89 mol/L ( 1.0 mg/dL ) to 266 mol/L ( 3.0 mg/dL ) in women or of 106 mol/L ( 1.2 mg/dL ) to 266 mol/L ( 3.0 mg/dL ) in men , and baseline seated blood pressure greater than 135/85 mm Hg . The institutional review boards of each center approved the protocol . All patients gave written informed consent . Treatment and R and omization Patients were r and omly assigned central ly by computer to receive treatment with irbesartan , 300 mg/d ( Avapro , Bristol-Myers Squibb , Princeton , New Jersey ) ; amlodipine , 10 mg/d ( Norvasc , Pfizer , New York ) ; or matched placebo . To minimize any center effect , r and omization was blocked by center . All patients had blood pressure controlled to the same blood pressure goal of less than 135/85 mm Hg by using antihypertensive agents other than ACE inhibitors , angiotensin II receptor blocking agents , or calcium-channel blockers . For the analysis of cardiovascular end points , patients were followed to initiation of treatment for end-stage renal failure ( dialysis or renal transplantation ) , reaching a serum creatinine level of 530.4 mol/L ( 6.0 mg/dL ) or higher , death , or administrative censoring in December 2000 . Outcomes We prospect ively established cardiovascular outcomes , defined in the Appendix Table . Appendix Table . Classification for Fatal and Nonfatal Cardiovascular Events Ascertainment of Cardiovascular Events Information about hospitalizations and adverse events were screened at Bristol-Myers Squibb , Princeton , New Jersey , by trained , blinded clinical research associates to identify potential cardiovascular events . Investigators used study forms to report and characterize all cardiovascular outcomes . For all potential events , records , including laboratory values , electrocardiograms , and radiographic reports were obtained for clarification . Since myocardial infa rct ions may go unrecognized , a central electrocardiogram reading center was established at Brigham and Women 's Hospital , Boston , Massachusetts , where two cardiologists review ed every electrocardiogram . Electrocardiography was performed at baseline , 6 months , 12 months , and annually thereafter . A total of 5698 electrocardiograms were review ed at the center . When a new Q-wave infa rct ion was found , the cardiologists asked whether a clinical myocardial infa rct ion was reported . Even when myocardial infa rct ions were not clinical ly reported , these Q-wave infa rct ions were adjudicated as myocardial infa rct ions . Adjudication of Cardiovascular Events Investigators at each center reported cardiovascular events , defined in the Appendix Table . The information on all potential events was referred to one member of the Outcomes Confirmation and Classification Committee ( Appendix ) . If the committee member agreed with the judgment of the center investigator , their combined judgment was accepted . If the center investigator and the committee member differed , the case material was review ed by the membership of the committee , whose decision was accepted . Deaths were adjudicated by a Mortality Committee ( Appendix ) . Each death was review ed by two members of the committee and presented to the membership , whose decision was accepted as final . Statistical Analysis For graphical presentation ( Figure ) and overall testing for statistically significant differences among the three treatment groups , time to the first occurrence of either a specific cardiovascular outcome or one of the composite outcomes was analyzed by product-limit survival curves and the log-rank test ( 15 ) . We used proportional hazards modeling to determine hazard ratios . For the cardiovascular death outcome , which could occur only once , we used the st and ard proportional hazards model ( 16 ) , with treatment assignment as the only independent covariate . For other cardiovascular outcomes , which could occur more than once , we used the And ersonGill formulation of the proportional hazards model ( 17 ) , in which patients are considered at risk for the first event from r and omization to the first event , at risk for the second event from the day following the first event to the second event , and so forth , permitting use of all the data . In accordance with the method of Lee and colleagues ( 18 ) , we used a robust variance estimate that accounts for the possibility of correlation of risk for several events within a patient . We believed that occurrence of a first event of a given type increases the likelihood of a subsequent similar event . Therefore , both treatment assignment and a time-dependent covariate indicating whether the event was the first of its type or a subsequent event were included in these analyses . The time-dependent covariate was statistically significant in each case , confirming the above assumption . There was no statistically significant interaction between treatment and the time-dependent covariatethe effects of treatment assignment were similar for first and subsequent events and inclusion of the time-dependent covariate did not change either the estimates of the treatment effect or their statistical significance s. Figure . Time to first cardiovascular composite event as a function of treatment assignment . P Data management and computations were done by using SAS software for Windows , version 8 ( SAS Institute , Inc. , Cary , North Carolina ) , or S-Plus for Windows , version 6.0 ( Insightful Corp. , Seattle , Washington ) . Statistical tests were two sided . A P value of 0.05 or less , unadjusted for the multiple comparisons , was considered statistically significant . Role of the Funding Sources The funding sources were involved in the data collection but not in the analysis or interpretation or the decision to su bmi t the manuscript for publication . Results The baseline characteristics of the three groups are shown in Table 1 . A flow diagram of the study is shown in the Appendix Figure . Table 1 . Baseline Characteristics Appendix Figure . Flow diagram for the Irbesartan Diabetic Nephropathy Trial . Clinical Management During the study , the blood pressure decreased from the baseline values to 140/77 mm Hg in the irbesartan group , 141/77 mm Hg in the amlodipine group , and 144/80 mm Hg in the placebo group . Blood pressure in the two active treatment groups did not differ ; values in both groups were statistically significantly lower than in the placebo group ( P = 0.001 ) . The distribution of non study drugs used to achieve the target blood pressure was similar 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 The 4 year prospect i ve trial on the effectiveness of the antihypertensive treatment was performed in 100 mild hypertensive patients of the aged , the average age being 76.1 years . Dropouts during the drug-off control period were 9 cases . The matched pair group was selected by the age , sex , and blood pressure . Forty-four drug treated cases and 47 placebo treated cases were comparable in blood pressure as well as in laboratory data . Cerebrovascular and cardiac complications were observed in 4 cases or 10.5 % in the drug group , and in 9 cases or 22.0 % in the placebo group . When 8 cases of blood pressure elevation over 200/110 mmHg in the placebo group were added to the cardiovascular complications , dropouts in placebo group reached 41.5 % , and this showed the significant difference . Other complications were observed in 12 cases or 31.6 % in the drug group and in 17 cases or 41.5 % in the placebo group . Major complications were cancers , infections , and bone or joint diseases . Blood pressure was decreased from 171/87 to 151/80 in the drug group , and the average decrease was 20/7 mmHg in 4 year period . No significant changes in hematocrit , serum protein , urea nitrogen , uric acid , sodium , and potassium were observed during the trial period . The present study suggested that antihypertensive treatment was effective in the aged with mild hypertension , and that careful follow up was needed not only for cardiovascular complications but also for general health condition Summary The Hypertension in the Very Elderly Trial ( HYVET ) is a multicentre , open , r and omised , controlled trial . The aim of this trial is to investigate the effect of active treatment on stroke incidence in hypertensive patients over the age of 80 years . Secondary end-points include total cardiovascular mortality and morbidity . Entry criteria include a sustained sitting systolic blood pressure of 160 to 219 mm Hg plus a sustained sitting diastolic pressure of 95 to 109 mm Hg . Also required is a st and ing systolic blood pressure of at least 140 mm Hg . Patients must give their informed consent , and be free of congestive heart failure requiring treatment , gout , renal failure or a recent cerebral haemorrhage . Patients are to be r and omised to 3 groups — ( i ) no treatment ; ( ii ) treatment with a diuretic [ bendroflumethiazide ( bendrofluazide ) ] ; or ( iii ) treatment with an angiotensin converting enzyme ( ACE ) inhibitor (lisinopril).Starting dosage for bendroflumethiazide and lisinopril is 2.5 mg/day . In order to achieve goal sitting systolic and diastolic blood pressures ( < 150/80 mm Hg ) , a doubling of the dosage is allowed . Furthermore , slow release diltiazem ( 120 mg/day increasing to 240 mg/day if required ) may be added to the medication of the actively treated groups . These drugs have been chosen as inexpensive and appropriate representatives of their therapeutic classes.700 patients in each group ( a total of 2100 ) will be sufficient to detect a 40 % difference in cerebrovascular events between no treatment and active treatment ( α = 0.01 , 1−β = 0.90 ) . These numbers will also detect a difference in total mortality of 25 % and in cardiovascular mortality of 35%.The pilot phase of the trial has been started with support from the British Heart Foundation . Centres which are interested in taking part should contact C. J. Bulpitt or any of the other authors Background : Earlier angiographic studies have suggested that calcium antagonists may prevent the formation of new coronary lesions and the progression of minimal lesions . Conversely , a meta- analysis suggested that these drugs may increase cardiovascular mortality and morbidity in patients with coronary heart disease . Objective : To investigate whether nisoldipine retards the progression of coronary atherosclerosis or reduces the occurrence of clinical events . Design and setting : The NICOLE study ( NIsoldipine  in COronary artery disease in LEuven ) is a single centre , r and omised , double blind , placebo controlled trial with coronary angiography at baseline , six months , and three years of follow up . Patients : 826 patients who had undergone successful coronary angioplasty were r and omised to nisoldipine 40 mg once daily or placebo . The intention to treat and per protocol population consisted of 819 and 578 patients , respectively . Results : In the per protocol population , 625 of the nisoldipine treated and 655 of the placebo treated patients ( NS ) showed angiographic progression in at least one coronary arterial segment , defined as an increase in diameter stenosis of ≥ 13 % . The average minimum luminal diameter of the non-dilated lesions decreased by 0.163 mm and 0.167 mm in the nisoldipine and placebo groups , respectively ( NS ) . The respective numbers of new lesions detected were 7 and 13 ( NS ) . In the intention to treat population , the rates of death , stroke , and acute myocardial infa rct ion were similar in both treatment groups . However , nisoldipine use was associated with fewer revascularisation procedures and thus the percentage of patients with any clinical event was lower ( 44.6 % v 52.6 % , p = 0.02 ) . Conclusions : Nisoldipine has no demonstrable effect on the angiographic progression of coronary atherosclerosis or the risk of major cardiovascular events but its use is associated with fewer revascularisation procedures Results of the European Working Party on High Blood Pressure in the Elderly ( EWPHE ) trial have been analysed in relation to age , sex , blood pressure , and previous cardiovascular disease . Cardiovascular mortality and the cardiovascular study -terminating events were significantly and independently related to treatment , age , cardiovascular complications at r and omisation , and systolic but not diastolic blood pressure . The benefits of treatment observed in the trial seemed to be independent of entry blood pressure and the presence or absence of cardiovascular complications at entry . There was some evidence that treatment effect decreases with advancing age . Little or no benefit from treatment could be demonstrated in patients over the age of 80 years , the great majority of whom were women This report from the double-blind placebo-controlled SYST-EUR trial investigated whether modern antihypertensive drugs are suitable for maintaining long-term BP control in older ( > or = 60 years of age ) subjects with isolated systolic hypertension ( SBP 160 - 219 mmHg and DBP < 95 mmHg ) . Active treatment consisted of nitredipine ( 10 - 40 mg/day ) with the possible addition of enalapril ( 5 - 20 mg/day ) and hydrochlorothiazide ( 12.5 - 25 mg/day ) , if necessary to reduce SBP to < 150 mmHg and by > or = 20 mmHg . Matching placebos were used in the control group . This analysis was restricted to 18 months of follow-up . The placebo ( n = 456 ) and active treatment ( n = 485 ) groups had similar characteristics at r and omisation ( sitting pressure 176/85 mmHg ; age 73 years ) .  SBP fell ( P < 0.001 ) on average 10 mmHg more on active treatment than on placebo and DBP 4 mmHg more . Fewer patients remained on monotherapy in the placebo than in the active treatment group ( P < 0.001 ) ; on placebo the second and third line medications were started earlier ( P < 0.001 ) . Nitrendipine tablets were discontinued in nine patients on placebo and in 29 patients assigned to active treatment ( P < 0.001 ) . In conclusion , a significant BP reduction can be achieved and maintained in older patients with isolated systolic hypertension treated with a calcium antagonist ( associated with a converting-enzyme inhibitor and a thiazide , where necessary ) . Whether this BP reduction results in a clinical ly meaningful decrease of cardiovascular complications is under investigation The relation between serum cholesterol and mortality was investigated in 822 elderly hypertensive patients r and omly assigned to treatment with diuretics , with or without methyldopa , or placebo .  Cox 's proportional hazards model showed that pretreatment serum total cholesterol levels were independently and inversely correlated with total mortality ( p = 0.03 ) , noncardiovascular mortality ( p = 0.02 ) , and cancer mortality ( p = 0.04 ) during treatment . Total and noncardiovascular mortality were also negatively correlated with pretreatment hemoglobin levels and body weight . All factors being equal , an increase in total serum cholesterol of 2.3 mmol/L was associated with a one-year prolongation of survival . After adjustment for gender , age , pretreatment cardiovascular complications , and systolic pressure , the correlations between serum cholesterol and cardiovascular and cardiac mortality were not significant Angiotensin-converting enzyme inhibitors improve endothelial function , inhibit experimental atherogenesis , and decrease ischemic events . The Quinapril Ischemic Event Trial was design ed to test the hypothesis that quinapril 20 mg/day would reduce ischemic events ( the occurrence of cardiac death , resuscitated cardiac arrest , nonfatal myocardial infa rct ion , coronary artery bypass grafting , coronary angioplasty , or hospitalization for angina pectoris ) and the angiographic progression of coronary artery disease in patients without systolic left ventricular dysfunction . A total of 1,750 patients were r and omized to quinapril 20 mg/day or placebo  and followed a mean of 27 + /- 0.3 months . The 38 % incidence of ischemic events was similar for both groups ( RR 1.04 ; 95 % confidence interval 0.89 to 1.22 ; p = 0.6 ) . There was also no significant difference in the incidence of patients having angiographic progression of coronary disease ( p = 0.71 ) . The rate of development of new coronary lesions was also similar in both groups ( p = 0.35 ) . However , there was a difference in the incidence of angioplasty for new ( previously unintervened ) vessels ( p = 0.018 ) . Quinapril was well tolerated in patients after angioplasty with normal left ventricular function . Quinapril 20 mg did not significantly affect the overall frequency of clinical outcomes or the progression of coronary atherosclerosis . However , the absence of the demonstrable effect of quinapril may be due to several limitations in study design 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 BACKGROUND Treatment with angiotensin-converting-enzyme ( ACE ) inhibitors reduces the rate of cardiovascular events among patients with left-ventricular dysfunction and those at high risk of such events . We assessed whether the ACE inhibitor perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease and no apparent heart failure . METHODS We recruited patients from October , 1997 , to June , 2000 . 13655 patients were registered with previous myocardial infa rct ion ( 64 % ) , angiographic evidence of coronary artery disease ( 61 % ) , coronary revascularisation ( 55 % ) , or a positive stress test only ( 5 % ) . After a run-in period of 4 weeks , in which all patients received perindopril , 12218 patients were r and omly assigned perindopril 8 mg once daily ( n=6110 ) , or matching placebo ( n=6108 ) . The mean follow-up was 4.2 years , and the primary endpoint was cardiovascular death , myocardial infa rct ion , or cardiac arrest . Analysis was by intention to treat . FINDINGS Mean age of patients was 60 years ( SD 9 ) , 85 % were male , 92 % were taking platelet inhibitors , 62 % beta blockers , and 58 % lipid-lowering therapy . 603 ( 10 % ) placebo and 488 ( 8 % ) perindopril patients experienced the primary endpoint , which yields a 20 % relative risk reduction ( 95 % CI 9 - 29 , p=0.0003 ) with perindopril . These benefits were consistent in all predefined subgroups and secondary endpoints . Perindopril was well tolerated . INTERPRETATION Among patients with stable coronary heart disease without apparent heart failure , perindopril can significantly improve outcome . About 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event . Treatment with perindopril , on top of other preventive medications , should be considered in all patients with coronary heart disease 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 The Systolic Hypertension in the Elderly Program ( SHEP ) Pilot Study was conducted to determine the feasibility of conducting a long-term placebo-controlled r and omized clinical trial in elderly subjects . Enrolled in the study were 551 men and women between the ages of 60 and 90 years with isolated systolic hypertension ( SBP greater than or equal to 160 mmHg and DBP less than 90 mmHg ) . The study showed that it is possible to recruit old and very old subjects into a clinical trial ; the elderly are good compliers ( drugs and follow-up visits ) , with some decline after the age of 80 ; control of blood pressure was accomplished in the large majority of patients ; evaluation of side effects represents a potential problem as varied complaints increase with age thus creating difficulties in distinguishing those attributed to the study drug ; and finally , cause-specific mortality is probably preferable to all-cause mortality as an end-point in prevention trials of antihypertensive regimens BACKGROUND Microalbuminuria and hypertension are risk factors for diabetic nephropathy . Blockade of the renin-angiotensin system slows the progression to diabetic nephropathy in patients with type 1 diabetes , but similar data are lacking for hypertensive patients with type 2 diabetes . We evaluated the renoprotective effect of the angiotensin-II-receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria . METHODS A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this multinational , r and omized , double-blind , placebo-controlled study of irbesartan , at a dose of either 150 mg daily or 300 mg daily , and were followed for two years . The primary outcome was the time to the onset of diabetic nephropathy , defined by persistent albuminuria in overnight specimens , with a urinary albumin excretion rate that was greater than 200 microg per minute and at least 30 percent higher than the base-line level . RESULTS The base-line characteristics in the three groups were similar . Ten of the 194 patients in the 300-mg group ( 5.2 percent ) and 19 of the 195 patients in the 150-mg group ( 9.7 percent ) reached the primary end point , as compared with 30 of the 201 patients in the placebo group ( 14.9 percent ) ( hazard ratios , 0.30 [ 95 percent confidence interval , 0.14 to 0.61 ; P < 0.001 ] and 0.61 [ 95 percent confidence interval , 0.34 to 1.08 ; P=0.081 for the two irbesartan groups , respectively ) . The average blood pressure during the course of the study was 144/83 mm Hg in the placebo group , 143/83 mm Hg in the 150-mg group , and 141/83 mm Hg in the 300-mg group ( P=0.004 for the comparison of systolic blood pressure between the placebo group and the combined irbesartan groups ) . Serious adverse events were less frequent among the patients treated with irbesartan ( P=0.02 ) . CONCLUSIONS Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria The purpose of this study was to evaluate the long-term safety and efficacy of moexipril , a non-sulphydryl angiotensin converting enzyme inhibitor , alone or in combination with hydrochlorothiazide in older patients with hypertension . One hundred and seventy two hypertensive men and women , 65 - 80 years old , with seated DBP between 95 and 114 mm Hg were studied . The study was a 2 year , multicentre ( 12 centres ) , open-label protocol of moexipril monotherapy or combination therapy ( with hydrochlorothiazide ) .  Blood pressure , pulse rate , weight , adverse effects and laboratory studies were assessed following moexipril at 7.5 or 15 mg once daily or 7.5 or 15 mg daily in combination with 25 mg of hydrochlorothiazide if the seated DBP remained > or = 90 mm Hg on moexipril monotherapy . The primary measure of efficacy was a change from baseline in seated DBP . Secondary outcome measures included changes in seated DBP , pulse rate , laboratory parameters and adverse side-effects . Following 1 year of therapy in 135 patients , the BP fell 16/14 mm Hg among patients receiving moexipril monotherapy and 27/17 mm Hg for those receiving combined therapy compared with baseline ( P < 0.001 for both ) . After 2 years of treatment , reductions were similar in 120 patients . Nineteen patients ( 11 % ) were prematurely withdrawn from the study because of inadequate therapeutic response and 28 ( 16 % ) because of adverse experiences . There were no significant changes in pulse rate or postural reductions in BP on either moexipril monotherapy or combination treatment . Three adverse side-effects occurred at a frequency exceeding 2 % that were possibly or probably attributable to moexipril or combination therapy : hypotension ( 2 % ) , dizziness ( 6 % ) and increased cough ( 12 % ) . There were no clinical ly relevant mean group changes from baseline laboratory values in the treatment groups . In conclusion , these long-term data demonstrate that moexipril , either alone or in combination with hydrochlorothiazide , has long-term anti-hypertensive efficacy and is generally well tolerated in elderly patients with hypertension BACKGROUND Angiotensin-converting-enzyme ( ACE ) inhibitors are effective in reducing the risk of heart failure , myocardial infa rct ion , and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure . ACE inhibitors have also been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure . METHODS In the Prevention of Events with Angiotensin Converting Enzyme Inhibition ( PEACE ) Trial , we tested the hypothesis that patients with stable coronary artery disease and normal or slightly reduced left ventricular function derive therapeutic benefit from the addition of ACE inhibitors to modern conventional therapy . The trial was a double-blind , placebo-controlled study in which 8290 patients were r and omly assigned to receive either  tr and olapril  at a target dose of  4 mg  per  day ( 4158 patients ) or matching placebo ( 4132 patients ) . RESULTS The mean ( + /-SD ) age of the patients was 64+/-8 years , the mean blood pressure 133+/-17/78+/-10 mm Hg , and the mean left ventricular ejection fraction 58+/-9 percent . The patients received intensive treatment , with 72 percent having previously undergone coronary revascularization and 70 percent receiving lipid-lowering drugs . The incidence of the primary end point -- death from cardiovascular causes , myocardial infa rct ion , or coronary revascularization -- was 21.9 percent in the tr and olapril group , as compared with 22.5 percent in the placebo group ( hazard ratio in the tr and olapril group , 0.96 ; 95 percent confidence interval , 0.88 to 1.06 ; P=0.43 ) over a median follow-up period of 4.8 years . CONCLUSIONS In patients with stable coronary heart disease and preserved left ventricular function who are receiving " current st and ard " therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease , there is no evidence that the addition of an ACE inhibitor provides further benefit in terms of death from cardiovascular causes , myocardial infa rct ion , or coronary revascularization Syst-Eur is a multicentre placebo-controlled outcome trial , design ed by the European Working Party on High Blood Pressure in the Elderly ( EWPHE ) , to investigate the effect of antihypertensive treatment on the incidence of stroke in elderly patients with isolated systolic hypertension ( ISH ) . Eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160 - 219 mmHg with a diastolic blood pressure less than 95 mmHg . The present paper in an interim report on the first 316 patients r and omized into this trial . The placebo ( N = 170 ) and active treatment ( N = 146 ) groups were similar at r and omization with respect to age ( 73 + /- 8 years ; mean + /- st and ard deviation ) , sitting blood pressure ( 178 + /- 12/85 + /- 7 mmHg ) , percentage men ( 34 % ) and percentage of patients with cardiovascular complications ( 29 % ) . After r and omization blood pressure fell more ( p < 0.001 ) on active treatment than in the placebo group ( 19 + /- 20/6 + /- 10 mmHg versus 7 + /- 19/1 + /- 10 mmHg for the sitting blood pressure ) . This first interim report on the Syst-Eur trial demonstrates that a multinational trial in elderly patients with ISH is feasible and that a significant blood pressure difference between the 2 treatment groups can be achieved and maintained . New centres are being recruited in order to r and omize a total of 3,000 patients Elderly hypertensive patients were r and omly assigned to treatment with diuretics and methyldopa  ( n = 352 ) or placebo ( n = 339 ) , and divided into three groups , each according to their blood pressures , after nine months of treatment . Subsequently , 65 placebo patients and 56 treated patients died . A U-shaped relation was seen in treated patients between mortality and systolic blood pressure , and in placebo patients between mortality and diastolic blood pressure . Whereas in treated patients , the highest mortality was seen in patients with the lowest diastolic pressure , the lowest mortality was seen in the group with the highest diastolic pressure . The increased mortality in treated patients with the lowest blood pressure may not be drug-induced , but an expression of deterioration in general health , as indicated by the decreases in body weight and hemoglobin levels found in patients with the lowest blood pressures in previous analyses of these data Although limited numbers of elderly subjects have occasionally been included in population -based studies , only a few studies have been conducted specifically on elderly hypertensives , and practically none at a population level . We studied 655 hypertensive subjects from a cohort of 2,254 elderly subjects . The intervention consisted of the creation of a Hypertension Out patients ' Clinic under our auspices but with complete co-operation from general practitioners , r and omizing the identified hypertensive patients into pre-established therapeutic drug regimens , and early follow-up recording of mortality for 7 years . The drugs used were clonidine ( n = 61 ) , nifedipine ( n = 146 ) and the fixed combination of atenolol+chlorthalidone ( n = 144 ) ; 304 subjects underwent " free therapy " by their personal physicians without any special intervention . There were 1,404 normotensive subjects . Overall 7-year follow-up mortality was 34.9 % in the hypertensive subjects receiving " free therapy " , 22.5 % in those receiving " special care " , and 24.2 % in the normotensives . Cardiovascular mortality was respectively 23.7 % , 12.2 % , and 12.0 % . Overall and cardiovascular annual cumulative mortality were significantly lower in the < < special therapy > > than in the < < free therapy > > group . The fixed combination of atenolol and chlorthalidone  reduced mortality below that of the normotensives , independent of other cardiovascular risk factors Orthostatic fall in blood pressure in the very elderly hypertensive : results from the Hypertension in the Very Elderly Trial ( HYVET ) — A r and omised trial of the treatment of hypertension in 884 patients aged 60 to 79 years at the onset showed a reduction of 18/11 mm Hg in blood pressure over a mean follow up period of 4.4 years . The principal antihypertensive agents were atenolol and bendrofluazide . There was a reduction in the rate of fatal stroke in the treatment group to 30 % of that in the control group ( 95 % confidence interval 11 - 84 % , p less than 0.025 ) . The rate of all strokes ( fatal and non-fatal ) in the treatment group was 58 % of that in the control group ( 95 % confidence interval 35 - 96 % , p less than 0.03 ) . The incidence of myocardial infa rct ion and total mortality was unaffected by treatment . Question naires completed by the patients and their relatives failed to identify any differences in symptoms that were likely to be due to treatment BACKGROUND Characteristics such as age and race are often cited as determinants of the response of blood pressure to specific antihypertensive agents , but this clinical ly important issue has not been examined in sufficiently large trials , involving all st and ard treatments , to determine the effect of such factors . METHODS In a r and omized , double-blind study at 15 clinics , we assigned 1292 men with diastolic blood pressures of 95 to 109 mm Hg , after a placebo washout period , to receive  placebo or one of six drugs : hydrochlorothiazide ( 12.5 to 50 mg per day ) , atenolol ( 25 to 100 mg per day ) , captopril ( 25 to 100 mg per day ) , clonidine ( 0.2 to 0.6 mg per day ) , a sustained-release preparation of diltiazem ( 120 to 360 mg per day ) , or prazosin ( 4 to 20 mg per day ) . The drug doses were titrated to a goal of less than 90 mm Hg for maximal diastolic pressure , and the patients continued to receive therapy for at least one year . RESULTS The mean ( + /- SD ) age of the r and omized patients was 59 + /- 10 years , and 48 percent were black . The average blood pressure at base line was 152 + /- 14/99 + /- 3 mm Hg . Diltiazem therapy  had the highest rate of success : 59 percent of the treated patients had reached the blood-pressure goal at the end of the titration phase and had a diastolic blood pressure of less than 95 mm Hg at one year .  Atenolol  was successful by this definition in 51 percent of the patients , clonidine in 50 percent , hydrochlorothiazide in 46 percent , captopril in 42 percent , and prazosin in 42 percent ; all these agents were superior to placebo ( success rate , 25 percent ) . Diltiazem ranked first for younger blacks ( < 60 years ) and older blacks ( > or = 60 years ) , among whom the success rate was 64 percent , captopril for younger whites ( success rate , 55 percent ) , and atenolol for older whites ( 68 percent ) . Drug intolerance was more frequent with clonidine ( 14 percent ) and prazosin ( 12 percent ) than with the other drugs . CONCLUSIONS Among men , race and age have an important effect on the response to single-drug therapy for hypertension . In addition to cost and quality of life , these factors should be considered in the initial choice of a drug BACKGROUND In 1989 , the European Working Party on High Blood Pressure in the Elderly started the double-blind , placebo-controlled , Systolic Hypertension in Europe Trial to test the hypothesis that antihypertensive drug treatment would reduce the incidence of fatal and nonfatal stroke in older patients with isolated systolic hypertension . This report addresses whether the benefit of antihypertensive treatment varied according to sex , previous cardiovascular complications , age , initial blood pressure ( BP ) , and smoking or drinking habits in an intention-to-treat analysis and explores whether the morbidity and mortality results were consistent in a per- protocol analysis . METHODS After stratification for center , sex , and cardiovascular complications , 4695 patients 60 years of age or older with a systolic BP of 160 to 219 mm Hg and diastolic BP less than 95 mm Hg were r and omized . Active treatment consisted of nitrendipine ( 10 - 40 mg/d ) , with the possible addition of enalapril maleate ( 5 - 20 mg/d ) and /or hydrochlorothiazide ( 12.5 - 25 mg/d ) , titrated or combined to reduce the sitting systolic BP by at least 20 mm Hg , to below 150 mm Hg . In the control group , matching placebo tablets were employed similarly . RESULTS In the intention-to-treat analysis , male sex , previous cardiovascular complications , older age , higher systolic BP , and smoking at r and omization were positively and independently correlated with cardiovascular risk . Furthermore , for total ( P = .009 ) and cardiovascular ( P = .09 ) mortality , the benefit of antihypertensive drug treatment weakened with advancing age ; for total mortality ( P = .05 ) , the benefit increased with higher systolic BP at entry , while for fatal and nonfatal stroke ( P = .01 ) , it was most evident in nonsmokers ( 92.5 % of all patients ) . In the per protocol analysis , active treatment reduced total mortality by 24 % ( P = .05 ) , reduced all fatal and nonfatal cardiovascular end points by 32 % ( P<.001 ) , reduced all strokes by 44 % ( P = .004 ) , reduced nonfatal strokes by 48 % ( P = .005 ) , and reduced all cardiac end points , including sudden death , by 26 % ( P = .05 ) . CONCLUSIONS In elderly patients with isolated systolic hypertension , stepwise antihypertensive drug treatment , starting with the dihydropyridine calcium channel blocker nitrendipine , improves prognosis . The per- protocol analysis suggested that treating 1000 patients for 5 years would prevent 24 deaths , 54 major cardiovascular end points , 29 strokes , or 25 cardiac end points . The effects of antihypertensive drug treatment on total and cardiovascular mortality may be attenuated in very old patients Five hundred and seven elderly hypertensive patients were followed for 1 year , 371 for 2 years and 270 for 3 years in a double-blind , r and omized , controlled trial in which they received either placebo or 25 - 50 mg hydrochlorothiazide and 50 - 100 mg of triamterene daily . One third of the active treatment group also received 250 mg to 2 g methyldopa daily . After 1 year the active treatment group had an average increase in fasting blood sugar of 2.5 mg/dl compared with an average fall of 1.4 mg/dl in the placebo group ( P = 0.01 ) . The increase in blood sugar 1 hour and 2 hours after 50 g oral glucose tended to be greater in the actively treated group but these increases did not achieve statistical significance . The effects of diuretic treatment were established after one year and did not increase further over the next 2 years . Overall there was an increase in fasting blood sugar of 5 mg/dl in the active treatment group which occurred mainly in the first year . The hyperglycaemic effect of diuretics appeared to be partly or wholly related to potassium loss since , in both groups , impairment of glucose tolerance was most marked in those in whom serum potassium decreased . The measures of blood sugar were also positively related to systolic pressure before and after treatment 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 Objective This long-term study investigated the widely accepted hypothesis that ambulatory pressure does not decrease in patients given  placebo . Methods : One hundred and twelve older ( ±60 years ) out patients with isolated systolic hypertension were recruited . Treatment consisted of a placebo during a 3-month baseline period and long-term follow-up . Results : At baseline , on placebo  treatment , clinic systolic/diastolic ( SBP/DBP ) blood pressure ( ±SD ) averaged 176±12/86±7 mmHg and 24-h SBP/DBP 151 ± 15/81 ± 10mmHg . These pressures were unaltered in 51 patients in whom the baseline measurements were repeated after a further month on placebo . After the 112 patients had received placebo for 1 year ( median ) , clinic SBP/DBP fell by 6.6±15.9 ( P < 0.001)/1.4±7.4 (P=0.06)mmHg and 24-h SBP by 2.4±10.7mmHg ( P<0.05 ) , whereas 24-h DBP did not change significantly . The 24-h SBP decreased more with higher baseline level and longer follow-up ( 5–21 months ) . Conclusions : These findings in older patients with isolated systolic hypertension suggest that in long-term studies the ambulatory pressure may slightly but significantly decrease on a placebo . Like those using conventional sphygmomano-metry , long-term studies using non-invasive ambulatory monitoring require a placebo-controlled design 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 BACKGROUND Renal function declines progressively in patients who have diabetic nephropathy , and the decline may be slowed by antihypertensive drugs . The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy . METHODS We performed a r and omized , controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was > or = 500 mg per day and the serum creatinine concentration was < or = 2.5 mg per deciliter ( 221 mumol per liter ) .  Blood-pressure goals were defined to achieve control during a median follow-up of three years . The primary end point was a doubling of the base-line serum creatinine concentration . RESULTS Two hundred seven patients received captopril , and 202 placebo .  Serum creatinine concentrations doubled in 25 patients in the captopril group , as compared with 43 patients in the placebo group ( P = 0.007 ) . The associated reductions in risk of a doubling of the serum creatinine concentration were 48 percent in the captopril group as a whole , 76 percent in the subgroup with a baseline serum creatinine concentration of 2.0 mg per deciliter ( 177 mumol per liter ) , 55 percent in the subgroup with a concentration of 1.5 mg per deciliter ( 133 mumol per liter ) , and 17 percent in the subgroup with a concentration of 1.0 mg per deciliter ( 88.4 mumol per liter ) . The mean ( + /- SD ) rate of decline in creatinine clearance was 11 + /- 21 percent per year in the captopril group and 17 + /- 20 percent per year in the placebo group ( P = 0.03 ) . Among the patients whose base-line serum creatinine concentration was > or = 1.5 mg per deciliter , creatinine clearance declined at a rate of 23 + /- 25 percent per year in the captopril group and at a rate of 37 + /- 25 percent per year in the placebo group ( P = 0.01 ) . Captopril treatment was associated with a 50 percent reduction in the risk of the combined end points of death , dialysis , and transplantation that was independent of the small disparity in blood pressure between the groups . CONCLUSIONS Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone Abstract Morbidity , mortality , and target organ function have been followed in a double-blind study of a predominantly Negro clinic population with mild to moderately severe hypertension over a 2-year period . Patients were placed r and omly on either hypotensive drug therapy ( reserpine , thiazide , guanethedine ) or matched placebos . There were 6 treatment failures among 45 patients in the treatment group and 19 failures among 42 patients in the placebo group . All but one of the failures in the placebo group improved or cleared upon early institution of appropriate hypertensive and supportive therapy . Abnormalities in carbohydrate metabolism and serum uric acid levels were found in patients receiving long-term thiazide therapy .  Hypertensive disease in the Negro population of Baltimore is a serious , life-threatening condition . Our study provides evidence of the need for continuous close supervision , and the provision of organized teams devoted to the care , of such a population Abstract Aims /hypothesisThe renal and cardiovascular protective effects of angiotensin receptor blocker ( ARB ) remain controversial in type 2 diabetic patients treated with a contemporary regimen including an angiotensin converting enzyme inhibitor ( ACEI ) . Methods We examined the effects of olmesartan , an ARB , on primary composite outcome of doubling of serum creatinine , endstage renal disease and death in type 2 diabetic patients with overt nephropathy . Secondary outcome included composite cardiovascular outcomes , changes in renal function and proteinuria . R and omisation and allocation to trial group were carried out by a central computer system . Participants , caregivers , the people carrying out examinations and people assessing the outcomes were blinded to group assignment . Results Five hundred and seventy-seven ( 377 Japanese , 200 Chinese ) patients treated with antihypertensive therapy ( 73.5 % [ n = 424 ] received concomitant ACEI ) , were given either once-daily olmesartan ( 10–40 mg ) ( n = 288 ) or placebo ( n = 289 ) over 3.2 ± 0.6 years ( mean±SD ) . In the olmesartan group , 116 developed the primary outcome ( 41.1 % ) compared with 129 ( 45.4 % ) in the placebo group ( HR 0.97 , 95 % CI 0.75 , 1.24 ; p = 0.791 ) . Olmesartan significantly decreased blood pressure , proteinuria and rate of change of reciprocal serum creatinine . Cardiovascular death was higher in the olmesartan group than the placebo group ( ten vs three cases ) , whereas major adverse cardiovascular events ( cardiovascular death plus non-fatal stroke and myocardial infa rct ion ) and all-cause death were similar between the two groups ( major adverse cardiovascular events 18 vs 21 cases , all-cause deaths ; 19 vs 20 cases ) . Hyperkalaemia was more frequent in the olmesartan group than the placebo group ( 9.2 % vs 5.3 % ) . Conclusions /interpretationOlmesartan was well tolerated but did not improve renal outcome on top of ACEI . Trial registration : Clinical Trials.gov NCT00141453 Funding : The ORIENT study was supported by a research grant from Daiichi Sankyo OBJECTIVES The purpose of this study was to investigate the effects of angiotensin II receptor blockers on the prevention of cardiovascular events in patients with coronary artery disease ( CAD ) . BACKGROUND Angiotensin II may contribute to the pathogenesis of CAD . Long-term clinical trials have shown that blockade of the renin-angiotensin system can reduce cardiovascular events in patients with acute myocardial infa rct ion complicated by heart failure . METHODS Patients with a history of coronary intervention and no significant coronary stenosis on follow-up angiography 6 months after intervention were r and omly assigned into a c and esartan group ( n = 203 ; baseline treatment plus c and esartan 4 mg/d ) or a control group ( n = 203 ; baseline treatment alone ) . The primary end point was a composite of revascularization , nonfatal myocardial infa rct ion , or cardiovascular death . The secondary end point was hospitalization for cardiovascular causes . RESULTS There were no changes in blood pressure and in other coronary risk factors in either group during a mean follow-up of 24 months . Primary end point risk was significantly lower in the c and esartan group ( n = 12 ) than in control group patients ( n = 25 ) ( P = .03 ) . C and esartan treatment reduced primary end point risk ( 5.9 % vs 12.3 % for control subjects ; relative risk , 0.47 ; 95 % CI , 0.24 to 0.93 ) . The incidence of all events including secondary end points and noncardiovascular death was significantly lower in the c and esartan group than in control group patients ( 23 vs 40 cases ) ( P = .02 ) . CONCLUSIONS Relatively low-dose c and esartan , which did not alter blood pressure levels , reduces cardiovascular risk in high-risk patients with CAD 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 & NA ; Isolated systolic hypertension ( ISH ) is a definite risk factor for cardiovascular complications ( i.e. , cardiac failure , coronary artery disease , and stroke ) independent of diastolic elevation . The prevalence of ISH is estimated to be approximately 15‐20 % in the population above the age of 60 years , and increases with advancing age . The Systolic Hypertension in the Elderly ( SHELL ) study is planned to evaluate the efficacy and tolerability of lacidipine , matched with the diuretic chlorthalidone , in treatment of ISH in elderly hypertensive patients ( EHP ) . One hundred fifteen Italian centers will participate in the study . Fifty centers are associated with the Società Italiana di Geriatria Ospedaliera and 65 centers are departments of internal medicine or outpatient clinics for management of hypertension . A total of 4,800 patients will be enrolled in the trial . Two subprojects will consist of periodical echocardiographic evaluation and 24‐h ambulatory blood pressure monitoring . The primary end point of the SHELL study is the incidence of cardiovascular and cerebrovascular events in EHP with ISH , treated with either lacidipine or chlorthalidone . In particular , the SHELL trial is intended to determine whether lacidipine treatment will significantly reduce fatal myocardial events and total cardiovascular mortality BACKGROUND One third of patients treated for hypertension attain adequate blood pressure ( BP ) control , and multidrug regimens are often required . Given the lifelong nature of hypertension , there is a need to evaluate the long-term efficacy and tolerability of higher doses of combination anti-hypertensive therapies . OBJECTIVE This study investigated the efficacy and tolerability of valsartan ( VAL ) or hydrochlorothiazide (HCTZ)-monotherapy and higher-dose combinations in patients with essential hypertension . METHODS The first part of this study was an 8-week , multicenter , r and omized , double-blind , placebo controlled , parallel-group trial . Patients with essential hypertension ( mean sitting diastolic BP [ MSDBP ] , > or = 95 mm Hg and < 110 mm Hg ) were r and omized to 1 of 8 treatment groups : VAL 160 or 320 mg ; HCTZ 12.5 or 25 mg ; VAL/HCTZ 160/12.5 , 320/12.5 , or 320/25 mg ; or placebo .  Mean changes in MSDBP and mean sitting systolic BP ( MSSBP ) were analyzed at the 8-week core study end point . VAL/HCTZ 320/12.5 and 320/25 mg were further investigated in a 54-week , open-label extension . Response was defined as MSDBP < 90 mm Hg or a > or = 10 mm Hg decrease compared to baseline . Control was defined as MSDBP < 90 mm Hg compared with baseline . Tolerability was assessed by monitoring adverse events at r and omization and all subsequent study visits and regular evaluation of hematology and blood chemistry . RESULTS A total of 1346 patients were r and omized into the 8-week core study ( 734 men , 612 women ; 924 white , 291 black , 23 Asian , 108 other ; mean age , 52.7 years ; mean weight , 92.6 kg ) . All active treatments were associated with significantly reduced MSSBP and MSDBP during the core 8-week study , with each monotherapy significantly contributing to the overall effect of combination therapy ( VAL and HCTZ , P < 0.001 ) . Each combination was associated with significantly greater reductions in MSSBP and MSDBP compared with the monotherapies and placebo ( all , P < 0.001 ) . The mean reduction in MSSBP/MSDBP with VAL/HCTZ 320/25 mg was 24.7/16.6 mm Hg , compared with 5.9/7.0 mm Hg with placebo . The reduction in MSSBP was significantly greater with VAL/HCTZ 320/25 mg compared with VAL/HCTZ 160/12.5 mg ( P < 0.002 ) . Rates of response and BP control were significantly higher in the groups that received combination treatment compared with those that received monotherapy . The incidence of hypokalemia was lower with VAL/HCTZ combinations ( 1.8%-6.1 % ) than with HCTZ monotherapies ( 7.1%-13.3 % ) . The majority of adverse events in the core study were of mild to moderate severity . The efficacy and tolerability of VAL/HCTZ combinations were maintained during the extension ( 797 patients ) . CONCLUSIONS In this study population , combination therapies with VAL/HCTZ were associated with significantly greater BP reductions compared with either monotherapy , were well tolerated , and were associated with less hypokalemia than HCTZ alone Summary 1 . A total of 450 hypertensive patients above the age of 60 years have entered the double-blind multicentre trial of the European Working Party on High blood pressure in Elderly ( EWPHE ) . After stratification and r and omization half were treated with one capsule daily containing 25 mg of hydrochlorothiazide and 50 mg of triamterene and half were given placebo . In those receiving active treatment , if blood pressure control was not adequate they were given a second capsule and if necessary up to 2 g of methyldopalday . 2 . No significant differences between the groups were present before r and omization . A significant blood pressure difference of 25/10 mmHg was obtained between the groups and maintained during 4 years of follow-up . No major disturbances in serum potassium or serum sodium were noted with the present drug combination . 3 . During the initial phase an increase in serum creatinine and serum uric acid was noted in the actively treated group , which was maintained during the later years . This increase in serum creatinine in the actively treated group was related ( P = 0.003 and r = -0.247 ) to the decrease in sitting systolic blood pressure . Changes in serum uric acid were ( r = 0.3 and P = 0 - 003 ) correlated with the changes in serum creatinine both in the placebo and in the actively treated group , but Correspondence : Professor Dr A. Amery , Hypertension and Cardiovascular Rehabilitation Unit , Academic Hospital , St Raphael , Kapucijnenvoer 35 , B-3000 Leuven , Belgium . independent of the change in creatinine ; the serum uric acid was on average 1 mg higher in the actively treated than in the placebo group . 4 . Fasting blood glucose did not change significantly in the placebo-treated group but in the active treatment group the rise was statistically signficant . 5 . A favourable influence on prognosis by active treatment can be expected on the basis of the blood pressure reduction and in the absence of major electrolytes disturbances . However , the balance between this decreased risk and the increased risk produced by the rise in blood glucose and the other treatment effects remains to be determined . Therefore the trial continues and more patients are being admitted Background and Purpose : & bgr;‐Blockers prevent vascular events in patients after myocardial infa rct ion and lower blood pressure , the main risk factor for stroke . Hence , we assessed the effects of atenolol on the occurrence of death from vascular causes , stroke , or myocardial infa rct ion and on blood pressure in patients after a transient ischemic attack or nondisabling ischemic stroke . Methods : In a double‐blind , placebo‐controlled r and omized clinical trial we studied the occurrence of the outcome event death from vascular causes , nonfatal stroke , or nonfatal myocardial infa rct ion and the outcome event fatal or nonfatal stroke as well as blood pressure on follow‐up . A total of 1,473 aspirin‐treated patients with transient ischemic attack or nondisabling ischemic stroke were r and omized to 50 mg atenolol daily or placebo . The mean follow‐up was 2.6 years . Results : Patients on atenolol had a risk of 97/732 ( 13.3 % ) for the combined outcome event versus a risk of 95/741 ( 12.8 % ) for those on placebo ( adjusted hazard ratio , 1.00 ; 95 % confidence interval , 0.76‐1.33 ) . The adjusted hazard ratio for fatal or nonfatal stroke was 0.82 ( 95 % confidence interval , 0.57‐1.19 ) . More patients on & bgr;‐blocker ( 153 ) reported adverse effects than on placebo ( 103 ) . At the first follow‐up visit after r and omization ( median at 4 months ) systolic blood pressure in the atenolol group had dropped by 8.0 mm Hg compared with 2.2 mm Hg in the placebo group ( difference , 5.8 mm Hg ; 95 % confidence interval , 2.9‐8.6 mm Hg ) . For diastolic blood pressure this difference was 2.9 mm Hg ( 95 % confidence interval , 1.5‐4.4 mm Hg ) . Conclusions : Our data neither confirm nor rule out that atenolol prevents important vascular events in patients after transient ischemic attack or nondisabling ischemic stroke , given the modest effect on blood pressure , the restrictions in patient selection , and the limited number of patient‐years . ( Stroke 1993;24:543‐548 BACKGROUND Drugs that inhibit the renin-angiotensin-aldosterone system benefit patients at risk for or with existing cardiovascular disease . However , evidence for this effect in Asian population s is scarce . We aim ed to investigate whether addition of an angiotensin receptor blocker , valsartan , to conventional cardiovascular treatment was effective in Japanese patients with cardiovascular disease . METHODS We initiated a multicentre , prospect i ve , r and omised controlled trial of 3081 Japanese patients , aged 20 - 79 years , ( mean 65 [ SD 10 ] years ) who were undergoing conventional treatment for hypertension , coronary heart disease , heart failure , or a combination of these disorders . In addition to conventional treatment , patients were assigned either to valsartan ( 40 - 160 mg per day ) or to other treatment without angiotensin receptor blockers . Our primary endpoint was a composite of cardiovascular morbidity and mortality . Analysis was by intention to treat . The study was registered at clintrials.gov with the identifier NCT00133328 . FINDINGS After a median follow-up of 3.1 years ( range 1 - 3.9 ) the primary endpoint was recorded in fewer individuals given valsartan than in controls ( 92 vs 149 ; absolute risk 21.3 vs 34.5 per 1000 patient years ; hazard ratio 0.61 , 95 % CI 0.47 - 0.79 , p=0.0002 ) . This difference was mainly attributable to fewer incidences of stroke and transient ischaemic attack ( 29 vs 48 ; 0.60 , 0.38 - 0.95 , p=0.028 ) , angina pectoris ( 19 vs 53 ; 0.35 , 0.20 - 0.58 , p<0.0001 ) , and heart failure ( 19 vs 36 ; 0.53 , 0.31 - 0.94 , p=0.029 ) in those given valsartan than in the control group . Mortality or tolerability did not differ between groups . INTERPRETATION The addition of valsartan to conventional treatment prevented more cardiovascular events than supplementary conventional treatment . These benefits can not be entirely explained by a difference in blood pressure control 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 The Systolic Hypertension in the Elderly ( SHEP ) pilot trial was a five-center study in which 551 persons aged 60 years or older with isolated systolic hypertension were given antihypertensive drugs or placebos in order to determine the effects on blood pressure control and possible side effects of therapy . A life events inventory was administered to the cohort one year into the study . Results of this inventory were then compared to blood pressure and changes in blood pressure in the placebo and active therapy groups . One or more of the life events assessed were present in about 65 % of the population . Although the sample was too small to detect very subtle effects , there was no evidence in this study that either individual or groups of life events play a major role in blood pressure regulation of persons with isolated systolic hypertension Background This long-term , multicenter , r and omized , double-blind , placebo-controlled , 2 × 2 factorial , angiographic trial evaluated the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis in normocholesterolemic patients . Methods and Results There were a total of 460 patients : 230 received simvastatin and 230 , a simvastatin placebo , and  229 received enalapril and 231 , an enalapril placebo ( some subjects received both drugs and some received a double placebo ) . Mean baseline measurements were as follows : cholesterol level , 5.20 mmol/L ; triglyceride level , 1.82 mmol/L ; HDL , 0.99 mmol/L ; and LDL , 3.36 mmol/L. Average follow-up was 47.8 months . Changes in quantitative coronary angiographic measures between simvastatin and placebo , respectively , were as follows : mean diameters , −0.07 versus −0.14 mm ( P = 0.004 ) ; minimum diameters , −0.09 versus −0.16 mm ( P = 0.0001 ) ; and percent diameter stenosis , 1.67 % versus 3.83 % ( P = 0.0003 ) . These benefits were not observed in patients on enalapril when compared with placebo . No additional benefits were seen in the group receiving both drugs . Simvastatin patients had less need for percutaneous transluminal coronary angioplasty ( 8 versus 21 events;P = 0.020 ) , and fewer enalapril patients experienced the combined end point of death/myocardial infa rct ion/stroke ( 16 versus 30;P = 0.043 ) than their respective placebo patients . Conclusions This trial extends the observation of the beneficial angiographic effects of lipid-lowering therapy to normocholesterolemic patients . The implication s of the neutral angiographic effects of angiotensin-converting enzyme inhibition are uncertain , but they deserve further investigation in light of the positive clinical benefits suggested here and seen elsewhere The present study of primary prevention in white men aged 40 to 64 years attempts to investigate whether a beta-blocker given as initial antihypertensive treatment would lower total mortality to a greater extent than thiazide diuretics .  Patients were r and omized to metoprolol ( n = 1609 , 8110 patient-years ) or a thiazide diuretic ( n = 1625 , 8070 patient-years ) . The median follow-up time was 4.2 years . The mean dose of metoprolol was 174 mg/d , and of thiazide diuretics , 46 mg/d of hydrochlorothiazide or 4.4 mg/d of bendroflumethiazide . Identical control of blood pressure was achieved using a fixed therapeutic schedule . Total mortality was significantly lower for metoprolol than for thiazide diuretics because of fewer deaths from coronary heart disease and stroke . Total mortality was also significantly lower in smokers r and omized to metoprolol .  The benefit demonstrated in patients treated with metoprolol seems to have important implication s for clinical practice The Hypertension Optimal Treatment ( HOT ) Study is an ongoing prospect i ve , r and omized , multicenter trial conducted in 26 countries . Its two main aims are to evaluate the relationship between three levels of target diastolic blood pressure ( < or = 90 , < or = 85 or < or = 80 mmHg ) and the incidence of cardiovascular morbidity and mortality in hypertensive patients and the effects on morbidity and mortality of a low dose , 75 mg daily , of acetylsalicylic acid ( ASA , aspirin ) compared with placebo .  Altogether 19,193 patients have been recruited and r and omized and one-year data are now available for all patients . This is a report on the blood pressures achieved , the tolerability and other available data after 12 months of follow-up of all patients . Special reference will be given to the subgroup of elderly patients ( > or = 65 years , n = 6,113 ) as compared to younger patients ( < 65 years , n = 13,080 ) . On average , the target group < or = 90 mmHg in diastolic blood pressure has reached 86 mmHg , the target group < or = 85 mmHg has reached 83 mmHg and the target group < or = 80 mmHg has reached 81 mmHg . The percentage of patients that has obtained their target blood pressures is 84 % in the target group < or = 90 mmHg , 72 % in the target group < or = 85 mmHg and 57 % in the target group < or = 80 mmHg at 12 months of follow-up . In the elderly subgroup ( > or = 65 years of age ) the percentage of patients at target is higher for all target groups , being 86 , 76 and 61 % , respectively , at 12 months . Antihypertensive treatment is initiated with a calcium antagonist , felodipine , at a dose of 5 mg once daily . If target blood pressure is not reached , additional antihypertensive therapy , with either an angiotensin converting enzyme ( ACE ) inhibitor or a beta-adrenoceptor blocking agent , is given . Further dose adjustments are made in accordance with a set protocol . As a fifth and final step a diuretic may be added . Side effects have been relatively few in this large multinational series of intensively treated hypertensive patients . Only ankle edema , 2.6 % and 3.0 % , and coughing , 1.3 % and 0.8 % , in young and elderly patients , respectively , exceed a frequency of 1 % , and 88 % of all patients are still taking their baseline therapy felodipine after one year . The one-year data presented here indicate that it should be possible to fulfill the primary aims of the HOT Study 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 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 Background and objective . This interim report from the Syst-Eur trial investigated the level of blood pressure control achieved during the double-blind period in patients followed in general practice s. Methods . In the Syst-Eur trial elderly patients ( 60 years or older ) with isolated systolic hypertension were r and omized to either active or placebo treatment . Active treatment consisted of nitrendipine combined with enalapril and /or hydrochlorothiazide to reduce systolic pressure to Results . This analysis was restricted to patients of general practitioners who had been followed for at least 12 months . The placebo ( N = 204 ) and active treatment ( N = 217 ) groups had similar characteristics at r and omization . At one year , the difference in sitting pressure between the two treatment groups was 10 mmHg systolic and 4 mmHg diastolic . Fewer patients remained on monotherapy in the placebo than in the active treatment group and on placebo the second and third line medications were started earlier . Nitrendipine tablets were discontinued in 10 patients on placebo and in 21 patients assigned to active treatment ( P Conclusions . A significant blood pressure reduction can be achieved and maintained in older patients with isolated systolic hypertension followed by general practitioners . Whether this blood pressure reduction results in a clinical ly meaningful decrease of cardiovascular complications is under investigation . Keywords . Antihypertensive treatment , general practice , isolated systolic hypertension , r and omized clinical trial OBJECTIVE To compare the rate of progression of mean maximum intimal-medial thickness ( IMT ) in carotid arteries , using quantitative B-mode ultrasound imaging , during  antihypertensive therapy with isradipine vs hydrochlorothiazide . DESIGN R and omized , double-blind , positive-controlled trial . SETTING Nine medical center clinics . POPULATION A total of 883 patients with baseline mean + /- SD systolic and diastolic blood pressure ( SBP and DBP , respectively ) of 149.7 + /- 16.6 and 96.5 + /- 5.1 mm Hg , age of 58.5 + /- 8.5 years , and maximum IMT of 1.17 + /- 0.20 mm . INTERVENTIONS Twice daily doses of isradipine ( 2.5 - 5.0 mg ) or hydrochlorothiazide ( 12.5 - 25 mg ) . MAIN OUTCOME MEASURE ( PRIMARY END POINT ) : Rate of progression of mean maximum IMT in 12 carotid focal points over 3 years . RESULTS There was no difference in the rate of progression of mean maximum IMT between isradipine and hydrochlorothiazide over 3 years ( P=.68 ) . There was a higher incidence of major vascular events ( eg , myocardial infa rct ion , stroke , congestive heart failure , angina , and sudden death ) in isradipine ( n=25 ; 5.65 % ) vs hydrochlorothiazide ( n=14 ; 3.17 % ) ( P=.07 ) , and a significant increase in nonmajor vascular events and procedures ( eg , transient ischemic attack , dysrhythmia , aortic valve replacement , and femoral popliteal bypass graft ) in isradipine ( n=40 ; 9.05 % ) vs hydrochlorothiazide ( n=23 ; 5.22 % ) ( P=.02 ) . At 6 months , mean DBP decreased by 13.0 mm Hg in both groups , and mean SBP decreased by 19.5 mm Hg in hydrochlorothiazide and 16.0 mm Hg in isradipine ( P=.002 ) ; the difference in SBP between the 2 groups persisted throughout the study but did not explain the increased incidence of vascular events in patients treated with isradipine . CONCLUSION The rate of progression of mean maximum IMT in carotid arteries , the surrogate end point in this study , did not differ between the 2 treatment groups . The increased incidence of vascular events in patients receiving isradipine compared with hydrochlorothiazide is of concern and should be studied further 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 Men aged 40 - 64 years with mild to moderate hypertension [ diastolic blood pressure ( DBP ) 100 - 130 mmHg ] were r and omized to treatment with a  diuretic ( n = 3272 ) or a  beta-blocker ( n = 3297 ) , with additional drugs if necessary , to determine whether a beta-blocker based treatment differs from thiazide diuretic based treatment with regard to the prevention of coronary heart disease ( CHD ) events and death .  Patients with previous CHD , stroke or other serious diseases , or with contraindications to diuretics or beta-blockers were excluded . If normotension ( DBP less than 95 mmHg ) was not achieved by monotherapy , other antihypertensive drugs were added , but the two basic drugs were not crossed over . Patients were assessed at 6-monthly intervals . The mean follow-up for end-points was 45.1 months . Blood pressure ( BP ) side effects and end-points were recorded in a st and ardized manner . Entry characteristics and the BP reduction achieved were very similar in both treatment groups . All analyses were made on an intention-to-treat basis . The incidence of CHD did not differ between the two treatment groups . The incidence of fatal stroke tended to be lower in the beta-blocker treated group than in the diuretic treated group . Total mortality and the total number of end-points were similar in both groups . The percentage of patients withdrawn due to side effects was similar , whereas the number of reported symptoms , according to a question naire , was higher for patients on beta-blockers . The incidence of diabetes did not differ between the two groups . Subgroup analyses did not detect a difference in the effect of beta-blockers compared with diuretics in smokers as opposed to non-smokers , and beta-blockers also had the same effects as diuretics in the quartile with the highest predicted risk for CHD . Beta-blockers and thiazide diuretics were approximately equally well tolerated . The two drugs had a similar BP reducing effect although additional drugs had to be given more often in the diuretic group . Antihypertensive treatment based on a beta-blocker or on a thiazide diuretic could not be shown to affect the prevention of hypertensive complications , including CHD , to a different extent Obesity and hypertension are often found in the same patients , particularly in elderly women . However , few data on the joint impact of these two conditions in women and the elderly are available . In the current study of 800 elderly hypertensive patients r and omly assigned to active treatment or placebo , the initial mean body mass index ( BMI ) was 26.7 kg/m2 in 560 women and 25.7 kg/m2 in 240 men . During the trial , total mortality and cardiovascular and noncardiovascular terminating events were highest in the patients at the leanest BMI quintile . The association between BMI and cardiovascular end points was U-shaped , whereas noncardiovascular mortality decreased with increasing BMI . The results in the women were similar to those in the total group . The U-shaped relation was confirmed with Cox 's proportional hazards model , controlling for age , gender , systolic blood pressure , hemoglobin , serum cholesterol , blood glucose , and cardiovascular complications at entry . The BMI level with the lowest risk was 28 to 29 kg/m2 for total mortality and cardiovascular terminating events , 26 to 27 kg/m2 for cardiovascular mortality , and 31 to 32 kg/m2 for noncardiovascular mortality . BMI did not modify the favorable effects of drug treatment . There was no evidence that obesity would protect elderly hypertensive men or women from cardiovascular complications The Systolic Hypertension in the Elderly Program ( SHEP ) is a r and omized , blinded test of the efficacy of antihypertensive drug treatment . In a large feasibility trial , 551 men and women who had isolated systolic hypertension and were at least 60 years old received chlorthalidone ( 25 to 50 mg/day ) or matching placebo as the step I drug . After 1 year , 83 % of the chlorthalidone group and 80 % of the placebo group were still taking SHEP medications . Of those still taking chlorthalidone , 88 % had reached goal blood pressure ( BP ) without requiring a step II drug , and most had responded to the lower dose ( 25 mg/day ) . The BP response was similar in all age , sex and race subgroups , with an overall mean difference between r and omized groups of 17 mm Hg for systolic BP ( p less than 0.001 ) and 6 mm Hg for diastolic BP ( p less than 0.001 ) . The only common adverse effects were asymptomatic changes in the serum levels of potassium ( 0.5 mEq/liter lower in the chlorthalidone group , p less than 0.001 ) , uric acid ( 0.9 mg/dl higher , p less than 0.001 ) and creatinine ( 0.08 mg/dl higher , p = 0.02 ) . This study indicates that chlorthalidone is effective for lowering BP in elderly patients with systolic hypertension and sets the stage for a larger trial of the effects of such treatment on the incidence of cardiovascular disease BACKGROUND Diabetic nephropathy is the leading cause of end-stage renal disease . Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes , but similar data are not available for patients with type 2 , the most common form of diabetes . We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy . METHODS A total of 1513 patients were enrolled in this r and omized , double-blind study comparing losartan ( 50 to 100 mg once daily ) with placebo , both taken in addition to conventional antihypertensive treatment ( calcium-channel antagonists , diuretics , alpha-blockers , beta-blockers , and central ly acting agents ) , for a mean of 3.4 years . The primary outcome was the composite of a doubling of the base-line serum creatinine concentration , end-stage renal disease , or death . Secondary end points included a composite of morbidity and mortality from cardiovascular causes , proteinuria , and the rate of progression of renal disease . RESULTS A total of 327 patients in the losartan group reached the primary end point , as compared with 359 in the placebo group ( risk reduction , 16 percent ; P=0.02 ) . Losartan reduced the incidence of a doubling of the serum creatinine concentration ( risk reduction , 25 percent ; P=0.006 ) and end-stage renal disease ( risk reduction , 28 percent ; P=0.002 ) but had no effect on the rate of death . The benefit exceeded that attributable to changes in blood pressure . The composite of morbidity and mortality from cardiovascular causes was similar in the two groups , although the rate of first hospitalization for heart failure was significantly lower with losartan ( risk reduction , 32 percent ; P=0.005 ) . The level of proteinuria declined by 35 percent with losartan ( P<0.001 for the comparison with placebo ) . CONCLUSIONS Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy , and it was generally well tolerated A study protocol for a double-blind r and omised control trial of hypotensive treatment in elderly hypertensive patients has been tested in a number of pilot centres throughout Europe . It was shown that this study is possible from the logistic point of view . In these elderly patients , hydrochlorothiazide + triamterene treatment with or without methyldopa , maintained a significant hypotensive effect in the absence of major electrolyte disturbances . The initiation of hypotensive therapy did not provoke an excess of cardiovascular complications . The influence of hypotensive therapy on the general well-being and on the morbidity and the mortality of elderly patients with high blood pressure , is thereby being assessed . The study will continue for 5 years and other centres are invited to join BACKGROUND Angiotensin-converting enzyme ( ACE ) inhibitors reduce major cardiovascular events , but are not tolerated by about 20 % of patients . We therefore assessed whether the angiotensin-receptor blocker telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with end-organ damage . METHODS After a 3-week run-in period , 5926 patients , many of whom were receiving concomitant proven therapies , were r and omised to receive telmisartan 80 mg/day ( n=2954 ) or placebo ( n=2972 ) by use of a central automated r and omisation system . R and omisation was stratified by hospital . The primary outcome was the composite of cardiovascular death , myocardial infa rct ion , stroke , or hospitalisation for heart failure . Analyses were done by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00153101 . FINDINGS The median duration of follow-up was 56 ( IQR 51 - 64 ) months . All r and omised patients were included in the efficacy analyses . Mean blood pressure was lower in the telmisartan group than in the placebo group throughout the study ( weighted mean difference between groups 4.0/2.2 [ SD 19.6/12.0 ] mm Hg ) . 465 ( 15.7 % ) patients experienced the primary outcome in the telmisartan group compared with 504 ( 17.0 % ) in the placebo group ( hazard ratio 0.92 , 95 % CI 0.81 - 1.05 , p=0.216 ) . One of the secondary outcomes -a composite of cardiovascular death , myocardial infa rct ion , or stroke-occurred in 384 ( 13.0 % ) patients on telmisartan compared with 440 ( 14.8 % ) on placebo ( 0.87 , 0.76 - 1.00 , p=0.048 unadjusted ; p=0.068 after adjustment for multiplicity of comparisons and overlap with primary outcome ) . 894 ( 30.3 % ) patients receiving telmisartan were hospitalised for a cardiovascular reason , compared with 980 ( 33.0 % ) on placebo ( relative risk 0.92 , 95 % CI 0.85 - 0.99 ; p=0.025 ) . Fewer patients permanently discontinued study medication in the telmisartan group than in the placebo group ( 639 [ 21.6 % ] vs 705 [ 23.8 % ] ; p=0.055 ) ; the most common reason for permanent discontinuation was hypotensive symptoms ( 29 [ 0.98 % ] in the telmisartan group vs 16 [ 0.54 % ] in the placebo group ) . INTERPRETATION Telmisartan was well tolerated in patients unable to tolerate ACE inhibitors . Although the drug had no significant effect on the primary outcome of this study , which included hospitalisations for heart failure , it modestly reduced the risk of the composite outcome of cardiovascular death , myocardial infa rct ion , or stroke . FUNDING Boehringer Ingelheim BACKGROUND Antihypertensive therapy reduces the risk of cardiovascular events among high-risk persons and among those with a systolic blood pressure of 160 mm Hg or higher , but its role in persons at intermediate risk and with lower blood pressure is unclear . METHODS In one comparison from a 2-by-2 factorial trial , we r and omly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to receive either c and esartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo . The first co primary outcome was the composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke ; the second co primary outcome additionally included resuscitated cardiac arrest , heart failure , and revascularization . The median follow-up was 5.6 years . RESULTS The  mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg ; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo group . The first co primary outcome occurred in 260 participants ( 4.1 % ) in the active-treatment group and in 279 ( 4.4 % ) in the placebo group ( hazard ratio , 0.93 ; 95 % confidence interval [ CI ] , 0.79 to 1.10 ; P=0.40 ) ; the second co primary outcome occurred in 312 participants ( 4.9 % ) and 328 participants ( 5.2 % ) , respectively ( hazard ratio , 0.95 ; 95 % CI , 0.81 to 1.11 ; P=0.51 ) . In one of the three prespecified hypothesis-based subgroups , participants in the subgroup for the upper third of systolic blood pressure ( > 143.5 mm Hg ) who were in the active-treatment group had significantly lower rates of the first and second co primary outcomes than those in the placebo group ; effects were neutral in the middle and lower thirds ( P=0.02 and P=0.009 , respectively , for trend in the two outcomes ) . CONCLUSIONS Therapy with c and esartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who did not have cardiovascular disease . ( Funded by the Canadian Institutes of Health Research and AstraZeneca ; Clinical Trials.gov number , NCT00468923 . )
target: The reduction in cardiovascular mortality and morbidity was primarily due to a reduction in cerebrovascular mortality and morbidity .
  AUTHORS ' CONCLUSIONS Treating healthy adults 60 years or older with moderate to severe systolic and /or diastolic hypertension with antihypertensive drug therapy reduced all-cause mortality , cardiovascular mortality and morbidity , cerebrovascular mortality and morbidity , and coronary heart disease mortality and morbidity .
  Most evidence of benefit pertains to a primary prevention population using a thiazide as first-line treatment
background: BACKGROUND This is the second substantive up date of this review .
  It was originally published in 1998 and was previously up date d in 2009 .
  Elevated blood pressure ( known as ' hypertension ' ) increases with age - most rapidly over age 60 .
  Systolic hypertension is more strongly associated with cardiovascular disease than is diastolic hypertension , and it occurs more commonly in older people .
  It is important to know the benefits and harms of antihypertensive treatment for hypertension in this age group , as well as separately for people 60 to 79 years old and people 80 years or older .