Design of the Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events (OPERA) trial. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial of cardiovascular events in hypertension. Rationale and design. Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study. 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Effects of individual risk factors on the incidence of cardiovascular events in the treated hypertensive patients of the Hypertension Optimal Treatment Study. HOT Study Group. The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: The Systolic Blood Pressure Intervention Trial (SPRINT) The Australian Therapeutic Trial in Mild Hypertension. Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly hypertensive population Cardiovascular events in elderly patients with isolated systolic hypertension. A subgroup analysis of treatment strategies in STOP‐Hypertension‐2 Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: Objectives, protocol, and organization Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) analyses performed up to 1992. 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Influence of age, sex and blood pressure on the principal endpoints of the Nordic Diltiazem (NORDIL) Study Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) Morbidity, mortality, and antihypertensive treatment effects by extent of atherosclerosis in older adults with isolated systolic hypertension. Outcomes With Nifedipine GITS or Co-Amilozide in Hypertensive Diabetics and Nondiabetics in Intervention as a Goal in Hypertension (INSIGHT) Treatment of mild hypertension: a five year controlled drug trial. The Oslo study. On-treatment diastolic blood pressure and prognosis in systolic hypertension. Pulse pressure as a predictor of stroke Mortality and Morbidity Results from the European Working Party on High Blood Pressure in the Elderly Trial 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 [Statin therapy for hypertensive patients]. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy Baseline Characteristics of Participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) The Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients (JATOS): Protocol, Patient Characteristics, and Blood Pressure during the First 12 Months The Hypertension in the Very Elderly Trial (HYVET) Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial. Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: an analysis of findings from the VALUE trial Rationale and design for the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial. The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: rationale, design, and methods. The LIFE Study Group. Long-term renal and cardiovascular outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants by baseline estimated GFR. Subgroup and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. Practitioner's Trial on the Efficacy of Antihypertensive Treatment in the Elderly Hypertension (The PATE-Hypertension Study) in Japan. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Stent revascularization for the prevention of cardiovascular and renal events among patients with renal artery stenosis and systolic hypertension: rationale and design of the CORAL trial. Which Patients Does the SPRINT Study Not Apply To and What Are the Appropriate Blood Pressure Goals in These Populations? Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol Clinical Events in High-Risk Hypertensive Patients Randomly Assigned to Calcium Channel Blocker Versus Angiotensin-Converting Enzyme Inhibitor in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Diuretic-based treatment and cardiovascular events in patients with mild renal dysfunction enrolled in the systolic hypertension in the elderly program. The BBB Study: the effect of intensified antihypertensive treatment on the level of blood pressure, side-effects, morbidity and mortality in "well-treated" hypertensive patients. Behandla Blodtryck Bättre. Relationship of Antihypertensive Treatment Regimens and Change in Blood Pressure to Risk for Heart Failure in Hypertensive Patients Randomly Assigned to Doxazosin or Chlorthalidone: Further Analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). Reduced Glomerular Filtration Rate and Its Association with Clinical Outcome in Older Patients at Risk of Vascular Events: Secondary Analysis Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease
The Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events ( OPERA ) trial is a large clinical trial of omapatrilat , a vasopeptidase inhibitor , in patients with stage 1 isolated systolic hypertension ( ISH ) . OPERA is the first study to examine whether effective antihypertensive treatment can provide survival and clinical end point benefits in older persons with this common condition . This 5-year multinational , r and omized , double-blind , parallel-group , placebo-controlled , forced-titration study will be conducted in approximately 12,600 subjects r and omized by approximately 1100 study centers worldwide over a recruitment period of approximately 2 years . The primary objective of OPERA is to determine whether treatment with once-daily omapatrilat ( target dose 40 mg ) will reduce cardiovascular ( CV ) morbidity and mortality in older ( > or = 65 years ) men and women with enhanced risk for atherosclerotic events due to stage 1 ISH plus other risk factors for which currently there is no evidence -based requirement for treatment .  Blood pressure inclusion criteria are  systolic blood pressure ( SBP ) 140 to 159 mm Hg ( SBP 125 to 139 mm Hg in diabetic individuals ) and diastolic blood pressure ( DBP ) < 90 mm Hg . The primary end point is defined as the composite of fatal/nonfatal stroke , fatal/nonfatal myocardial infa rct ion , fatal/nonfatal heart failure , and other CV mortality . Secondary end points include the individual components of the primary end point , CV mortality , and major cardiovascular end points , as well as effects on cognitive function and initiation of treatment for diabetes . Additional analyses will be conducted in men and women , in diabetic patients , in different risk classes and according to prior evidence of vascular disease BACKGROUND The efficacy of new antihypertensive drugs has been question ed . We compared the effects of conventional and newer antihypertensive drugs on cardiovascular mortality and morbidity in elderly patients . METHODS We did a prospect i ve , r and omised trial in 6614 patients aged 70 - 84 years with hypertension ( blood pressure > or = 180 mm Hg systolic , > or = 105 mm Hg diastolic , or both ) . Patients were r and omly assigned conventional antihypertensive drugs ( atenolol 50 mg , metoprolol 100 mg , pindolol 5 mg , or hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily ) or newer drugs ( enalapril 10 mg or lisinopril 10 mg , or felodipine 2.5 mg or isradipine 2 - 5 mg daily ) . We assessed fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease . Analysis was by intention to treat . FINDINGS Blood pressure was decreased similarly in all treatment groups . The primary combined endpoint of fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease occurred in 221 of 2213 patients in the conventional drugs group ( 19.8 events per 1000 patient-years ) and in 438 of 4401 in the newer drugs group ( 19.8 per 1000 ; relative risk 0.99 [ 95 % CI 0.84 - 1.16 ] , p=0.89 ) . The combined endpoint of fatal and non-fatal stroke , fatal and non-fatal myocardial infa rct ion , and other cardiovascular mortality occurred in 460 patients taking conventional drugs and in 887 taking newer drugs ( 0.96 [ 0.86 - 1.08 ] , p=0.49 ) . INTERPRETATION Old and new antihypertensive drugs were similar in prevention of cardiovascular mortality or major events . Decrease in blood pressure was of major importance for the prevention of cardiovascular events OBJECTIVE To assess the ability of antihypertensive drug treatment to reduce the risk of nonfatal and fatal ( total ) stroke in isolated systolic hypertension . DESIGN Multicenter , r and omized , double-blind , placebo-controlled . SETTING Community-based ambulatory population in tertiary care centers . PARTICIPANTS 4736 persons ( 1.06 % ) from 447,921 screenees aged 60 years and above were r and omized ( 2365 to active treatment , 2371 to placebo ) . Systolic blood pressure ranged from 160 to 219 mm Hg and diastolic blood pressure was less than 90 mm Hg . Of the participants , 3161 were not receiving antihypertensive medication at initial contact , and 1575 were . The average systolic blood pressure was 170 mm Hg ; average diastolic blood pressure , 77 mm Hg . The mean age was 72 years , 57 % were women , and 14 % were black . INTERVENTIONS -- Participants were stratified by clinical center and by antihypertensive medication status at initial contact . For step 1 of the trial , dose 1 was chlorthalidone , 12.5 mg/d , or matching placebo ; dose 2 was 25 mg/d . For step 2 , dose 1 was atenolol , 25 mg/d , or matching placebo ; dose 2 was 50 mg/d . MAIN OUTCOME MEASURES Primary . Nonfatal and fatal ( total ) stroke . Secondary . Cardiovascular and coronary morbidity and mortality , all-cause mortality , and quality of life measures . RESULTS Average follow-up was 4.5 years . The 5-year average systolic blood pressure was 155 mm Hg for the placebo group and 143 mm Hg for the active treatment group , and the 5-year average diastolic blood pressure was 72 and 68 mm Hg , respectively . The 5-year incidence of total stroke was 5.2 per 100 participants for active treatment and 8.2 per 100 for placebo . The relative risk by proportional hazards regression analysis was 0.64 ( P = .0003 ) . For the secondary end point of clinical nonfatal myocardial infa rct ion plus coronary death , the relative risk was 0.73 . Major cardiovascular events were reduced ( relative risk , 0.68 ) . For deaths from all causes , the relative risk was 0.87 . CONCLUSION In persons aged 60 years and over with isolated systolic hypertension , antihypertensive stepped-care drug treatment with low-dose chlorthalidone as step 1 medication reduced the incidence of total stroke by 36 % , with 5-year absolute benefit of 30 events per 1000 participants . Major cardiovascular events were reduced , with 5-year absolute benefit of 55 events per 1000 Essential hypertension is a major Public Health issue . Although the number of treated hypertensive patients has increased , only 25 % of treated patients have their blood pressure levels under control . The benefit of treating hypertension has been proven , but cardiovascular morbidity and mortality rates remain high . The ideal antihypertensive drug should not only normalize blood pressure levels , but also reduce the associated cardiovascular morbidity and mortality rates . The role of angiotensin II in systemic hypertension and its complications has been recently redefined . The potent trophic effects of angiotensin II on blood vessels and on cardiac cells have been well demonstrated , especially the role of angiotensin II in left ventricular hypertrophy , vascular hypertrophy , endothelial dysfunction , and congestive heart failure . Of all ongoing mortality and morbidity trials in systemic hypertension , VALUE ( Valsartan Antihypertensive Long-term Use Evaluation ) is the only one comparing an angiotensin II antagonist ( valsartan ) with a third-generation calcium channel blocker ( amlodipine ) . The main hypothesis of the VALUE trial is that , for an equivalent decrease in blood pressure , valsartan will be more effective than amlodipine in decreasing cardiac mortality and morbidity . VALUE is a prospect i ve , multinational , multicentre , double-blind , r and omized , active-controlled , 2-arm parallel group comparison with a response-dependent dose titration scheme . VALUE involves 14,400 patients in over 30 countries , who will be followed for 4 years or until 1450 patients experience a primary endpoint . The population to be included in VALUE consists of hypertensive men and women , aged 50 years or older , and at a relatively high risk of sustaining a cardiovascular event . The high risk profile is defined taking into account age , gender , and a list of cardiovascular risk factors and disease factors . Risk factors are cigarette smoking , hypercholesterolaemia , diabetes mellitus , uncomplicated left ventricular hypertrophy , proteinuria , and high serum creatinine . Disease factors include documented history of myocardial infa rct ion , peripheral vascular disease , stroke or transient ischaemic attack , or the presence of left ventricular hypertrophy with strain on the ECG . A unique feature of VALUE is the assessment of the predictive power of this cardiovascular risk factor scale in a large population of treated hypertensive patients . The trial started on 10 September 1997 BACKGROUND Recent reports have drawn attention to the importance of pulse pressure as a predictor of cardiovascular events .  Pulse pressure is used neither by clinicians nor by guidelines to define treatable levels of blood pressure . METHODS In the Cardiovascular Health Study , 5888 adults 65 years and older were recruited from 4 US centers . At baseline in 1989 - 1990 , participants underwent an extensive examination , and all subsequent cardiovascular events were ascertained and classified . RESULTS At baseline , 1961 men and 2941 women were at risk for an incident myocardial infa rct ion or stroke . During follow-up that averaged 6.7 years , 572 subjects had a coronary event , 385 had a stroke , and 896 died . After adjustment for potential confounders , systolic blood pressure ( SBP ) , diastolic blood pressure ( DBP ) , and pulse pressure were directly associated with the risk of incident myocardial infa rct ion and stroke . Only SBP was associated with total mortality . Importantly , SBP was a better predictor of cardiovascular events than DBP or pulse pressure . In the adjusted model for myocardial infa rct ion , a 1-SD change in SBP , DBP , and pulse pressure was associated with hazard ratios ( 95 % confidence intervals ) of 1.24 ( 1.15 - 1.35 ) , 1.13 ( 1.04 - 1.22 ) , and 1.21 ( 1.12 - 1.31 ) , respectively ; and adding pulse pressure or DBP to the model did not improve the fit . For stroke , the hazard ratios ( 95 % confidence intervals ) were 1.34 ( 1.21 - 1.47 ) with SBP , 1.29 ( 1.17 - 1.42 ) with DBP , and 1.21 ( 1.10 - 1.34 ) with pulse pressure . The association between blood pressure level and cardiovascular disease risk was generally linear ; specifically , there was no evidence of a J-shaped relationship . In those with treated hypertension , the hazard ratios for the association of SBP with the risks for myocardial infa rct ion and stroke were less pronounced than in those without treated hypertension . CONCLUSION In this population -based study of older adults , although all measures of blood pressure were strongly and directly related to the risk of coronary and cerebrovascular events , SBP was the best single predictor of cardiovascular events BACKGROUND The efficacy of antihypertensive drugs newer than diuretics and beta-blockers has not been established . We compared the effects of the calcium-channel blocker nifedipine once daily with the diuretic combination co-amilozide on cardiovascular mortality and morbidity in high-risk patients with hypertension . METHODS We did a prospect i ve , r and omised , double-blind trial in Europe and Israel in 6321 patients aged 55 - 80 years with hypertension ( blood pressure > or = 150/95 mm Hg , or > or = 160 mm Hg systolic ) . Patients had at least one additional cardiovascular risk factor . We r and omly assigned patients nifedipine 30 mg in a long-acting gastrointestinal-transport-system ( GITS ) formulation ( n=3157 ) , or co-amilozide ( hydrochlorothiazide 25 mg [ corrected ] plus amiloride 2.5 mg ; n=3164 ) . Dose titration was by dose doubling , and addition of atenolol 25 - 50 mg or enalapril 5 - 10 mg . The primary outcome was cardiovascular death , myocardial infa rct ion , heart failure , or stroke . Analysis was done by intention to treat . FINDINGS Primary outcomes occurred in 200 ( 6.3 % ) patients in the nifedipine group and in 182 ( 5.8 % ) in the co-amilozide group ( 18.2 vs 16.5 events per 1000 patient-years ; relative risk 1.10 [ 95 % CI 0.91 - 1.34 ] , p=0.35 ) . Overall mean blood pressure fell from 173/99 mm Hg ( SD 14/8 ) to 138/82 mm Hg ( 12/7 ) . There was an 8 % excess of withdrawals from the nifedipine group because of peripheral oedema ( 725 vs 518 , p<0.0001 ) , but serious adverse events were more frequent in the co-amilozide group ( 880 vs 796 , p=0.02 ) . Deaths were mainly non-vascular ( nifedipine 176 vs co-amilozide 172 ; p=0.81 ) . 80 % of the primary events occurred in patients receiving r and omised treatment ( 157 nifedipine , 147 co-amilozide , difference 0.33 % [ -0.7 to 1.4 ] ) . INTERPRETATION Nifedipine once daily and co-amilozide were equally effective in preventing overall cardiovascular or cerebrovascular complications . The choice of drug can be decided by tolerability and blood-pressure response rather than long-term safety or efficacy The 2014 Evidence -Based Guideline for the Management of  High Blood Pressure In Adults : Report From the Panel Members Appointed to the Eighth Joint National Committee ( JNC 8) recommends several major changes from the JNC 7 report ( 1 , 2 ) . The 2014 guideline is based on a systematic review of r and omized , controlled trials ( RCTs ) by a multidisciplinary panel using a process informed by Institute of Medicine recommendations for guideline development ( 3 ) . Although there was almost unanimous agreement on nearly all recommendations , a minority of the panel ( the authors of this commentary ) disagreed with the recommendation to increase the target systolic blood pressure ( SBP ) from 140 to 150 mm Hg in persons aged 60 years or older without diabetes mellitus ( DM ) or chronic kidney disease ( CKD ) . This target guides both the initiation of therapy and treatment goals . Although this issue has major clinical and public health implication s , the guideline only briefly summarized the concerns underlying the minority opinion to maintain the target of less than 140 mm Hg . The Institute of Medicine recommendation for guideline development encourages guidelines to provide a description and explanation of any differences of opinion regarding the recommendation ( 3 ) . This summarizes the evidence and rationale underlying the minority opinion to maintain the SBP target of 140 mm Hg or lower in persons aged 60 years or older until there is greater certainty of the risks and benefits of a higher target . First , increasing the target will probably reduce the intensity of antihypertensive treatment in a large population at high risk for cardiovascular disease ( CVD ) ( Table 1 ) . The higher SBP goal would apply to some of the groups at highest cardiovascular risk , such as African Americans , hypertensive patients with multiple CVD risk factors other than DM or CKD , and those with clinical CVD . Second , the evidence supporting increasing the SBP target from 140 to 150 mm Hg in persons aged 60 years or older was insufficient and inconsistent with the evidence supporting the panel 's recommendations for an SBP target of less than 140 mm Hg in persons younger than 60 years and those aged 60 years or older with DM or CKD . Third , the higher SBP goal in individuals aged 60 years or older may reverse the decades-long decline in CVD , especially stroke mortality ( 4 ) . In the absence of definitive evidence defining the optimum SBP target , observational studies and RCT data that the panel did not systematic ally review more strongly support the SBP goal of less than 140 mm Hg , especially in high-risk individuals . Other recent guideline groups review ing similar evidence have recommended a goal of less than 140 mm Hg , particularly in persons aged 80 years or younger ( 59 ) . Table 1 . U.S. Cardiovascular Disease Death Rates for Persons Younger and Older Than 65 y Persons Aged 60 Years or Older With Hypertension and SBP Controlled to 140 mm Hg or Lower More than half of the 72 million persons with hypertension in the United States are aged 60 years or older ( 10 , 11 ) . Among these individuals , the 2014 guideline recommends the SBP goal of 140 mm Hg or lower only for those with DM and those younger than 70 years with CKD ( 2 ) . Although the prevalence of hypertension in this age group ( 65 % to 67 % ) did not change between 1999 and 2010 , the percentage with adequate blood pressure control increased from 27.4 % ( 19992000 ) to 50.5 % ( 20112012 ) , with 82.2 % now receiving antihypertensive medications ( 10 , 12 ) . Data from NHANES ( National Health and Nutrition Examination Survey ) from 2001 to 2008 show that among treated and untreated hypertensive adults aged 60 years or older , median SBPs were 136 mm Hg and 152 mm Hg , respectively ( 13 ) , and SBPs have been decreasing in this age group over the past 5 decades ( Figure ) ( 4 ) . Thus , a target of less than 150 mm Hg would likely increase blood pressures in the treated hypertensive population and would suggest that nearly half of the untreated hypertensive patients in this age range should remain untreated . The large population at high risk for CVD , with most currently at an SBP of 140 mm Hg or lower , creates concern that a higher SBP target will adversely affect public health . Figure . Smoothed weighted frequency distribution , median , and 90th percentile of systolic blood pressure for persons aged 60 to 74 y : United States , 19592010 . Reproduced from Lackl and and colleagues ( 4 ) . NHANES = National Health and Nutrition Examination Survey ; NHES = National Health Examination Survey . High Risk in Persons With the Higher Goal Age substantially increases risk for cardiovascular events ( Table 1 ) , so differences in cardiovascular risk do not justify different targets for patients older and younger than 60 years . The risk range for white and African American men aged 60 years is 9 % to 30 % , depending on risk factor profile . For men of both ethnicities who are aged 70 years or older and have SBP controlled to 140 mm Hg , even without clinical CVD or DM , the 10-year risk exceeds 20 % ( 14 ) . Thus , on the basis of absolute risk , using an age threshold of 60 years to define eligibility for less aggressive treatment lacks consistency . Persons aged 60 to 79 years are at higher risk than those who are younger , even if the younger persons have DM . Insufficient Evidence for Differential Hypertension Treatment Benefit for Patients Older and Younger Than 60 Years The 2014 guideline panel failed to identify evidence of differential benefits or harms of treatment using an SBP goal of 140 mm Hg with an age threshold of 60 years . There is little RCT evidence of risk or benefit in treating persons younger than 60 years to this target , except in those with diastolic hypertension . The guideline indicates that no qualifying evidence was found comparing an SBP less than 140 mm Hg to any other SBP goal for persons younger than 60 years ( 2 ) . However , in persons aged 60 years or older , the SHEP ( Systolic Hypertension in the Elderly Program ) trial showed benefit of treating hypertension to an SBP goal between 140 and 145 mm Hg ( Table 2 ) ( 15 ) . HYVET ( Hypertension in the Very Elderly Trial ) found a benefit of an SBP target of less than 150 mm Hg on health outcomes , including mortality in persons aged 80 years or older ( 16 ) . Patients in the HYVET treatment group achieved an SBP of 144 mm Hg at 2 years compared with 159 mm Hg in the control group , and blood pressures continued to decrease in both groups until the end of the trial . Therefore , HYVET and the SHEP trial provide evidence that reducing SBP to around 140 mm Hg has substantial benefit without major harm in older persons . Thus , the best evidence available for an SBP target around 140 mm Hg , which meets the guideline RCT criteria , is in persons older than 60 years . The lack of benefit seen in 2 Japanese trials in older individuals ( JATOS [ Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients ] [ 17 ] and the VALISH [ Valsartan in Elderly Isolated Systolic Hypertension ] trial [ 18 ] ) was cited by some to rationalize the higher SBP target , but these trials were underpowered ( Table 2 ) . The SHEP trial and HYVET together reported 365 strokes and more than 285 coronary heart disease events , whereas JATOS and the VALISH trial only had a combined total of 125 strokes and 67 coronary heart disease events . In addition , the much larger FEVER ( Felodipine Event Reduction ) trial ( 19 ) did not meet criteria for inclusion in the panel 's deliberation ( Table 2 ) . This trial , which was conducted in a Chinese population ( age range , 50 to 79 years ; mean age , 62 years ) , reported a significant 27 % reduction in its primary outcome , as well as significant reductions in all CVD , total mortality , coronary heart disease , and heart failure in patients treated to an SBP of 137 mm Hg with a thiazide diureticcalcium-channel blocker combination versus 143 mm Hg with a thiazide diuretic plus placebo ( 19 ) . Table 2 . Trials Comparing Different Systolic Blood Pressure Thresholds In addition , generalizability of the Japanese trials to other population s of patients older than 60 years , such as African Americans , is uncertain . African Americans are at highest risk for all complications of hypertension and are historically undertreated . Thus , we believe that recommending less aggressive targets in this or other high-risk population s requires stronger justification than the guideline cites . Three recent guidelines from other countries have concluded that the appropriate cut point for an age-related differential SBP goal is 80 years or older ( 57 ) . We agree that this higher treatment target in frail hypertensive patients aged 80 years or older better reflects existing evidence . Safety and Adverse Event Risk in Hypertensive Patients Aged 60 Years or Older Despite the limited number of end points in JATOS and the VALISH trial , their size and duration provide evidence of safety of the SBP target of less than 140 mm Hg . The VALISH investigators concluded that this target was safe in relatively healthy patients aged 70 years or older with isolated systolic hypertension ( 18 ) . In JATOS , adverse events requiring treatment discontinuation were reported in only 36 patients , with no differences in discontinuation rate between groups ( 17 ) . This evidence and the favorable results at slightly higher blood pressures in the SHEP trial and HYVET provide reassurance of the safety of an SBP goal of less than 140 mm Hg in older , nonfrail persons . Other Trial Evidence of Benefit of Treatment at an SBP of 140 mm Hg or Lower Results of the SPS3 ( Secondary Prevention of Small Subcortical Strokes ) trial indicated that an SBP target of less than 130 mm Hg versus 144 mm Hg in 3020 patients ( mean age , 63 years ) reduced subsequent strokes by 19 % ( P= 0.08 ) and hemorrhagic strokes by nearly 50 % ( P < 0.01 ) ( 20 ) . Of note , the FEVER trial reported a 44 % ( P < 0.001 ) reduction in all strokes in a subgroup analysis of patients older than 65 years ( 17 ) . Finally , 2 meta-analyses Objective To investigate the associations of diastolic blood pressure ( DBP ) and systolic blood pressure ( SBP ) with the risk of coronary heart disease , sudden cardiac and all-cause death in elderly men . Design A cohort study . Setting The Dutch town of Zutphen . Subjects Eight hundred and eighty-five r and omly selected men , aged 64 - 84 years . Main outcome measures Relative risks adjusted for age , body mass index , total and high-density lipoprotein cholesterol , cigarette smoking , alcohol consumption , use of blood pressure-lowering medications without a specific indication for hypertension , and the physician who measured the blood pressure . Results Neither DBP nor SBP was associated significantly with the incidence of a first coronary heart disease event and no clear associations were observed with mortality from coronary heart disease . However , positive associations with sudden cardiac death were observed . The adjusted relative risk for men with definite isolated systolic hypertension was 9.20 . The risk of dying from coronary heart disease not recorded additionally as sudden death was highest in men at the lower end of the DBP and SBP distributions and in men using antihypertensives . DBP and SBP were positively associated with all-cause mortality when possible comorbidity at the time of the blood pressure measurement was accounted for . Overall , the highest risk for all endpoints was observed in men on antihypertensive medication , who formed a distinct group with a clustering of cardiovascular risk factors . Conclusion Elevated DBP and SBP , and especially isolated systolic hypertension , are important predictors of sudden cardiac death in elderly men . The highest risk of nonsudden coronary heart disease mortality was found at the lower end of the blood pressure distributions and among men on antihypertensive medication OBJECTIVE The Captopril Prevention Project ( CAPPP ) evaluated the effects of an ACE inhibitor-based therapeutic regimen on  cardiovascular mortality and morbidity in hypertension .  One planned sub analysis of the CAPPP was to evaluate the outcome in the diabetic patient group . RESEARCH DESIGN AND METHODS In the CAPPP , 572 ( 4.9 % of 10,985 hypertensive patients ) had diabetes at baseline and were studied according to a prospect i ve , r and omized , open , blinded , end point trial design . Patients aged 25 - 66 years with diastolic blood pressure > or = 100 mmHg were included and r and omized to receive either captopril or conventional antihypertensive treatment ( diuretics and /or beta-blockers ) . RESULTS The primary end point , fatal and nonfatal myocardial infa rct ion and stroke as well as other cardiovascular deaths , was markedly lower in the captopril than in the conventional therapy group ( relative risk [ RR ] = 0.59 ; P = 0.018 ) . Specifically , cardiovascular mortality , defined as fatal stroke and myocardial infa rct ion , sudden death , and other cardiovascular death , tended to be lower in the captopril group ( RR = 0.48 ; P = 0.084 ) , and no difference was observed between the study groups for stroke ( RR = 1.02 ; P = 0.96 ) . Myocardial infa rct ions were less frequent in the captopril group than in the conventional therapy group ( RR = 0.34 ; P = 0.002 ) . Furthermore , total mortality was lower in the captopril as compared with the conventional therapy group ( RR = 0.54 ; P = 0.034 ) . Patients with impaired metabolic control seemed to benefit the most from ACE inhibitor-based therapy . CONCLUSIONS Captopril is superior to a diuretic/beta-blocker antihypertensive treatment regimen in preventing cardiovascular events in hypertensive diabetic patients , especially in those with metabolic decompensation 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 Atherosclerotic renal-artery stenosis is a common problem in the elderly . Despite two r and omized trials that did not show a benefit of renal-artery stenting with respect to kidney function , the usefulness of stenting for the prevention of major adverse renal and cardiovascular events is uncertain . METHODS We r and omly assigned 947 participants who had atherosclerotic renal-artery stenosis and either systolic hypertension while taking two or more antihypertensive drugs or chronic kidney disease to medical therapy plus renal-artery stenting or medical therapy alone . Participants were followed for the occurrence of adverse cardiovascular and renal events ( a composite end point of death from cardiovascular or renal causes , myocardial infa rct ion , stroke , hospitalization for congestive heart failure , progressive renal insufficiency , or the need for renal-replacement therapy ) . RESULTS Over a median follow-up period of 43 months ( interquartile range , 31 to 55 ) , the rate of the primary composite end point did not differ significantly between participants who underwent stenting in addition to receiving medical therapy and those who received medical therapy alone ( 35.1 % and 35.8 % , respectively ; hazard ratio with stenting , 0.94 ; 95 % confidence interval [ CI ] , 0.76 to 1.17 ; P=0.58 ) . There were also no significant differences between the treatment groups in the rates of the individual components of the primary end point or in all-cause mortality . During follow-up , there was a consistent modest difference in systolic blood pressure favoring the stent group ( -2.3 mm Hg ; 95 % CI , -4.4 to -0.2 ; P=0.03 ) . CONCLUSIONS Renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive , multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease . ( Funded by the National Heart , Lung and Blood Institute and others ; Clinical Trials.gov number , NCT00081731 . ) BACKGROUND The Hypertension Optimal Treatment ( HOT ) Study has provided information about cardiovascular events in 18790 hypertensives , subjected to pronounced blood pressure ( BP ) lowering for a mean of 3.8 years . The HOT study data have subsequently been analysed after stratification of the patients according to global cardiovascular risk , and it has been found that , despite intensive blood pressure lowering in all risk strata , morbid event rates increased with increasing risk stratum . OBJECTIVES Previously analysed global risk strata were based on combinations of risk factors . The analyses presented here were intended to provide information on the relative role that the presence of each individual factor may have in increasing cardiovascular risk , despite good BP control . METHODS Risk ratios ( RR ) for patients with and those without a risk factor were calculated with 95 % confidence intervals ( CI ) using a Cox proportional hazard model , and adjusted for all variables except the one under examination . RESULTS For all risk factors considered and for all types of event , RR were always greater than 1 , indicating a greater risk in the presence , compared with that in the absence of each factor . The male gender was a statistically significant risk for cardiovascular ( CV ) events , CV and total mortality and particularly for myocardial infa rct ion ( MI ) ; age > or = 65 years for CV events , stroke , CV and particularly total mortality ; smoking for all events analysed , but particularly for total mortality ( twice higher in smokers than in non-smokers ) ; high serum cholesterol ( > 6.8 mmol/l ) for CV events , MI and CV mortality ; high serum creatinine ( > 155 micromol/l ) for CV events , stroke , CV and total mortality ; diabetes for CV events , stroke , total mortality and particularly CV mortality ; and ischaemic heart disease for all events analysed . Adjusted RR were often close to or greater than 2 . CONCLUSIONS Each of the risk factors considered was found to be an important cause of residual risk , despite good BP control . These findings emphasize the importance of addressing other correctable risk factors , e.g. smoking , hypercholesterolaemia and diabetes , as well as rigorous control of blood pressure , and of initiating antihypertensive therapy before cardiovascular and renal damage becomes manifest Background : High blood pressure is an important public health concern because it is highly prevalent and a risk factor for adverse health outcomes , including coronary heart disease , stroke , decompensated heart failure , chronic kidney disease , and decline in cognitive function . Observational studies show a progressive increase in risk associated with blood pressure above 115/75 mm Hg . Prior research has shown that reducing elevated systolic blood pressure lowers the risk of subsequent clinical complications from cardiovascular disease . However , the optimal systolic blood pressure to reduce blood pressure – related adverse outcomes is unclear , and the benefit of treating to a level of systolic blood pressure well below 140 mm Hg has not been proven in a large , definitive clinical trial . Purpose : To describe the design considerations of the Systolic Blood Pressure Intervention Trial ( SPRINT ) and the baseline characteristics of trial participants . Methods : The Systolic Blood Pressure Intervention Trial is a multicenter , r and omized , controlled trial that compares two strategies for treating systolic blood pressure : one targets the st and ard target of < 140 mm Hg , and the other targets a more intensive target of < 120 mm Hg . Enrollment focused on volunteers of age ≥50 years ( no upper limit ) with an average baseline systolic blood pressure ≥130 mm Hg and evidence of cardiovascular disease , chronic kidney disease , 10-year Framingham cardiovascular disease risk score ≥15 % , or age ≥75 years . The Systolic Blood Pressure Intervention Trial recruitment also targeted three pre-specified subgroups : participants with chronic kidney disease ( estimated glomerular filtration rate < 60 mL/min/1.73 m2 ) , participants with a history of cardiovascular disease , and participants 75 years of age or older . The primary outcome is first the occurrence of a myocardial infa rct ion ( MI ) , acute coronary syndrome , stroke , heart failure , or cardiovascular disease death . Secondary outcomes include all-cause mortality , decline in kidney function or development of end-stage renal disease , incident dementia , decline in cognitive function , and small-vessel cerebral ischemic disease . Results : Between 8 November 2010 and 15 March 2013 , Systolic Blood Pressure Intervention Trial recruited and r and omized 9361 people at 102 clinics , including 3331 women , 2648 with chronic kidney disease , 1877 with a history of cardiovascular disease , 3962 minorities , and 2636 ≥75 years of age . Limitations : Although the overall recruitment target was met , the numbers recruited in the high-risk subgroups were lower than planned . Conclusions : The Systolic Blood Pressure Intervention Trial will provide important information on the risks and benefits of intensive blood pressure treatment targets in a diverse sample of high-risk participants , including those with prior cardiovascular disease , chronic kidney disease , and those aged ≥75 years In the Australian Therapeutic Trial in Mild Hypertension treated patients had significantly lower cardiovascular mortality and a significantly lower incidence of cerebrovascular complications than patients given placebos .  There was , however , no difference in the incidence of nonfatal myocardial infa rct ion or other new manifestations of ischaemic heart disease . Although the evidence of benefit from treatment was clear-cut , the number of cardiovascular complications in the control group was small . This was due to several factors . Patients admitted to the trial had no preceding evidence of cardiovascular complications  , the blood pressure fell spontaneously to below 95 mm Hg in almost half the control group , and patients whose blood pressures rose to levels above 110 mm Hg were given treatment , but remained in the placebo group for analysis . In both treated and placebo groups , trial end-points occurred more frequently in persons whose average diastolic blood pressure during the study remained raised . Ischaemic heart disease and many cases of stroke are due to atherosclerotic arterial disease . This appears not to be favourably influenced by antihypertensive drug therapy Objective To investigate whether baseline systolic blood pressure variability was a risk factor for stroke , cardiovascular mortality or cardiac events during the Syst-Eur trial . Design The Syst-Eur study was a r and omized , double-blind , placebo-controlled trial , powered to detect differences in stroke rate between participants on active antihypertensive treatment and placebo .  Systolic blood pressure variability measurements were made on 744 participants at the start of the trial . Systolic blood pressure variability was calculated over three time frames : 24 h , daytime and night-time . The placebo and active treatment subgroups were analysed separately using an intention-to-treat principle , adjusting for confounding factors using a multiple Cox regression model . Participants An elderly hypertensive European population . Main outcome measures Stroke , cardiac events ( fatal and non-fatal heart failure , fatal and non-fatal myocardial infa rct ion and sudden death ) and cardiovascular mortality ( death attributed to stroke , heart failure , myocardial infa rct ion , sudden death , pulmonary embolus , peripheral vascular disease and aortic dissection ) . Results The risk of stroke increased by 80 % ( 95 % confidence interval : 17–176 % ) for every 5 mmHg increase in night-time systolic blood pressure variability in the placebo group . Risk of cardiovascular mortality and cardiac events was not significantly altered . Daytime variability readings did not predict outcome . Antihypertensive treatment did not affect systolic blood pressure variability over the median 4.4-year follow-up . Conclusion In the placebo group , but not the active treatment group , increased night-time systolic blood pressure variability on admission to the Syst-Eur trial was an independent risk factor for stroke during the trial Objective : To perform a subgroup analysis on those patients in STOP‐Hypertension‐2 who had isolated systolic hypertension . Design and methods : The STOP‐Hypertension‐2 study evaluated cardiovascular mortality and morbidity in elderly hypertensives comparing treatment with conventional drugs ( diuretics , beta‐blockers ) with that of newer ones [ angiotensin‐converting enzyme ( ACE ) inhibitors , calcium antagonists ] . In all , 6614 elderly patients with hypertension ( mean age 76.0 years , range 70–84 years at baseline ) were included in STOP‐Hypertension‐2 . In the present subgroup analysis of STOP‐Hypertension‐2 , isolated systolic hypertension was defined as systolic blood pressure at least 160 mmHg and diastolic blood pressure below 95 mmHg , in accordance with the Syst‐Eur and Syst‐China study criteria . In total , 2280 patients in STOP‐Hypertension‐2 met these criteria . In the study , patients were r and omized to one of three treatment groups : “ conventional ” antihypertensive therapy with beta‐blockers or diuretics ( atenolol 50 mg , metoprolol 100 mg , pindolol 5 mg , or fixed‐ratio hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily ) ; ACE inhibitors ( enalapril 10 mg or lisinopril 10 mg daily ) ; or calcium antagonists ( felodipine 2.5 mg or isradipine 2.5 mg daily ) . Analysis was by intention to treat . Results : The blood pressure lowering effect in patients with systolic hypertension was similar with all three therapeutic regimens : 35/13 mmHg in the conventional group ( n = 717 ) , 34/12 mmHg in the ACE inhibitor group ( n = 724 ) , and 35/13 mmHg in the calcium antagonist group ( n = 708 ) . Prevention of cardiovascular mortality , the primary endpoint of the study , did not differ between the three treatment groups . All stroke events , i.e. fatal and non‐fatal stroke together , were significantly reduced by 25 % in the newer‐drugs group compared with the conventional group ( 95 % CI 0.58–0.97 ; p = 0.027 ) . This difference was attributable to reduction of non‐fatal stroke while fatal stroke events did not differ between groups . New cases of atrial fibrillation were significantly increased by 43 % ( 95 % CI 1.02–1.99 ; p = 0.037 ) on “ newer ” drugs compared with “ conventional ” therapy , mainly attributable to the calcium antagonists . There were no significant differences between the three treatment groups with respect to the risks of myocardial infa rct ion , sudden death or congestive heart failure . Conclusions : The analysis demonstrated that “ newer ” therapy ( ACE inhibitors/calcium antagonists ) was significantly better ( 25 % ) than “ conventional ” ( diuretics/beta‐blockers ) in preventing all stroke in elderly patients with isolated systolic hypertension 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 ) Hypertension is increasingly common with advancing age and a risk factor for all kinds of cardiovascular complications . Moreover , cardiovascular disease is a major cause of morbidity and mortality in the elderly . The Swedish Trial in Old Patients with Hypertension ( STOP-Hypertension ) was set up by the Swedish Hypertension Society to investigate the value of antihypertensive treatment in the elderly . In this placebo controlled r and omised prospect i ve study 1,627 men and women aged 70 - 84 years with a supine blood pressure > or = 180/105 mmHg ( and /or ) but not isolated systolic hypertension participated . Three beta-blockers and one diuretic were used as blood pressure lowering agents and the average follow-up in the study was 25 months ( 3,390 patient-years ) . Administration of active antihypertensive therapy , reduced supine blood pressure from 195/102 mmHg to 167/87 mmHg at longest follow-up in comparison with placebo . A majority of the patients needed combined treatment to reach the goal blood pressure ( 160/95 mmHg ) . Associated with a fall in blood pressure were significant reductions in all cardiovascular primary endpoints ( -40 % , p = 0.0031 ) , in fatal and non-fatal stroke ( -47 % , p = 0.0081 ) and in total mortality ( -43 % , p = 0.0079 ) . In addition to the substantial effects on primary endpoints active treatment also showed clinical ly relevant effects on secondary endpoints ( e.g. heart failure ) . The impact on cardiovascular morbidity and mortality with antihypertensive treatment in this elderly cohort was greater than previously seen in middle-aged hypertensive patients , with maintained tolerability and a favourable cost-effectiveness ratio . Finally , women benefited from treatment at least as much as men CONTEXT Despite evidence of efficacy of antihypertensive agents in treating hypertensive patients , safety and efficacy of antihypertensive agents for coronary artery disease ( CAD ) have been discerned only from subgroup analyses in large trials . OBJECTIVE To compare mortality and morbidity outcomes in patients with hypertension and CAD treated with a calcium antagonist strategy ( CAS ) or a non-calcium antagonist strategy ( NCAS ) .  DESIGN , SETTING , AND PARTICIPANTS R and omized , open label , blinded end point study of 22 576 hypertensive CAD patients aged 50 years or older , which was conducted September 1997 to February 2003 at 862 sites in 14 countries . INTERVENTIONS Patients were r and omly assigned to either CAS ( verapamil sustained release ) or NCAS ( atenolol ) . Strategies specified dose and additional drug regimens . Tr and olapril and /or hydrochlorothiazide was administered to achieve blood pressure goals according to guidelines from the sixth report of the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure ( JNC VI ) of less than 140 mm Hg ( systolic ) and less than 90 mm Hg ( diastolic ) ; and less than 130 mm Hg ( systolic ) and less than 85 mm Hg ( diastolic ) if diabetes or renal impairment was present . Tr and olapril was also recommended for patients with heart failure , diabetes , or renal impairment . MAIN OUTCOME MEASURES Primary : first occurrence of death ( all cause ) , nonfatal myocardial infa rct ion , or nonfatal stroke ; other : cardiovascular death , angina , adverse experiences , hospitalizations , and blood pressure control at 24 months . RESULTS At 24 months , in the CAS group , 6391 patients ( 81.5 % ) were taking verapamil sustained release ; 4934 ( 62.9 % ) were taking tr and olapril ; and 3430 ( 43.7 % ) were taking hydrochlorothiazide . In the NCAS group , 6083 patients ( 77.5 % ) were taking atenolol ; 4733 ( 60.3 % ) were taking hydrochlorothiazide ; and 4113 ( 52.4 % ) were taking tr and olapril . After a follow-up of 61 835 patient-years ( mean , 2.7 years per patient ) , 2269 patients had a primary outcome event with no statistically significant difference between treatment strategies ( 9.93 % in CAS and 10.17 % in NCAS ; relative risk [ RR ] , 0.98 ; 95 % confidence interval [ CI ] , 0.90 - 1.06 ) . Two-year blood pressure control was similar between groups . The JNC VI blood pressure goals were achieved by 65.0 % ( systolic ) and 88.5 % ( diastolic ) of CAS and 64.0 % ( systolic ) and 88.1 % ( diastolic ) of NCAS patients . A total of 71.7 % of CAS and 70.7 % of NCAS patients achieved a systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg . CONCLUSION The verapamil-tr and olapril-based strategy was as clinical ly effective as the atenolol-hydrochlorothiazide-based strategy in hypertensive CAD patients Context Experts debate the consequences of excessive lowering of diastolic pressure in patients with hypertension and coronary artery disease . Contribution This report is a secondary analysis of data from a large trial of 2 antihypertensive drug regimens in patients with known coronary artery disease . The authors found a J-shaped relationship between diastolic blood pressure and all-cause death and myocardial infa rct ion , with the increased risk occurring at diastolic blood pressures below 70 to 80 mm Hg , that is , the lower the diastolic pressure , the higher the risk . Caution s The study examined associations between blood pressure and outcomes ; it could not prove that the antihypertensive therapy that lowered diastolic pressure too much caused the adverse outcomes . The Editors For 2 decades , the hypertension literature has been haunted by the phenomenon of a paradoxical increase in morbidity and mortality with an excessive decrease in blood pressure ( J-curve ) . Indeed , several reports have shown that low diastolic pressure is associated with an increased risk for coronary heart disease and related mortality in older adults and in patients taking antihypertensive medications ( 1 - 13 ) . After doing a review and meta- analysis of pertinent studies , Farnett and colleagues ( 14 ) concluded that although there was no consistent J-shaped relationship between stroke and systolic or diastolic pressure , there was a consistent J-shaped relationship for cardiac events and diastolic pressure . These authors stated that this dichotomy in the relationship between diastolic pressure and target organ disease may leave a clinician with the uncomfortable choice of whether to prevent stroke or renal disease at the expense of coronary heart disease . These findings were at variance with the generally accepted dogma formulated by the sixth report of the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure ( JNC VI ) ( 15 ) , which stated that the relationship between pressure and risk was strong , continuous , independent , predictive and etiologically significant . Within the past decade , the phenomenon of a J-curve has been studied in several large trials of normotensive and hypertensive patients ( 16 - 30 ) . Not surprisingly , arguments regarding whether a J-curve could be clinical ly significant have become somewhat contentious . That is , some rely on evidence that on-treatment diastolic pressure below 70 mm Hg does not increase risk for cardiovascular disease and thus deny an impairment of vital organ perfusion within the usual values achievable by antihypertensive treatment . Others , however , consider the J-curve a more real possibility , particularly for the heart . In contrast to other organs , the heart is perfused mostly during diastole and thus could be more vulnerable to diastolic pressure reduction . If a J-curve did exist , it should be most evident in patients with limited coronary perfusion , in other words , in those with manifest coronary artery disease ( CAD ) . Optimal blood pressure in patients with hypertension and CAD remains controversial because few r and omized clinical trials have been done in this population ( 31 , 32 ) . The International Verapamil-Tr and olapril Study ( INVEST ) ( 33 ) , a r and omized trial , evaluated more than 22000 patients with CAD and hypertension . This patient profile , together with unprecedented levels of blood pressure control , provided a unique opportunity to critically investigate the hypothesis that the risk for CAD would increase with an excessive decrease in diastolic pressure . Methods Study Design and Intervention The INVEST design , methods , and principal results have been previously published ( 33 ) . The trial used an open design with blinded end point assessment . In brief , clinical ly stable patients with CAD and hypertension were r and omly assigned to a verapamil sustained-releasebased or atenolol-based strategy .  Patients with previous myocardial infa rct ion ( MI ) within 3 months of enrollment or class IV or V congestive heart failure were excluded .  Blood pressure goals were based on JNC VI ( systolic pressure < 140 mm Hg and diastolic pressure < 90 mm Hg or systolic pressure < 130 mm Hg and diastolic pressure < 85 mm Hg in patients with diabetes or renal impairment ) ( 15 ) . The addition of tr and olapril or hydrochlorothiazide was recommended when necessary to achieve blood pressure goals . Tr and olapril was also recommended for patients with heart failure , diabetes , or renal impairment . Documented CAD was defined as any of the following : remote ( 3 months before enrollment ) confirmed MI , coronary angiography showing more than 50 % narrowing of at least 1 major coronary artery , diagnosis of classic angina pectoris , or concordant abnormalities on 2 different signals ( electrocardiography , echocardiography , or radionuclide scans ) from stress test findings concordant for ischemia ( for example , ST-segment depression or perfusion defects on radionuclide scanning or wall-motion abnormalities on echocardiography or radionuclide scanning ) . Patient Monitoring and Follow-up Protocol visits were scheduled every 6 weeks for the first 6 months and then biannually until 2 years after the last patient was enrolled . Patients were assessed for response to treatment , symptoms , treatment adherence , and adverse effects at each visit and at the end of the study as detailed elsewhere ( 33 ) . Patient follow-up was complete when we received a final assessment form through the online data system or a death report . The Internet-based electronic data collection method used in INVEST did not accept the entry until all required fields were complete . Blood pressure  was measured by using a st and ard mercury sphygmomanometer with an appropriately sized cuff applied to the upper nondominant arm at heart level . By auscultation at the brachial artery , systolic pressure was recorded at the first Korotkoff sound and diastolic pressure was recorded at the disappearance of the fifth Korotkoff sound . Blood pressure was measured twice , at least 2 minutes apart , and the measurements were averaged . Study Outcomes The primary outcome was the first occurrence of all-cause death , nonfatal MI , or nonfatal stroke by intention-to-treat analysis . The MI and stroke definitions are detailed elsewhere ( 34 ) . These 3 components individually were the main secondary outcomes . For this analysis , additional outcomes included fatal and nonfatal MI , fatal and nonfatal stroke , and average on-treatment blood pressure before outcome or censoring . Ascertainment and blinded adjudication of outcomes were described previously ( 32 ) . Follow-up data were available for 22008 ( 97.5 % ) patients . Statistical Analysis The main conclusions of INVEST were that the 2 treatment strategies were equivalent with respect to the primary outcome , main secondary outcomes , and on-treatment systolic and diastolic pressures . Thus , data for all enrolled patients were combined and included in these analyses following the intention-to-treat principle . A P value of 0.05 or less was considered statistically significant . Patients without a primary outcome event were censored at their latest follow-up visit . Average follow-up systolic and diastolic pressures were calculated for each patient by using all post-baseline results , up to the date of primary outcome or censoring . The baseline value was substituted for patients with no post-baseline data ( n= 1154 ) . In this exploratory analysis , the proportions of patients were pooled by 10 mm Hg strata of average follow-up systolic pressure , and the distribution of primary outcome event rate was evaluated to determine whether the relationship was linear . A similar presentation was prepared for diastolic pressure . Because the frequency distributions seemed consistent with a quadratic curve , a quadratic Cox proportional hazards model was formed for the time to primary outcome for each blood pressure variable , with factors for blood pressure and blood pressure squared . Similarly , the relationship between each 10 mm Hg stratum of average systolic pressure and diastolic pressure and all-cause death , fatal and nonfatal MI , and fatal and nonfatal stroke was evaluated . For the time to primary outcome , a second model was fitted , adjusting for the following baseline covariates : age ( 10-year increments ) , sex , race and ethnicity ( white , Asian , black , Hispanic , multiracial , or other ) , previous MI , heart failure ( classes I to III ) , body mass index in increments of 5 kg/m2 , U.S. residency , renal impairment , peripheral vascular disease , left ventricular hypertrophy , smoking history , coronary revascularization , dyslipidemia , stroke or transient ischemic attack , angina pectoris , arrhythmia , diabetes , cancer , aspirin use , and average systolic pressure or diastolic pressure and systolic pressure squared or diastolic pressure squared . To identify clinical ly relevant interactions between the J-shaped curve and baseline diastolic pressure , demographic characteristics , and comorbid conditions for the primary outcome , a 2-step procedure was used . First , baseline covariates were tested individually by adding the variable and 2 interaction terms ( variablediastolic pressure and variable[diastolic pressure squared ] ) to the Cox proportional hazards model . Variables included were age older than 70 years , sex , previous MI , heart failure ( classes I to III ) , previous stroke or transient ischemic attack , diabetes , cancer , renal impairment , hypercholesterolemia , peripheral vascular disease , smoking history , U.S. residency , body mass index greater than 29 kg/m2 ( mean baseline body mass index ) , and diastolic pressure greater than 86 mm Hg ( mean baseline diastolic pressure ) . The change in log likelihood was used to assess the significance of simultaneously adding the 2 interaction terms . The second step in identifying clinical ly relevant interactions between the J-shaped curve and baseline covariates was to plot the hazard ratios for the primary outcome versus diastolic pressure in the OBJECTIVES The purpose of this study was to assess cost-effectiveness and long-term clinical benefits of renal denervation in resistant hypertensive patients . BACKGROUND Resistant hypertension affects 12 % of hypertensive persons . In the Symplicity HTN-2 r and omized controlled trial , catheter-based renal denervation ( RDN ) lowered systolic blood pressure by 32 ± 23 mm Hg from 178 ± 18 mm Hg at baseline . METHODS A state-transition model was used to predict the effect of RDN and st and ard of care on 10-year and lifetime probabilities of stroke , myocardial infa rct ion , all coronary heart disease , heart failure , end-stage renal disease , and median survival . We adopted a societal perspective and estimated an incremental cost-effectiveness ratio in U.S. dollars per quality -adjusted life-year , both discounted at 3 % per year . Robustness and uncertainty were evaluated using deterministic and probabilistic sensitivity analyses . RESULTS Renal denervation substantially reduced event probabilities ( 10-year/lifetime relative risks : stroke 0.70/0.83 ; myocardial infa rct ion 0.68/0.85 ; all coronary heart disease 0.78/0.90 ; heart failure 0.79/0.92 ; end-stage renal disease 0.72/0.81 ) . Median survival was 18.4 years for RDN versus 17.1 years for st and ard of care . The discounted lifetime incremental cost-effectiveness ratio was $ 3,071 per quality -adjusted life-year . Findings were relatively insensitive to variations in input parameters except for systolic blood pressure reduction , baseline systolic blood pressure , and effect duration . The 95 % credible interval for incremental cost-effectiveness ratio was cost-saving to $ 31,460 per quality -adjusted life-year . CONCLUSIONS The model suggests that catheter-based renal denervation , over a wide range of assumptions , is a cost-effective strategy for resistant hypertension that might result in lower cardiovascular morbidity and mortality Background The aim of the Nordic Diltiazem ( NORDIL ) Study was to compare patients with essential hypertension receiving calcium-antagonist-based treatment with diltiazem and similar patients receiving conventional diuretic/β-blocker-based treatment  , with respect to cardiovascular morbidity and mortality . Objective To assess the influence of age , sex , severity of hypertension and heart rate on treatment effects , in a sub- analysis . Methods The NORDIL study was prospect i ve , r and omized , open and endpoint-blinded . It enrolled , at health centres in Norway and Sweden , 10 881 patients aged 50–74 years who had diastolic blood pressure ( DBP ) of 100 mmHg or more . Systolic blood pressure ( SBP ) and DBP were decreased by 20.3/18.7 mmHg in the diltiazem group and by 23.3/18.7 mmHg in the diuretic/β-blocker group – a significant difference in SBP ( P < 0.001 ) . Results The incidence of the primary endpoint – a composite of cardiovascular death , cerebral stroke and myocardial infa rct ion – was similar for the two treatments . Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 patients in the conventional treatment group [ relative risk ( RR ) 0.80 , 95 % confidence interval ( CI ) 0.65 to 0.99;P = 0.040 ] , whereas there was a non-significant inverse tendency with respect to all myocardial infa rct ion . There were significantly fewer cerebral strokes in patients receiving diltiazem in the subgroups with baseline SBP > 170 mmHg ( n = 5420 , RR 0.75 , 95 % CI 0.58 to 0.98;P = 0.032 ) , DBP ⩾ 105 mmHg ( n = 5881 , RR 0.74 , 95 % CI 0.57 to 0.97;P = 0.030 ) and pulse pressure ⩾ 66 mmHg ( n = 5461 , RR 0.76 , 95 % CI 0.58 to 0.99 , P = 0.041 ) , and more myocardial infa rct ions in those with heart rate less than 74 beats/min ( n = 5303 , RR 1.13 , 95 % CI 1.01 to 1.87;P = 0.040 ) . However , the tendencies for fewer strokes and greater incidence of myocardial infa rct ion were present across subgroups when results were analysed for age , sex , severity of hypertension and heart rate , and treatment – subgroup interaction analyses were not statistically significant . Conclusions Compared with a conventional diuretic/β-blocker-based antihypertensive regimen , there were additional 25 % reductions in stroke in the diltiazem-treated patients with blood pressure or pulse pressure greater than the medians , and an increase in myocardial infa rct ion in those with heart rate less than the median . Such findings may be attributable to chance , but the consistency of , in particular , the stroke findings may also suggest an ability of diltiazem , beyond conventional treatment , to prevent cerebral stroke in hypertensive patients with the greatest cardiovascular risk Context It is not clear whether variability in a patient 's outpatient blood pressure ( BP ) measurements has prognostic importance . Contribution Patients with greater visit-to-visit variability in BP readings had an increased risk for cardiovascular events and mortality , which was independent of their overall degree of BP control . Implication Further studies are warranted to assess whether reducing visit-to-visit BP variations will alter the risk for adverse cardiovascular outcomes . The prognostic value of blood pressure ( BP ) is mainly based on measurements obtained in a clinical setting , typically from a few visits ( 1 ) . Until recently , variability of BP across outpatient visits was dismissed as r and om fluctuation around a patient 's true underlying BP ( 2 , 3 ) . Although some studies have reported associations between higher visit-to-visit variability ( VVV ) of systolic BP ( SBP ) and an increased risk for stroke and coronary heart disease ( CHD ) , other analyses have failed to show such associations ( 410 ) . The method applied in estimating VVV of BP varied widely across previous studies . In addition , studies have used as few as 3 visits and as many as 56 visits to estimate the VVV of BP , and the time between visits has ranged from 2 days to as long as 4 years ( 5 , 11 , 12 ) . These factors not only influence VVV of BP but could also affect the strength of its association with cardiovascular disease ( CVD ) outcomes ( 4 , 13 ) . To address the inconsistent findings from previous studies , we did a secondary data analysis of ALLHAT ( Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ) to examine whether VVV of BP is associated with CVD and mortality events . ALLHAT provides the opportunity to evaluate the association between VVV of BP and major clinical outcomes in a large and diverse population with hypertension in which visits were conducted at set time intervals , BP was measured by following a st and ardized protocol , and outcomes were evaluated over several years of follow-up . Methods Study Design We did a cohort study as a secondary analysis using data from ALLHAT . Figure 1 shows the timeline for assessment of VVV of BP and outcome events within ALLHAT . The primary exposure of interest , VVV of SBP , was ascertained at the 7 study visits conducted between 6 and 28 months after r and omization . We studied 4 outcomes : fatal CHD or nonfatal myocardial infa rct ion ( MI ) , all-cause mortality , stroke , and heart failure . Participants were followed from their 28-month visit until the occurrence of an outcome event or the end of active ALLHAT follow-up ( October 2001 to March 2002 ) . Participants who had an event before their 28-month visit were excluded from all analyses . Figure 1 . Study design evaluating the association between VVV of BP and cardiovascular outcomes and all-cause mortality in ALLHAT . ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ; BP = blood pressure ; DBP = diastolic blood pressure ; SBP = systolic blood pressure ; VVV = visit-to-visit variability . * Participants were followed for a mean of 2.7 to 2.9 y ( maximum , 5.7 y ) depending on the outcome after assessment of VVV of BP . ALLHAT was a multicenter , double-blind , r and omized clinical trial sponsored by the National Heart , Lung , and Blood Institute of the National Institutes of Health . A complete description of the rationale and design of ALLHAT has been previously published ( 14 ) . In brief , ALLHAT was design ed to determine whether treatment initiated with a calcium-channel blocker ( amlodipine ) , angiotensin-converting enzyme inhibitor ( lisinopril ) , or -blocker (doxazosin)each compared with treatment initiated with a diuretic (chlorthalidone)would lower major cardiovascular outcomes . The primary end point was incidence of fatal CHD or nonfatal MI .  A total of 42418 hypertensive adults aged 55 years or older with 1 or more additional risk factor for CVD were enrolled at 623 clinical sites across the United States , Canada , Puerto Rico , and the U.S. Virgin Isl and s between February 1994 and January 1998 . The doxazosin treatment group was discontinued in 2000 because of the small chance of finding a benefit on CHD outcomes and an increased risk for CVD than in the chlorthalidone group ( 15 ) . The main results comparing participants r and omly assigned to chlorthalidone , amlodipine , or lisinopril were published in December 2002 ( 16 ) . The trial was approved by local institutional review boards , and all participants provided written informed consent . Our current analysis was approved by the Institutional Review Board at the University of Alabama at Birmingham . Study Visits , BP Measurements , and Calculation of VVV of BP To calculate intraindividual VVV of SBP and diastolic BP ( DBP ) , we used data from 7 follow-up visits that occurred 6 , 9 , 12 , 16 , 20 , 24 , and 28 months after r and omization . We chose to begin the assessment period at the 6-month follow-up visit to avoid confounding by the initial reduction in BP that occurred between r and omization and this visit ( SBP , 6 to 10 mm Hg ; DBP , approximately 5 mm Hg ) due to early medication titration . To increase the precision of estimates , we calculated VVV of BP for participants with BP measurements at 5 , 6 , or 7 visits conducted between month 6 and 28 after r and omization . The VVV of BP was imputed for participants who attended fewer than 5 visits between months 6 and 28 . To maximize follow-up time , we did not extend the assessment past the 28-month follow-up visit . At each follow-up visit ,  BP was measured twice by a trained observer by means of a st and ardized technique ( 17 ) . Using the average BP at each visit , we defined VVV of BP by the intraindividual SD across visits . Average real variability ( ARV ) and SD independent of the mean ( SDIM ) were calculated as alternative metrics for VVV of BP ( Appendix Figure ) ( 18 ) . The VVV of DBP was also calculated in secondary analyses . Appendix Figure . Formulas used to calculate VVV of BP metrics . ARV = average real variability ; BP = blood pressure ; SDIM = SD independent of the mean ; VVV = visit-to-visit variability . Outcome Ascertainment We studied 4 outcomes , including fatal CHD or nonfatal MI , all-cause mortality , stroke , and heart failure . The event ascertainment process is detailed elsewhere ( 14 , 16 ) . Participants were followed from the end of the assessment period to the date of each outcome , their date of death , or the end of active ALLHAT follow-up ( 1 October 2001 through 31 March 2002 ) . Covariate Information Covariates used for adjustment were selected a priori on the basis of their potential role as confounders . Baseline ( before r and omization ) variables included age , sex , race/ethnicity , education , current cigarette smoking status , body mass index , use of aspirin , high-density lipoprotein cholesterol level less than 0.91 mmol/L ( < 35 mg/dL ) ( at 2 occasions in the 5 years before ALLHAT enrollment ) ,  total cholesterol level , estimated glomerular filtration rate ( eGFR ) , diabetes , history of MI or stroke , documentation of other atherosclerotic CVD , history of revascularization , atrial fibrillation by electrocardiography , left ventricular hypertrophy ( LVH ) , the presence of ST depression and T-wave inversion , and use of antihypertensive medication  before ALLHAT r and omization . The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation ( 19 ) . Data collected at visits conducted 6 to 28 months after r and omization were used to calculate mean SBP and DBP ; pulse pressure ; the use of antihypertensive medications beyond the r and omization drug ; changes in antihypertensive medication regimen ( adding , stopping , or changing antihypertensive medications ) ; use of statins ; and low adherence , which is defined as a report of a participant receiving less than 80 % of the r and omization drug at any visit between months 6 and 28 . Participants who reported taking 80 % or more of their r and omization drug at every visit between months 6 and 28 were considered to have high adherence . Statistical Analysis Because of limited follow-up available after the assessment period for participants r and omly assigned to receive doxazosin , we restricted our analyses to the 33357 ALLHAT participants r and omly assigned to receive chlorthalidone , amlodipine , or lisinopril .  We excluded 7543 participants who had CVD events or died before the 28-month visit . We imputed VVV of BP for participants with fewer than 5 visits and BP measurements between months 6 and 28 of follow-up . In addition , missing data for covariates were imputed ( Appendix Table 1 ) . Imputation was performed with 10 data sets using chained equations . Appendix Table 1 . Percentage of Missing Data for Participants Included in the Current Analyses Characteristics of participants included in the current analyses were calculated after participants were stratified into a quintile of SD of SBP . The KaplanMeier method was used to calculate the cumulative incidence of each outcome by quintile of SD of SBP . Cox proportional hazards regression was used to calculate multivariable-adjusted hazard ratios ( HRs ) for each outcome associated with a quintile of SD of SBP , with the lowest quintile serving as the reference . Four nested models were constructed . Model 1 included adjustment for age , race/ethnicity , sex , region of residence , and antihypertensive r and omization assignment . Model 2 includes the variables in model 1 and additional adjustment for education , smoking status , body mass index , use of aspirin , low high-density lipoprotein cholesterol level , total cholesterol level , eGFR , diabetes , history of MI or stroke , history of other atherosclerotic CVD , history of coronary revascularization , atrial fibrillation by electrocardiography , major ST depression or T-wave inversion , LVH , use of antihypertensive medications before ALLHAT r and omization , and  statin use during the assessment period ( months 6 through 28 of follow-up ) . Model 3 includes the variables in model 2 and additional adjustment for mean pulse pressure , BACKGROUND Angiotensin-converting-enzyme ( ACE ) inhibitors have been used for more than a decade to treat high blood pressure  , despite the lack of data from r and omised intervention trials to show that such treatment affects cardiovascular morbidity and mortality . The Captopril Prevention Project ( CAPPP ) is a r and omised intervention trial to compare the effects of ACE inhibition and conventional therapy on cardiovascular morbidity and mortality in patients with hypertension . METHODS CAPPP was a prospect i ve , r and omised , open trial with blinded endpoint evaluation . 10,985 patients were enrolled at 536 health centres in Sweden and Finl and . Patients aged 25 - 66 years with a measured diastolic blood pressure of 100 mm Hg or more on two occasions were r and omly assigned captopril or conventional antihypertensive treatment ( diuretics , beta-blockers ) . Analysis was by intention-to-treat . The primary endpoint was a composite of fatal and non-fatal myocardial infa rct ion , stroke , and other cardiovascular deaths . FINDINGS Of 5492 patients assigned captopril and 5493 assigned conventional therapy , 14 and 13 , respectively , were lost to follow-up . Primary endpoint events occurred in 363 patients in the captopril group ( 11.1 per 1000 patient-years ) and 335 in the conventional-treatment group ( 10.2 per 1000 patient-years ; relative risk 1.05 [ 95 % CI 0.90 - 1.22 ] , p=0 - 52 ) . Cardiovascular mortality was lower with captopril than with conventional treatment ( 76 vs 95 events ; relative risk 0.77 [ 0.57 - 1 - 04 ] , p=0.092 ) , the rate of fatal and non-fatal myocardial infa rct ion was similar ( 162 vs 161 ) , but fatal and non-fatal stroke was more common with captopril ( 189 vs 148 ; 1.25 [ 1 - 01 - 1 - 55 ] . p=0.044 ) . INTERPRETATION Captopril and conventional treatment did not differ in efficacy in preventing cardiovascular morbidity and mortality . The difference in stroke risk is probably due to the lower levels of blood pressure obtained initially in previously treated patients r and omised to conventional therapy 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 AND PURPOSE The Systolic Hypertension in the Elderly Program ( SHEP ) demonstrated a significant reduction in stroke and coronary event rates among participants r and omly assigned to active blood pressure treatment . Selected participants were evaluated for peripheral atherosclerosis and followed up for cardiovascular events beyond the end of the SHEP trial . Antihypertensive treatment effects were evaluated based on the presence or absence of clinical or sub clinical atherosclerosis . METHODS As an ancillary study to SHEP , 190 participants at the Pittsburgh center were evaluated for peripheral atherosclerosis , defined as either an internal carotid stenosis ( by duplex scan ) or lower extremity arterial disease ( identified by ankle blood pressure ) . Participants were subsequently followed up for cardiovascular events . RESULTS Estimates of 4-year mortality rates were 4.8 % for participants with no atherosclerosis , 16.7 % for those with sub clinical atherosclerosis , and 23 % among those with clinical evidence of atherosclerosis ( P < .001 ) . Fatal plus nonfatal cardiovascular event rates were 10.9 % , 29.8 % , and 58.3 % for the three groups , respectively ( P < .001 ) . Differences remained significant after adjustment for age , sex , treatment assignment , smoking , and high-density lipoprotein cholesterol . Individuals assigned to placebo at the beginning of SHEP had higher cardiovascular event rates than individuals assigned to active treatment ( P = .011 ) , with the most striking difference 3 or more years after the end of the SHEP trial . When this analysis was stratified by the presence or absence of detectable atherosclerosis , the absolute treatment effect was largest among those with evidence of disease . CONCLUSIONS Individuals with systolic hypertension and evidence of peripheral atherosclerosis are at high risk for cardiovascular events . Targeting this group for antihypertensive therapy would result in the prevention of a large number of cardiovascular events Abstract —To investigate the impact of treatment on cardiovascular mortality and morbidity , we assessed outcomes in patients with hypertension and diabetes who received co-amilozide or nifedipine in the International Nifedipine GITS Study : Intervention as a Goal in Hypertension . Participants had to be 55 to 80 years of age , with hypertension ( ≥150/95 or ≥160 mm Hg ) and at least one additional cardiovascular risk factor . Patients received 30 mg nifedipine once daily or co-amilozide ( 25 mg hydrochlorothiazide and 2.5 mg amiloride ) daily . Doses were doubled if target blood pressures ( < 140/90 mm Hg ) were not achieved . Primary ( composite of cardiovascular death , myocardial infa rct ion , heart failure , and stroke ) and secondary outcomes ( composite of primary outcomes , including all-cause mortality and death from vascular and nonvascular causes ) were assessed by means of intent-to-treat analyses . There was no significant difference in the incidence of primary outcomes between nifedipine-treated and  co-amilozide – treated patients with diabetes at baseline ( n=1302 ) ( 8.3 % versus 8.4 % ; relative risk , 0.99 , 95 % CI , 0.69 to 1.42;P = 1.00 ) . A significant benefit for nifedipine-treated patients was seen for the composite secondary outcome ( 14.2 % versus 18.7 % ; relative risk , 0.76 , 95 % CI , 0.59 to 0.97;P = 0.03 ) . Among patients without diabetes at baseline ( n=5019 ) , there was a significant difference in the incidence of new diabetes ( nifedipine 4.3 % versus co-amilozide 5.6 % , P = 0.023 ) . Nifedipine GITS once daily is as effective as  diuretic therapy in reducing cardiovascular complications in hypertensive diabetics . Nifedipine-treated patients were also less likely to have diabetes or have secondary events ( a composite of all-cause mortality , death from a vascular cause , and death from a nonvascular cause ) than co-amilozide recipients . Our results suggest that nifedipine could be considered as first-line therapy for hypertensive diabetics In 1972 - -1973 , 785 symptom-free men , aged 40 to 49 years , without target organ damage , with systolic blood pressures between 150 and 179 mm Hg and diastolic blood pressure below 110 mm Hg , were assigned at r and om to one of two groups : ( 406 to a drug treatment group and 379 to a control group ) for a five-year controlled drug treatment trial to evaluate the effect of therapy on cardiovascular complications . Drug treatment started with hydrochlorothiazide . If systolic blood pressure remained above 140 mm Hg and /or diastolic blood pressure above 90 mm Hg , alphamethyldopa was added . If there were side effects , methyldopa was replaced with propranolol . The control group was not given a placebo . The mean observation time was 66 months ( range 60 to 78 months ) . A difference in blood pressure between groups of about 17 mm Hg systolic and 10 mm Hg diastolic was maintained throughout the study . The study protocol had a rather low " ethical " blood pressure roof , 180 mm Hg systolic and /or 110 mm Hg diastolic . Seventeen percent of the control group had an increase in blood pressure above this level during the trial , and drug treatment was started . There was no effect on major cardiovascular morbidity comparing groups as established by r and omization , with 18 events in the treatment group and 20 events in the control group . There was no difference between the groups in total mortality and mortality from cardiovascular events . However , in the subgroups with diastolic blood pressure greater than or equal to 100 mm Hg before r and omization , there was a probable reduction in total morbidity from cardiovascular events in favor or the group receiving drug therapy , 7.6 and 16.4 percent events in the treated and control groups , respectively . Cerebrovascular events occurred only in the control group , 7 versus 0 . Two cases of fatal aortic aneurysms also occurred in the control group . Other " pressure " complications , such as marked left ventricular hypertrophy in the electrocardiogram and left ventricular failure , occurred only in the control group . However , regarding coronary heart disease , including sudden death , the incidence tended to be higher in the treated group , although it was not statistically significant . Only 13 men ( 1.7 percent ) failed to meet for regular examinations . At the end of the study these men were also followed up with regard to possible cardiovascular events BACKGROUND It has been suggested that low diastolic blood pressure ( BP ) while receiving antihypertensive treatment ( hereinafter called on-treatment BP ) is harmful in older patients with systolic hypertension . We examined the association between on-treatment diastolic BP , mortality , and cardiovascular events in the prospect i ve placebo-controlled Systolic Hypertension in Europe Trial . METHODS Elderly patients with systolic hypertension were r and omized into the double-blind first phase of the trial , after which all patients received active study drugs ( phase 2 ) . We assessed the relationship between outcome and on-treatment diastolic BP by use of multivariate Cox regression analysis during receipt of placebo ( phase 1 ) and during active treatment ( phases 1 and 2 ) . RESULTS Rates of noncardiovascular mortality , cardiovascular mortality , and cardiovascular events were 11.1 , 12.0 , and 29.4 , respectively , per 1000 patient-years with active treatment ( n = 2358 ) and 11.9 , 12.6 , and 39.0 , respectively , with placebo ( n = 2225 ) . Noncardiovascular mortality , but not cardiovascular mortality , increased with low diastolic BP with active treatment ( P < .005 ) and with placebo ( P < .05 ) ; for example , hazard ratios for lower diastolic BP , that is , 65 to 60 mm Hg , were , respectively , 1.15 ( 95 % confidence interval , 1.00 - 1.31 ) and 1.28 ( 95 % confidence interval , 1.03 - 1.59 ) . Low diastolic BP with active treatment was associated with increased risk of cardiovascular events , but only in patients with coronary heart disease at baseline ( P < .02 ; hazard ratio for BP 65 - 60 mm Hg , 1.17 ; 95 % confidence interval , 0.98 - 1.38 ) . CONCLUSIONS These findings support the hypothesis that antihypertensive treatment can be intensified to prevent cardiovascular events when systolic BP is not under control in older patients with systolic hypertension , at least until diastolic BP reaches 55 mm Hg . However , a prudent approach is warranted in patients with concomitant coronary heart disease , in whom diastolic BP should probably not be lowered to less than 70 mm Hg The current guidelines for the detection and management of  high blood pressure  depend exclusively on the measurement of  systolic and diastolic blood pressure  , although these are only two specific points on the arterial pressure wave form [ 1,2 ] . However , it may be more appropriate to describe the cardiac cycle as consisting of a pulsatile ( pulse pressure ) and a steady ( mean pressure ) component . Pulse pressure is defined as the difference between systolic and diastolic pressures and primarily reflects the stiffness of large arteries , especially the aorta . Elevated pulse pressure increases the stretch of arteries , induces fatigue and fracture of elastic elements , and accelerates the development of aneurysms , and ultimately their rupture . Similarly , an increased pulse pressure is more likely to contribute to intimal damage , the prelude to atherosclerosis and arterial thrombotic events . Increased pulse pressure has also been associated with thickening of the carotid intima and media [ 3,4 ] . Systolic blood pressure increases across all age groups , whereas diastolic blood pressure increases until the sixth decade of life and then declines thereafter . As a result , pulse pressure increases as age rises , especially in older people as systolic and diastolic blood pressure move in opposite directions . Hence , pulse pressure may become the key blood pressure measure in older individuals and increase in importance as a risk factor for cerebrovascular diseases and death [ 5,6 ] . Several observational studies have found that pulse pressure is an independent predictor of cardiovascular risk in middle aged and older people , in subjects with high blood pressure , in survivors of myocardial infa rct ion and in patients with left ventricular dysfunction [ 7–11 ] . A meta analysis based on individual patient data from three large trials ( Syst-Eur , SystChina and EWPHE [ 12–14 ] ) showed that isolated systolic hypertension and pulse pressure were the major determinants of cardiovascular risk in elderly hypertensives [ 7 ] . A further meta- analysis of individual patient data in control groups of seven r and omized clinical trials ( SHEP , Syst-Eur , MRC 1 , HEP , MRC 2 , EWPHE and STOP ) in the INDANA project [ 8 ] also reported that pulse pressure , rather than mean pressure , was the major risk factor for adverse cardiovascular events . A 10-mmHg increase in pulse pressure at baseline was associated independently with a 6 % rise in total mortality , a 7 % rise in cardiovascular mortality and a 7 % rise in fatal coronary events . A similar rise in fatal stroke was present , although this was statistically nonsignificant due to the limited number of events . However , the relationship between pulse pressure and fatal stroke became significant ( p = 0.04 ) at higher age [ 8 ] . Importantly , pulse pressure calculated from 24 h ambulatory blood pressure recordings is a better predictor of adverse events than if derived from officemeasured blood pressure in older patients with isolated systolic hypertension [ 15 ] Summary The latter was due to a reduction in cardiac mortality ( −38 % , p=0.036 ) and a nonsignificant decrease in cerebrovascular mortality ( −32 % , p=0.16 ) . In the double-blind part of the trial , the total mortality rate was not significantly reduced ( −26 % , p=0.077 ) . However , cardiovascular mortality was reduced in the actively treated group ( −38 % , p=0.023 ) , owing to a reduction in cardiac deaths ( −47 % , p=0.048 ) and a non-significant decrease in cerebrovascular mortality ( −43 % , p=0.15 ) . Deaths from myocardial infa rct ion were reduced ( −60 % , p=0.043 ) , and study -terminating morbid cardiovascular events were significantly reduced by active treatment ( −60 % , p=0.0064 ) . Non-terminating cerebrovascular events were reduced ( −52 % , p=0.026 ) , but the non-terminating cardiac events were not ( + 3 % , p=0.98 ) . In the patients r and omised to active treatment there were 29 fewer cardiovascular events and 14 fewer cardiovascular deaths per 1000 patient years during the double-blind part of the trial . A double-blind r and omised placebo-controlled trial of antihypertensive treatment was conducted in patients over the age of 60 . Entry criteria included both a sitting diastolic blood pressure on placebo treatment in the range 90 to 119 mm Hg and a systolic pressure in the range 160 to 239 mm Eg . 840 patients were r and omised either to active treatment ( hydrochlorothiazide and triamterene ) or to  matching placebo  . If the blood pressure remained raised , methyldopa was added to the active regimen and matching placebo in the placebo group . An overall intention-to-treat analysis , combining the double-blind part of the trial and all subsequent follow-up , revealed a non-significant change in total mortality rate ( −9 % , p=0.41 ) but a significant reduction in cardiovascular mortality rate ( −27 % , p=0.037 ) 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 The majority of cardiovascular events and deaths attributable to both raised blood pressure and dyslipidaemia occur in subjects with relatively " normal " blood pressure and lipid levels respectively . The study was design ed to evaluate the potential benefits of cholesterol lowering in the primary prevention of coronary heart disease in hypertensive subjects with average and below average levels of serum cholesterol . MATERIAL AND METHODS Out of 19 342 hypertensive subjects ( aged 40 - 79 ) who were initially r and omized to one of two antihypertensive treatment strategies in the Anglo-Sc and inavian Cardiac Outcomes Trial ( ASCOT ) , 10 305 subjects with total cholesterol levels < or = 6.5 mmol/L were additionally r and omized to either 10 mg atorvastatin or placebo . The primary endpoint was non-fatal myocardial infa rct ion or fatal coronary heart disease . RESULTS The lipid arm of the study was prematurely stopped after a median follow-up period of 3.3 years . One hundred events occurred in those r and omized to atorvastatin compared to 154 events in those receiving placebo , a 36 % relative risk reduction ( p = 0.0005 ) in the primary endpoint . Among secondary and tertiary endpoints , stroke was reduced with 27 % ( p = 0.02 ) . There was a non-significant 13 % reduction in total mortality . Non-cardiovascular mortality was similar in the two treatment limbs of the trial . After three years of follow-up , atorvastatin lowered total serum cholesterol by 1.1 mmol/L compared with placebo . INTERPRETATION Treatment with 10 mg atorvastatin o.d . in hypertensive patients at moderate risk gives a significant risk reduction of coronary heart disease , independent of baseline level of total cholesterol BACKGROUND Diabetes mellitus is a strong risk factor for cardiovascular and renal disease . We investigated whether the angiotensin-converting-enzyme ( ACE ) inhibitor ramipril can lower these risks in patients with diabetes . METHODS 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study , aged 55 years or older , who had a previous cardiovascular event or at least one other cardiovascular risk factor , no clinical proteinuria , heart failure , or low ejection fraction , and who were not taking ACE inhibitors , were r and omly assigned ramipril ( 10 mg/day ) or placebo , and vitamin E or placebo , according to a two-by-two factorial design . The combined primary outcome was myocardial infa rct ion , stroke , or cardiovascular death . Overt nephropathy was a main outcome in a sub study . FINDINGS The study was stopped 6 months early ( after 4.5 years ) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo . Ramipril lowered the risk of the combined primary outcome by 25 % ( 95 % CI 12 - 36 , p=0.0004 ) , myocardial infa rct ion by 22 % ( 6 - 36 ) , stroke by 33 % ( 10 - 50 ) , cardiovascular death by 37 % ( 21 - 51 ) , total mortality by 24 % ( 8 - 37 ) , revascularisation by 17 % ( 2 - 30 ) , and overt nephropathy by 24 % ( 3 - 40 , p=0.027 ) . After adjustment for the changes in systolic ( 2.4 mm Hg ) and diastolic ( 1.0 mm Hg ) blood pressures , ramipril still lowered the risk of the combined primary outcome by 25 % ( 12 - 36 , p=0.0004 ) . INTERPRETATION Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes . The cardiovascular benefit was greater than that attributable to the decrease in blood pressure . This treatment represents a vasculoprotective and renoprotective effect for people with diabetes Diuretics and & bgr;-blockers have been shown to reduce the risk of cardiovascular morbidity and mortality in people with hypertension in long-term clinical trials . No study has compared newer more costly antihypertensive agents ( calcium antagonists , ACE inhibitors , and & agr;-adrenergic blockers ) with diuretics for reducing the incidence of cardiovascular disease in an ethnically diverse group of middle-aged and elderly hypertensive patients . The study is a r and omized , double-blind , active-controlled clinical trial design ed to determine whether the incidence of the primary outcome , fatal coronary heart disease or nonfatal myocardial infa rct ion , differs between treatment initiation with a diuretic versus each of 3 other antihypertensive drugs . Men and women aged ≥55 years with at least 1 other cardiovascular disease risk factor were r and omly assigned to chlorthalidone ( 12.5 to 25 mg/d ) , amlodipine ( 2.5 to 10 mg/d ) , lisinopril ( 10 to 40 mg/d ) , or doxazosin ( 2 to 8 mg/d ) for planned follow-up of 4 to 8 years . This report describes the baseline characteristics of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) participants . A total of 42 448 participants were r and omized from 625 sites in the United States , Canada , Puerto Rico , and the US Virgin Isl and s. The mean age was 67 years , with 35 % aged ≥70 years . Among those r and omized , 36 % were black , 19 % were Hispanic , and 47 % were women . The sample includes a high proportion of people with diabetes ( 36 % ) , patients with existing cardiovascular disease ( 47 % ) , and smokers ( 22 % ) . There were no important differences between the r and omized treatment groups at baseline . ALLHAT will add greatly to our underst and ing of the management of hypertension by providing an answer to the following question : are newer antihypertensive agents similar , superior , or inferior to traditional treatment with diuretics The benefits of a systolic blood pressure ( BP ) below 150–160 mmHg are well established ; whether a systolic BP of less than 140 mmHg provides additional benefits remains controversial . This study was design ed to compare the 2-year effect of a strict treatment to maintain systolic BP below 140 mmHg ( group A ) and that of a mild treatment to maintain systolic BP at between 140 and below 160 mmHg ( group B ) . The study design followed the Prospect i ve R and omized Open Blinded End-point ( PROBE ) study . The subjects were elderly patients ( 65–85 years old ) who consistently had a systolic BP of 160 mmHg or higher . The baseline drug was efonidipine hydrochloride ( efonidipine ) , a long-acting dihydropiridine calcium antagonist . The primary endpoints were stroke , cardiac disease , vascular disease , and renal failure . After a run-in period of 2 to 4 weeks , 2,165 patients were assigned to group A and 2,155 patients to group B. There were no significant differences between the groups in sex , age , baseline BP , or other cardiovascular risk factors . The systolic BP was 7.2 mmHg lower ( p<0.0001 ) and the diastolic BP 2.4 mmHg lower ( p<0.0001 ) in group A than in group B after 12 months of treatment . As of this interim analysis , primary endpoints have occurred in 87 patients ( stroke in 58 patients , cardiac disease in 27 patients , occlusive arterial disease in 1 patient , and renal failure in 1 patient ) . Five patients have died of stroke and 2 patients of myocardial infa rct ion . The primary -endpoint-related morbidity rate was 20.9/1,000 patient-years , and the mortality rate was 1.7/1,000 patient-years . Currently available results indicate that this study , one of the largest r and omized trials of antihypertensive therapy in elderly patients in Japan , was conducted safely . The final results are expected to provide important and practical information for the management of hypertension in elderly patients 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 Elevated arterial pressure enhances the risk for cardiovascular ( CV ) events in patients with diabetic nephropathy . The optimal BP and the component of the elevated BP that affect the risk have not been defined . A post hoc analysis was performed to assess the impact of achieved systolic , diastolic , and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial ( IDNT ) and had a baseline serum creatinine above the normal range , up to 266 micromol/L ( 3.0 mg/dL ) , 24-h urine protein > 900 mg/d , and at least 6 mo of follow-up . Patients were r and omized to irbesartan , amlodipine , or placebo , with other antihypertensive agents to a BP goal of < or = 135/85 mmHg . Progressively lower achieved systolic BP ( SBP ) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure ( CHF ) but not myocardial infa rct ions ( MI ) . A SBP below this threshold was associated with increased risk for CV deaths and CHF events . Achieved diastolic BP < 85 mmHg was associated with a trend to increase in all-cause mortality , significant increase in MI , but decreased risk for strokes . Increased pulse pressure predicted increased all-cause mortality , CV mortality , MI , and CHF . It is concluded that achieved SBP approaching 120 mmHg and diastolic BP of 85 mmHg are associated with the best protection against CV events in these patients . BP < or = 120/85 may be associated with an increase in CV events Background In the Valsartan Antihypertensive Long-term Use Evaluation ( VALUE ) trial the primary outcome ( cardiac morbidity and mortality ) did not differ between valsartan and amlodipine-based treatment groups , although systolic blood pressure ( SBP ) and diastolic blood pressure reductions were significantly more pronounced with amlodipine . Stroke incidence was non-significantly , and myocardial infa rct ion was significantly lower in the amlodipine-based regimen , whereas cardiac failure was non-significantly lower on valsartan . Objectives The study protocol specified additional analyses of the primary endpoint according to : sex ; age ; race ; geographical region ; smoking status ; type 2 diabetes ; total cholesterol ; left ventricular hypertrophy ; proteinuria ; serum creatinine ; a history of coronary heart disease ; a history of stroke or transient ischemic attack ; and a history of peripheral artery disease . Additional subgroups were isolated systolic hypertension and classes of antihypertensive agents used immediately before r and omization . Methods The 15 245 hypertensive patients participating in VALUE were divided into subgroups according to baseline characteristics . Treatment by subgroup interaction analyses were carried out by a Cox proportional hazard model . Within each subgroup , treatment effects were assessed by hazard ratios and 95 % confidence intervals . Results For cardiac mortality and morbidity , the only significant subgroup by treatment interaction was of sex ( P = 0.016 ) , with the hazard ratio indicating a relative excess of cardiac events with valsartan treatment in women but not in men , but SBP differences in favour of amlodipine were distinctly greater in women . No other subgroup showed a significant difference in the composite cardiac outcome between valsartan and amlodipine-based treatments . For secondary endpoints , a sex-related significant interaction was found for heart failure ( P < 0.0001 ) , with men but not women having a lower incidence of heart failure with valsartan . Conclusion As in the whole VALUE cohort , in no subgroup of patients were there differences in the incidence of the composite cardiac endpoint with valsartan and amlodipine-based treatments , despite a greater blood pressure decrease in the amlodipine group . The only exception was sex , in which the amlodipine-based regimen was more effective than valsartan in women , but not in men , whereas the valsartan regimen was more effective in preventing cardiac failure in men than in women The Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints ( CONVINCE ) Trial is a r and omized , prospect i ve , double-blind , parallel-group , two-arm , actively controlled , multicenter , international 5-year clinical trial involving 15,000 patients . CONVINCE will compare the incidence of fatal or nonfatal myocardial infa rct ion ( MI ) , fatal or nonfatal stroke , or cardiovascular-disease-related death in two antihypertensive treatment regimens . One treatment arm begins with controlled onset-extended release (COER)-verapamil , which has its major antihypertensive effect 6 - 12 hours after administration . The other arm ( st and ard of care ( SOC ) ) begins with either hydrochlorothiazide ( HCTZ ) or atenolol , one of which is preselected by the investigator for an individual patient prior to r and omization . Secondary objectives include comparisons of the regimens for each of the components of the primary endpoint ( separately ) , death or hospitalization related to cardiovascular disease , efficacy in lowering blood pressure to goal , primary events occurring between 6 am and noon , all-cause mortality , withdrawals from blinded therapy , cancer , and hospitalizations due to bleeding .  Patients may be enrolled if they are hypertensive and at least 55 years of age and have an established second risk factor for cardiovascular disease . Initial medications include COER-verapamil ( 180 mg/d ) , HCTZ ( 12.5 mg/d ) , or atenolol ( 50 mg/d ) . Initial doses are doubled if blood pressure ( BP ) does not reach goal ( systolic BP < 140 mm and diastolic BP < 90 mm Hg ) . If BP is not controlled by the higher dose of the initial medication , HCTZ is added to COER-verapamil , or the SOC choice not initially selected is added in the SOC arm . An ACE-inhibitor is recommended ( although nearly any open-label medication is allowed ) as the third step for patients whose BP is not adequately controlled or who have a contraindication to one of the two SOC medications . Patients take two sets of tablets daily , one in the morning and one in the evening . Although most patients switch from an established antihypertensive medication to r and omized treatment , untreated patients with stages I-III hypertension ( SBP between 140 and 190 or DBP between 90 and 110 mm Hg ) are eligible . Outcomes are monitored by an independent Data and Safety Monitoring Board . Enrollment began during the third quarter of 1996 , and follow-up is to be completed in the third quarter of 2002 The treatment of hypertension mainly with diuretics and beta blockers reduces cardiovascular mortality and morbidity , largely due to a decreased incidence of stroke , whereas the beneficial effects of antihypertensive therapy on the occurrence of coronary events have been less than expected from epidemiological studies . Furthermore , treated hypertensive patients still have a higher cardiovascular complication rate , compared with matched normotensives . This is particularly evident in patients with left ventricular hypertrophy ( LVH ) , a major independent risk indicator for cardiovascular disease . In addition to elevating blood pressure , angiotensin II ( A-II ) exerts an important influence on cardiac structure and function , stimulating cell proliferation and growth . Thus , to further reduce morbidity and mortality when treating hypertensive patients , it may be important to effectively block the effects of A-II . This can be achieved directly at the A-II receptor level by losartan , the first of a new class of antihypertensive agents . It therefore seems pertinent to investigate whether selective A-II receptor blockade with losartan not only lowers blood pressure but also reduces LVH more effectively than current therapy , and thus improves prognosis . The Losartan Intervention For Endpoint reduction ( LIFE ) in Hypertension study is a double-blind , prospect i ve , parallel group study design ed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality in approximately 8,300 hypertensive patients ( initial sitting diastolic blood pressure 95 to 115 mm Hg or systolic blood pressure 160 to 200 mm Hg ) with electrocardiographically documented LVH . The study , which will continue for at least 4 years and until 1,040 patients experience one primary endpoint , has been design ed with a statistical power that will detect a difference of at least 15 % between groups in the incidence of combined cardiovascular morbidity and mortality . It is also the first prospect i ve study with adequate power to link reversal of LVH to reduction in major cardiovascular events . The rationale of the study , which will involve more than 800 clinical centers in Sc and inavia , the United Kingdom , and the United States , is discussed , and the major features of its design and general organization are described . On April 30 , 1997 , when inclusion was stopped , 9,218 patients had been r and omized BACKGROUND AND OBJECTIVES CKD is common among older patients . This article assesses long-term renal and cardiovascular outcomes in older high-risk hypertensive patients , stratified by baseline estimated GFR ( eGFR ) , and long-term outcome efficacy of 5-year first-step treatment with amlodipine or lisinopril , each compared with chlorthalidone . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS This was a long-term post-trial follow-up of hypertensive participants ( n=31,350 ) , aged ≥55 years , r and omized to receive chlorthalidone , amlodipine , or lisinopril for 4 - 8 years at 593 centers . Participants were stratified by baseline eGFR ( ml/min per 1.73 m(2 ) ) as follows : normal/increased ( ≥90 ; n=8027 ) , mild reduction ( 60 - 89 ; n=17,778 ) , and moderate/severe reduction ( < 60 ; n=5545 ) . Outcomes were cardiovascular mortality ( primary outcome ) , total mortality , coronary heart disease , cardiovascular disease , stroke , heart failure , and ESRD . RESULTS After an average 8.8-year follow-up , total mortality was significantly higher in participants with moderate/severe eGFR reduction compared with those with normal and mildly reduced eGFR ( P<0.001 ) . In participants with an eGFR < 60 , there was no significant difference in cardiovascular mortality  between chlorthalidone and amlodipine ( P=0.64 ) , or chlorthalidone and lisinopril ( P=0.56 ) . Likewise , no significant differences were observed for total mortality , coronary heart disease , cardiovascular disease , stroke , or ESRD . CONCLUSIONS CKD is associated with significantly higher long-term risk of cardiovascular events and mortality in older hypertensive patients . By eGFR stratum , 5-year treatment with amlodipine or lisinopril was not superior to chlorthalidone in preventing cardiovascular events , mortality , or ESRD during 9-year follow-up . Because data on proteinuria were not available , these findings may not be extrapolated to proteinuric CKD 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 BACKGROUND The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain . METHODS We r and omly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk , but without diabetes , to a systolic blood-pressure target of less than 120 mm Hg ( intensive treatment ) or a target of less than 140 mm Hg ( st and ard treatment ) . The primary composite outcome was myocardial infa rct ion , other acute coronary syndromes , stroke , heart failure , or death from cardiovascular causes . RESULTS At 1 year , the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the st and ard-treatment group . The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the st and ard-treatment group ( 1.65 % per year vs. 2.19 % per year ; hazard ratio with intensive treatment , 0.75 ; 95 % confidence interval [ CI ] , 0.64 to 0.89 ; P<0.001 ) . All-cause mortality was also significantly lower in the intensive-treatment group ( hazard ratio , 0.73 ; 95 % CI , 0.60 to 0.90 ; P=0.003 ) . Rates of serious adverse events of hypotension , syncope , electrolyte abnormalities , and acute kidney injury or failure , but not of injurious falls , were higher in the intensive-treatment group than in the st and ard-treatment group . CONCLUSIONS Among patients at high risk for cardiovascular events but without diabetes , targeting a systolic blood pressure of less than 120 mm Hg , as compared with less than 140 mm Hg , result ed in lower rates of fatal and nonfatal major cardiovascular events and death from any cause , although significantly higher rates of some adverse events were observed in the intensive-treatment group . ( Funded by the National Institutes of Health ; Clinical Trials.gov number , NCT01206062 . ) Patients aged 60 years and older with essential hypertension were treated with an angiotensin-converting enzyme inhibitor ( ACE-I ) , delapril ( Adecut ) or a long-acting calcium (Ca)-antagonist , manidipine ( Calslot ) for 3 years . The incidences of cardiovascular events as well as drug-related side effects were compared between the two groups to investigate whether both classes of antihypertensive drugs are beneficial in elderly hypertensive patients . There were no significant differences in characteristics of patients between the two intervention groups , except for slightly lower blood pressure ( P = .08 ) in the Ca-antagonist group at the initiation of the study . There were no significant differences in total death between the two groups . Cardiovascular events ( both fatal and nonfatal ) were noted in 34 of 699 patients ( 22.5/1000 patient-years ) in the ACE-I group and 50 of 1049 patients ( 19.7/1000 patient-years ) in the Ca-antagonist group , with no significant difference found between the two groups . The correlation between cardiovascular incidence and the blood pressure attained during treatment showed a J-shaped phenomenon and suggests that an excessive reduction less than 120 mm Hg in systolic blood pressure ( SBP ) is unnecessary and may be harmful in certain cases . Side effects were more frequent in the ACE-I group than in the Ca-antagonist group ( P = .01 ) . Cough was the major adverse event , occurring in 5.0 % of patients in the ACE-I group . In conclusion , the study indicates that both ACE-I ( delapril ) and Ca-antagonist ( manidipine ) were equally beneficial for reducing cardiovascular morbidity and mortality in elderly hypertensive patients . However , tolerability of ACE-I was lower due to the adverse event of coughing CONTEXT Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality , but the optimal first-step therapy is unknown . OBJECTIVE To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease ( CHD ) or other cardiovascular disease ( CVD ) events vs treatment with a diuretic . DESIGN The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , active-controlled clinical trial conducted from February 1994 through March 2002 . SETTING AND PARTICIPANTS A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers . INTERVENTIONS Participants were r and omly assigned to receive chlorthalidone , 12.5 to 25 mg/d ( n = 15 255 ) ; amlodipine , 2.5 to 10 mg/d ( n = 9048 ) ; or lisinopril , 10 to 40 mg/d ( n = 9054 ) for planned follow-up of approximately 4 to 8 years . MAIN OUTCOME MEASURES The primary outcome was combined fatal CHD or nonfatal myocardial infa rct ion , analyzed by intent-to-treat . Secondary outcomes were all-cause mortality , stroke , combined CHD ( primary outcome , coronary revascularization , or angina with hospitalization ) , and combined CVD ( combined CHD , stroke , treated angina without hospitalization , heart failure [ HF ] , and peripheral arterial disease ) . RESULTS Mean follow-up was 4.9 years . The primary outcome occurred in 2956 participants , with no difference between treatments . Compared with chlorthalidone ( 6-year rate , 11.5 % ) , the relative risks ( RRs ) were 0.98 ( 95 % CI , 0.90 - 1.07 ) for amlodipine ( 6-year rate , 11.3 % ) and 0.99 ( 95 % CI , 0.91 - 1.08 ) for lisinopril ( 6-year rate , 11.4 % ) . Likewise , all-cause mortality did not differ between groups . Five-year systolic blood pressures were significantly higher in the amlodipine ( 0.8 mm Hg , P = .03 ) and lisinopril ( 2 mm Hg , P<.001 ) groups compared with chlorthalidone , and 5-year diastolic blood pressure was significantly lower with amlodipine ( 0.8 mm Hg , P<.001 ) . For amlodipine vs chlorthalidone , secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine ( 10.2 % vs 7.7 % ; RR , 1.38 ; 95 % CI , 1.25 - 1.52 ) . For lisinopril vs chlorthalidone , lisinopril had higher 6-year rates of combined CVD ( 33.3 % vs 30.9 % ; RR , 1.10 ; 95 % CI , 1.05 - 1.16 ) ; stroke ( 6.3 % vs 5.6 % ; RR , 1.15 ; 95 % CI , 1.02 - 1.30 ) ; and HF ( 8.7 % vs 7.7 % ; RR , 1.19 ; 95 % CI , 1.07 - 1.31 ) . CONCLUSION Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive . They should be preferred for first-step antihypertensive therapy BACKGROUND Atherosclerotic renal artery stenosis is a problem with no consensus on diagnosis or therapy . The consequences of renal ischemia are neuroendocrine activation , hypertension , and renal insufficiency that can potentially result in acceleration of atherosclerosis , further renal dysfunction , myocardial infa rct ion , heart failure , stroke , and death . Whether revascularization improves clinical outcomes when compared with optimum medical therapy is unknown . METHODS CORAL is a r and omized clinical trial contrasting optimum medical therapy alone to stenting with optimum medical therapy on a composite cardiovascular and renal end point : cardiovascular or renal death , myocardial infa rct ion , hospitalization for congestive heart failure , stroke , doubling of serum creatinine , and need for renal replacement therapy . The secondary end points evaluate the effectiveness of revascularization in important subgroups of patients and with respect to all-cause mortality , kidney function , renal artery patency , microvascular renal function , and blood pressure control . We will also correlate stenosis severity with longitudinal renal function and determine the value of stenting from the perspectives of quality of life and cost-effectiveness . The primary entry criteria are ( 1 ) an atherosclerotic renal stenosis of > or = 60 % with a 20 mm Hg systolic pressure gradient or > or = 80 % with no gradient necessary and ( 2 ) systolic hypertension of > or = 155 mm Hg on > or = 2 antihypertensive medications . R and omization will occur in 1080 subjects . The study has 90 % power to detect a 28 % reduction in primary end point hazard rate . CONCLUSIONS CORAL represents a unique opportunity to determine the incremental value of stent revascularization , in addition to optimal medical therapy , for the treatment of atherosclerotic renal artery stenosis The Systolic Blood Pressure Intervention Trial ( SPRINT ) is a large National Institutes of Health– sponsored multicenter r and omized controlled trial that enrolled 9361 patients with a systolic blood pressure ( SBP ) of at least 130 mm Hg . The primary goal of SPRINT was to test whether reducing SBP to a lower goal ( < 120 mm Hg ) than currently recommended ( < 140 mm Hg ) would reduce the occurrence of cardiovascular disease ( CVD ) and chronic kidney disease ( CKD ) events . Enrolled patients were 50 years or older with an SBP ≥130 mm Hg and at least one of the following : a history of CVD , stage 3 CKD ( estimated glomerular filtration rate 20–59 mL/min/1.73 m ) , an intermediate to high risk for CVD other than stroke , or age 75 years or older . A patient was defined as having CVD if they had a prior myocardial infa rct ion , percutaneous coronary intervention , coronary artery bypass grafting , carotid endarterectomy or carotid stenting , peripheral arterial disease with revascularization , acute coronary syndrome , abdominal aortic aneurysm ≥5 cm with or without repair , a coronary calcium score > 400 , or left ventricular hypertrophy . Patients were defined as at intermediate or high risk for CVD based on the following : Framingham Risk Score for 10-year CVD risk of 15 % based on laboratory work performed for lipids within the past 12 months . The primary outcome was a composite of cardiovascular events . The SPRINT study was terminated early after 3.26 years on advisory of the data safety monitoring board . The results of the SPRINT study showed a 25 % reduction in the primary combined cardiovascular outcome and a 27 % reduction in mortality in the group r and omized to SBP < 120 mm Hg . This obviously has important implication s for blood pressure ( BP ) guidelines in this population . The baseline mean systolic and diastolic BPs were 139.7 mm Hg and 78.1 mm Hg , respectively . At 1 year , the mean SBP was 121.4 mm Hg in the intensive treatment group and 136.2 mm Hg in the st and ard treatment group . The SPRINT study included 28 % of patients with CKD , 28 % of patients were older than 75 years , 36 % were women , and 20 % had prior CVD . The sample was diverse and included 29.9 % black , 10.5 % Hispanic , and 57.7 % white patients .  Importantly , SPRINT excluded many patients with hypertension . Who were these population s ? The following groups of patients with hypertension were excluded : those with a history of prior stroke , diabetes , polycystic kidney disease , any secondary cause for hypertension , glomerular filtration rate ( GFR ) < 20 cc/ min , > 1 g of proteinuria per 24 hours , glomerulonephritis treated with immunosuppressive therapy , symptomatic heart failure within the past 6 months or left ventricular ejection fraction < 35 % , expected survival less than 3 years , cancer diagnosed within the past 2 years , organ transplant , cardiovascular event , procedure or hospitalization for unstable angina within the past 3 months , and all patients younger than 50 years . Why were these patients excluded ? Patients with diabetes were excluded as it was felt that this population had already been studied in the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) BP trial , which did not show a cardiovascular advantage of lower SBP ( < 120 mm Hg ) vs st and ard BP ( < 140 mm Hg ) although there was a decreased risk of stroke .  Patients with polycystic kidney disease have also been studied separately in the HALT Progression of Polycystic Kidney Disease study , which recently showed that rigorous BP control was associated with a slower increase in total kidney volume , no overall change in the estimated GFR , a greater decline in the left ventricular mass index , and greater reduction in urinary albumin excretion .  Patients with excessive proteinuria > 1 g per 24 hours were also excluded , but , based on data from the Modification of Diet in Renal Disease ( MDRD ) , the Blood Pressure Control for Renoprotection in Patients With Nondiabetic Chronic Renal Disease ( REIN ) , and the African American Study of Kidney Disease and Hypertension ( AASK ) studies , lower BP goals ( < 130/80 mm Hg ) have been suggested and recommended by some guidelines in this patient population . Renal transplant recipients were excluded in this population . There are no r and omized controlled trials examining optimal levels of BP and this is a population that needs to be studied . BP threshold for treatment of kidney transplant recipients remains at 130/80 mm Hg , regardless of proteinuria . The Secondary Prevention of Small Subcortical Strokes ( SPS3 ) trial , which compared an SBP treatment target of < 130 mm Hg with a target of 130 mm Hg to 149 mm Hg in participants with a recent lacunar stroke , showed a nonsignificant reduction in recurrent stroke in the group r and omized to the lower target . There are no specific studies that have evaluated BP targets in patients without other comorbidities who are Address for correspondence : Debbie L. Cohen , MD , Renal , Electrolyte and Hypertension Division , Perelman School of Medicine at the University of Pennsylvania , 1 Founders Building , 3400 Spruce Street , Philadelphia , PA 19104 E-mail : BACKGROUND The most suitable antihypertensive drug to reduce the risk of cardiovascular disease in patients with hypertension and diabetes is unclear . In prespecified analyses , we compared the effects of losartan and atenolol on cardiovascular morbidity and mortality in diabetic patients . METHODS As part of the LIFE study , in a double-masked , r and omised , parallel-group trial , we assigned a group of 1195 patients with diabetes , hypertension , and signs of left-ventricular hypertrophy ( LVH ) on electrocardiograms losartan-based or atenolol-based treatment . Mean age of patients was 67 years ( SD 7 ) and mean blood pressure 177/96 mm Hg ( 14/10 ) after placebo run-in . We followed up patients for at least 4 years ( mean 4.7 years [ 1.1 ] ) . We used Cox regression analysis with baseline Framingham risk score and electrocardiogram-LVH as covariates to compare the effects of the drugs on the primary composite endpoint of cardiovascular morbidity and mortality ( cardiovascular death , stroke , or myocardial infa rct ion ) . FINDINGS Mean blood pressure fell to 146/79 mm Hg ( 17/11 ) in losartan patients and 148/79 mm Hg ( 19/11 ) in atenolol patients . The primary endpoint occurred in 103 patients assigned losartan ( n=586 ) and 139 assigned atenolol ( n=609 ) ; relative risk 0.76 ( 95 % CI 0.58-.98 ) , p=0.031 . 38 and 61 patients in the losartan and atenolol groups , respectively , died from cardiovascular disease ; 0.63 ( 0.42 - 0.95 ) , p=0.028 . Mortality from all causes was 63 and 104 in losartan and atenolol groups , respectively ; 0.61 ( 0.45 - 0.84 ) , p=0.002 . INTERPRETATION Losartan was more effective than atenolol in reducing cardiovascular morbidity and mortality as well as mortality from all causes in patients with hypertension , diabetes , and LVH . Losartan seems to have benefits beyond blood pressure reduction The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial ( ALLHAT ) provides a unique opportunity to compare the long-term relative safety and efficacy of angiotensin-converting enzyme inhibitor and calcium channel blocker – initiated therapy in older hypertensive individuals . Patients were r and omized to amlodipine ( n=9048 ) or lisinopril ( n=9054 ) . The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infa rct ion , analyzed by intention-to-treat . Secondary outcomes included all-cause mortality , stroke , combined cardiovascular disease ( CVD ) , end-stage renal disease ( ESRD ) , cancer , and gastrointestinal bleeding . Mean follow-up was 4.9 years .  Blood pressure control was similar in nonblacks , but not in blacks . No significant differences were found between treatment groups for the primary outcome , all-cause mortality , ESRD , or cancer . Stroke rates were higher on lisinopril in blacks ( RR=1.51 , 95 % CI 1.22 to 1.86 ) but not in nonblacks ( RR=1.07 , 95 % CI 0.89 to 1.28 ) , and in women ( RR=1.45 , 95 % CI 1.17 to 1.79 ) , but not in men ( RR=1.10 , 95 % CI 0.92 to 1.31 ) . Rates of combined CVD were higher ( RR=1.06 , 95 % CI 1.00 to 1.12 ) because of higher rates for strokes , peripheral arterial disease , and angina , which were partly offset by lower rates for heart failure ( RR=0.87 , 95 % CI 0.78 to 0.96 ) on lisinopril compared with amlodipine .  Gastrointestinal bleeds and angioedema were higher on lisinopril . Patients with and without baseline coronary heart disease showed similar outcome patterns . We conclude that in hypertensive patients , the risks for coronary events are similar , but for stroke , combined CVD , gastrointestinal bleeding , and angioedema are higher and for heart failure are lower for lisinopril-based compared with amlodipine-based therapy . Some , but not all , of these differences may be explained by less effective blood pressure control in the lisinopril arm BACKGROUND It is expected that the treatment of hypertension in patients with renal disease decreases the risk of cardiovascular events , but the evidence in these patients is lacking . OBJECTIVE To assess the effect of diuretic-based treatment on cardiovascular events in patients with isolated systolic hypertension and renal dysfunction . METHODS A total of 4336 persons aged 60 years and older with systolic blood pressures of 160 mm Hg and higher and diastolic blood pressures of less than 90 mm Hg were r and omly assigned to receive either placebo or chlorthalidone ( 12.5 - 25.0 mg/d ) , with the addition of atenolol ( 25 - 50 mg/d ) or reserpine ( 0.05 - 0.10 mg/d ) if needed , and observed for 5 years . The risk of first-occurring cardiovascular events , including stroke , transient ischemic attack , myocardial infa rct ion , heart failure , coronary artery bypass surgery , angioplasty , aneurysm , endarterectomy , sudden death , or rapid death , was stratified according to baseline serum creatinine levels ( 35.4 - 84.0 , 84.1 - 101.6 , 101.7 - 119.3 , and 119.4 - 212.2 micromol/L [ 0.4 - 0.9 , 1.0 - 1.1 , 1.2 - 1.3 , and 1.4 - 2.4 mg/dL ] ) . RESULTS Systolic blood pressure reduction was not affected by baseline serum creatinine levels . Active treatment did not affect the risk of serum creatinine levels becoming elevated during follow-up . The risk of hypokalemia with active treatment decreased significantly with increasing baseline serum creatinine levels . In the 4 baseline serum creatinine groups , the relative risk ( 95 % confidence interval ) of cardiovascular events developing with active treatment was 0.73 ( 0.54 - 0.97 ) , 0.63 ( 0.49 - 0.82 ) , 0.62 ( 0.44 - 0.87 ) , and 0.59 ( 0.38 - 0.91 ) . The results were similar for the outcomes of stroke or coronary artery events and in analyses stratified by sex or age . CONCLUSION Diuretic-based treatment of patients with isolated systolic hypertension prevents the development of cardiovascular events in older persons with mild renal dysfunction The BBB study ( Swedish for Beh and la Blodtryck Bättre or Treat Blood Pressure Better ) was a multicenter trial design ed to investigate three aspects of antihypertensive treatment : i ) Is it possible to lower the diastolic blood pressure further in " well-treated " hypertensive patients through intensified therapy ? ii ) Can this aim be fulfilled without increasing the incidence or severity of side-effects ? iii ) If i ) and ii ) can be answered in the affirmative , will the further reduction in diastolic blood pressure be associated with a further reduction in hypertension-associated mortality and morbidity ? Altogether 2127 hypertensive men and women with an average age of 59.8 years ( 46 - 71 ) were recruited at 142 primary health care centers in Sweden . Approximately 10,000 patient-years were accumulated . All patients had treated essential hypertension and all had diastolic blood pressures in the range 90 - 100 mmHg on three consecutive visits before entering the study . The patients were r and omized to either intensified treatment aim ing at a blood pressure < or = 80 mmHg diastolic ( group A ) or to unchanged therapy ( group B ) . A difference between group A and group B in diastolic blood pressure of 7 - 7.5 mmHg was achieved for > 4 years . Adverse effects were studied in detail in 100 r and omly selected patients from each group using a special question naire and a visual analogue scale . The adverse effect score fell significantly in group A but remained unchanged in group B. Regarding cardiovascular morbidity and mortality there were no significant differences between groups A and B , the total number of strokes and myocardial infa rcts being 28 in group A and 29 in group B. ( ABSTRACT TRUNCATED AT 250 WORDS Context Previously published results of this r and omized , double-blind trial showed that hypertensive patients treated with doxazosin rather than chlorthalidone more often developed heart failure . Did differences in blood pressure control or treatment with other drugs explain these findings ? Contribution This analysis shows that the slightly worse blood pressure control achieved with doxazosin did not explain higher risks for heart failure . Risks with doxazosin versus chlorthalidone were highest among patients who received monotherapy ( relative risk , 3.10 ) and lowest among patients who received stepped care with additional drugs ( relative risk , 1.42 ) . Implication s Increased risks for heart failure with doxazosin versus chlorthalidone are attenuated but not eliminated when additional antihypertensive drugs are used . The Editors The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , multicenter clinical trial including 42 418 participants at 623 clinical sites , is design ed to determine whether treatment begun with a calcium-channel blocker ( amlodipine ) , an angiotensin-converting enzyme inhibitor ( lisinopril ) , or an -adrenergic blocker ( doxazosin ) compared to treatment with a diuretic ( chlorthalidone ) reduces the incidence of fatal coronary heart disease or nonfatal myocardial infa rct ion in high-risk patients with hypertension ( 1 ) . Secondary end points are all-cause mortality , stroke , and other cardiovascular events . A lipid-lowering trial in a subset of 10 356 participants is design ed to determine whether decreasing cholesterol levels with a hydroxymethyl glutamyl coenzyme A reductase inhibitor ( pravastatin ) compared with usual care reduces all-cause mortality in older , moderately hypercholesterolemic patients . In January 2000 , the doxazosin arm of the trial was discontinued ( 2 ) because major cardiovascular disease ( relative risk , 1.25 [ 95 % CI , 1.17 to 1.33 ] ; P < 0.001 ) , especially heart failure ( relative risk , 2.04 [ 95 % CI , 1.79 to 2.32 ] ; P < 0.001 ) , was significantly increased compared with the chlorthalidone arm . Equally important , a low probability existed that doxazosin would show benefit over chlorthalidone for the primary end point by the scheduled study end , given the lack of difference ( relative risk , 1.02 [ 95 % CI , 0.90 to 1.17 ] ; P > 0.2 ] at that time . These intention-to-treat analyses compared patients assigned to chlorthalidone with patients assigned to doxazosin . In this article , we analyze how treatment changes may have affected the comparison of doxazosin with chlorthalidone in terms of heart failure . Our major objectives are to ascertain to what extent the relative risk with doxazosin versus chlorthalidone depends on 1 ) whether the assigned drugs were used as monotherapy or in combination with other agents and 2 ) the difference in decreases in systolic and diastolic blood pressure . Methods Study Design The rationale and design of ALLHAT are described in detail elsewhere ( 1 ) . In brief , eligible participants were men and women 55 years of age or older who had systolic or diastolic hypertension ( 140/90 mm Hg or hypertension controlled with medication ) plus at least one additional risk factor for coronary heart disease events . The risk factors included previous ( > 6 months ) myocardial infa rct ion or stroke , left ventricular hypertrophy on electrocardiography or echocardiography , history of type 2 diabetes , current cigarette smoking , and a low high-density lipoprotein cholesterol level . Persons with a history of hospitalized or treated symptomatic heart failure or a known ejection fraction less than 0.35 were excluded . Unless the drug regimen required tapering for safety , participants who had been taking antihypertensive medications continued to do so until the day of r and omization , at which point they stopped taking all previous medications . On the day after r and omization , treatment with the study drug was initiated . Enrollment occurred from February 1994 through January 1998 . The original reported number of 42 448 participants and 625 sites changed because 30 patients with poor documentation of informed consent were excluded ( 2 ) . Participants were assigned by a computer-generated r and omization schedule in a ratio of 1.7:1 to receive chlorthalidone or doxazosin . R and omization was stratified by center and blocked over time to maintain the ratio . All participants gave written informed consent , and all centers obtained institutional review board approval . Ascertainment of Outcomes At each clinic visit , occurrence of study end points was assessed by the clinical investigator . A hospital discharge summary was required for each hospitalized study outcome , and a death certificate was required for each death . ALLHAT defined symptomatic heart failure as clear-cut signs or symptoms of left or right ventricular dysfunction that can not be attributed to other causes . A patient had to have at least one symptom ( paroxysmal nocturnal dyspnea , dyspnea at rest , New York Heart Association class III dyspnea or other symptoms [ on less than ordinary exertion ] , or orthopnea ) and one sign ( rales , ankle edema , tachycardia , cardiomegaly or characteristic pulmonary pattern on chest radiography , S3 gallop , or jugular venous distention ) ( 3 ) . Symptoms and signs were determined by the clinic investigator through patient history , chart review , or consultation with the treating physician , but such data were not collected central ly . A one-time sample of 24 hospitalized or fatal heart failure events was review ed in a blinded manner by the ALLHAT Endpoints Subcommittee ; 20 of 24 ( 83 % ) were deemed to have complete data for a definitive diagnosis . Of the 20 cases , the agreement rate between the subcommittee and the clinic investigators was 90 % ( 18 of 20 ) and similar in both treatment groups . Details on the validity of diagnosis of heart failure will be provided in a future report . Measurement and Treatment of Blood Pressure The ALLHAT protocol specified a stepped-care treatment program for hypertension . Trained observers using st and ardized techniques measured blood pressures during the trial ( 1 , 2 ) . All blood pressures were calculated as the average of two measurements obtained with a 30-second interval between them . The blood pressure goal in all four study arms was less than 140/90 mm Hg . This level was to be achieved with the lowest possible dose of blinded first-line drug , with addition of second- and third-line open-label therapy as needed after reaching the maximal dose of first-line drug . Chlorthalidone and doxazosin were to be taken once daily in the morning . By design , doses were selected to achieve equivalent blood pressure control in the treatment groups . The first , second , and third dosage levels were 12.5 mg/d , 12.5 mg/d ( sham titration ) , and 25 mg/d , respectively , for chlorthalidone and 2 mg/d , 4 mg/d , and 8 mg/d for doxazosin . Double-blinded 1-mg and 12.5-mg doses of doxazosin and chlorthalidone , respectively , were used for the first week to minimize the frequency of postural hypotension associated with doxazosin . The identity of drugs was masked at each dosage level , but dosage level was not . After r and omization , patients were seen for dose titration as needed at 1 and 3 months per the protocol , but they could return more often until target blood pressure was reached . Subsequently , required visits occurred at 3-month intervals during the first year and at 4-month intervals thereafter . Open-label second-step drugs were added as needed and tolerated . These agents were reserpine ( 0.05 to 0.2 mg/d ) , clonidine ( 0.1 to 0.3 mg twice daily ) , and atenolol ( 25 to 100 mg/d ) . The choice of second-step drug was at the discretion of the treating clinician-investigator . The third-step agent was hydralazine ( 25 to 100 mg twice daily ) . Details of these therapies are provided elsewhere ( 1 ) . Investigators could choose to prescribe open-label antihypertensive drugs other than those provided by the study . However , use of the drug classes under study thiazide diuretics , calcium antagonists , angiotensin-converting enzyme inhibitors , and -adrenergic blockerswas strongly discouraged to avoid dilution of treatment comparisons . When clinical conditions other than uncontrolled hypertension ( for example , angina or heart failure ) were present , drugs from any study class could be used . If a step 1 drug was specifically required for blood pressure control while blinded drug treatment was continued , the step 1 drug could be added as open-label therapy but the dose could not exceed one half the maximum recommended by the Fifth Joint National Committee ( 4 ) . In most such cases , unblinding the patient or the investigator to treatment assignment was not necessary . ( Overall , < 1 % of drug identities were provided to either participant or investigator . ) Any of nine possible open-label drug typesdiuretic , calcium-channel blocker , angiotensin-converting enzyme inhibitor , -adrenergic blocker , atenolol , reserpine , clonidine , hydralazine , and other antihypertensive drug ( which could include nonatenolol -blockers , although drug name was not logged)could be recorded at each visit . Because diuretics , angiotensin-converting enzyme inhibitors , and -blockers are beneficial in preventing or treating heart failure , we call these antihypertensive heart failure drugs . Data on  antihypertensive drug use before study enrollment were collected , but not by drug class . Statistical Analysis Data were analyzed for use of additional drugs according to participants ' r and omized treatment assignments and regardless of continuation of blinded study treatment . The outcomes all heart failure ( treated outside hospital , hospitalized , or fatal ) and hospitalized or fatal heart failure were examined by treatment group for the entire cohort . The time to event for the previously published as-r and omized analyses was the interval from r and omization to first diagnosis of heart failure for patients who had an outcome , or from r and omization to OBJECTIVE To assess the effect of low-dose , diuretic-based antihypertensive treatment on major cardiovascular disease ( CVD ) event rates in older , non-insulin-treated diabetic patients with isolated systolic hypertension ( ISH ) , compared with nondiabetic patients . DESIGN Double-blind , r and omized , placebo-controlled trial : the Systolic Hypertension in the Elderly Program ( SHEP ) . SETTING Multiple clinical and support centers in the United States . PARTICIPANTS A total of 4736 men and women aged 60 years and older at baseline with ISH ( systolic blood pressure [ BP ] , > or = 160 mm Hg ; diastolic BP , < 90 mm Hg ) at baseline , 583 non-insulin-dependent diabetic patients and 4149 nondiabetic patients ( 4 additional patients not so classifiable were r and omized but not included in these analyses ) . Diabetes mellitus defined as physician diagnosis , taking oral hypoglycemic drugs , fasting glucose level of 7.8 mmol/L or more ( > or = 140 mg/dL ) , or any combination of these characteristics . INTERVENTION The active treatment group received a low dose of chlorthalidone ( 12.5 - 25.0 mg/d ) with a step-up to atenolol ( 25.0 - 50.0 mg/d ) or reserpine ( 0.05 - 0.10 mg/d ) if needed . The placebo group received placebo and any active antihypertensive drugs prescribed by patient 's private physician for persistently high BP . MAIN OUTCOME MEASURES The 5-year rates of major CVD events , nonfatal plus fatal stroke , nonfatal myocardial infa rct ion ( MI ) and fatal coronary heart disease ( CHD ) , major CHD events , and all-cause mortality . RESULTS The SHEP antihypertensive drug regimen lowered BP of both diabetic and nondiabetic patients , with few adverse effects . For both diabetic and nondiabetic patients , all outcome rates were lower for participants r and omized to the active treatment group than for those r and omized to the placebo group . Thus , 5-year major CVD rate was lower by 34 % for active treatment compared with placebo , both for diabetic patients ( 95 % confidence interval [ CI ] , 6%-54 % ) and nondiabetic patients ( 95 % CI , 21%-45 % ) . Absolute risk reduction with active treatment compared with placebo was twice as great for diabetic vs nondiabetic patients ( 101/1000 vs 51/1000 r and omized participants at the 5-year follow-up ) , reflecting the higher risk of diabetic patients . CONCLUSION Low-dose diuretic-based ( chlorthalidone ) treatment is effective in preventing major CVD events , cerebral and cardiac , in both non-insulin-treated diabetic and nondiabetic older patients with ISH Hypertension is the most common condition seen in primary care and leads to myocardial infa rct ion , stroke , renal failure , and death if not detected early and treated appropriately . Patients want to be assured that blood pressure ( BP ) treatment will reduce their disease burden , while clinicians want guidance on hypertension management using the best scientific evidence . This report takes a rigorous , evidence -based approach to recommend treatment thresholds , goals , and medications in the management of hypertension in adults . Evidence was drawn from r and omized controlled trials , which represent the gold st and ard for determining efficacy and effectiveness . Evidence quality and recommendations were grade d based on their effect on important outcomes . There is strong evidence to support treating hypertensive persons aged 60 years or older to a  BP goal  of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg ; however , there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal , or in those younger than 30 years for a diastolic goal , so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion . The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease ( CKD ) as for the general hypertensive population younger than 60 years . There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor , angiotensin receptor blocker , calcium channel blocker , or thiazide-type diuretic in the nonblack hypertensive population , including those with diabetes . In the black hypertensive population , including those with diabetes , a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy . There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes . Although this guideline provides evidence -based recommendations for the management of high BP and should meet the clinical needs of most patients , these recommendations are not a substitute for clinical judgment , and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient Background Reduced glomerular filtration rate ( GFR ) is associated with increased cardiovascular risk in young and middle aged individuals . Associations with cardiovascular disease and mortality in older people are less clearly established . We aim ed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants r and omized in the Prospect i ve Study of Pravastatin in the Elderly at Risk ( PROSPER ) . Methods and Findings Glomerular filtration rate was estimated ( eGFR ) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ( [ 20–40 ] , [ 40–50 ] , [ 50–60 ] ) ≥ 60 ml/min/1.73 m2 . Baseline risk factors were analysed by category of eGFR , with and without adjustment for other risk factors . The associations between baseline eGFR and morbidity and mortality outcomes , accrued after an average of 3.2 y , were investigated using Cox proportional hazard models adjusting for traditional risk factors . We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status . Age , low-density lipoprotein ( LDL ) and high-density lipoprotein ( HDL ) cholesterol , C-reactive protein ( CRP ) , body mass index , fasting glucose , female sex , histories of hypertension and vascular disease were associated with eGFR ( p = 0.001 or less ) after adjustment for other risk factors . Low eGFR was independently associated with risk of all cause mortality , vascular mortality , and other noncancer mortality and with fatal and nonfatal coronary and heart failure events ( hazard ratios adjusted for CRP and other risk factors ( 95 % confidence intervals [ CIs ] ) for eGFR < 40 ml/min/1.73m2 relative to eGFR ≥ 60 ml/min/1.73m2 respectively 2.04 ( 1.48–2.80 ) , 2.37 ( 1.53–3.67 ) , 3.52 ( 1.78–6.96 ) , 1.64 ( 1.18–2.27 ) , 3.31 ( 2.03–5.41 ) . There were no nominally statistically significant interactions ( p < 0.05 ) between r and omized treatment allocation and eGFR for clinical outcomes , with the exception of the outcome of coronary heart disease death or nonfatal myocardial infa rct ion ( p = 0.021 ) , with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs . Conclusions We have established that , in an elderly population over the age of 70 y , impaired GFR is associated with female sex , with presence of vascular disease , and with levels of other risk factors that would be associated with increased risk of vascular disease . Further , impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes . Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin Background — Higher levels of red blood cell distribution width ( RDW ) may be associated with adverse outcomes in patients with heart failure . We examined the association between RDW and the risk of all-cause mortality and adverse cardiovascular outcomes in a population of people with coronary disease who were free of heart failure at baseline . Methods and Results — We performed a post hoc analysis of data from the Cholesterol and Recurrent Events study . Baseline RDW was measured in 4111 participants who were r and omized to receive pravastatin 40 mg daily or placebo and followed for a median of 59.7 months . We used Cox proportional hazards models to examine the association between RDW and adverse clinical outcomes . During nearly 60 months of follow-up , 376 participants died . A significant association was noted between baseline RDW level and the adjusted risk of all-cause mortality ( hazard ratio per percent increase in RDW , 1.14 ; 95 % confidence interval , 1.05 to 1.24 ) . After categorization based on quartile of baseline RDW and further adjustment for hematocrit and other cardiovascular risk factors , a grade d independent relation between RDW and death was observed ( P for trend=0.001 ) . For instance , participants with RDW in the highest quartile had an adjusted hazard ratio for death of 1.78 ( 95 % confidence interval , 1.28 to 2.47 ) compared with those in the lowest quartile . Higher levels of RDW were also associated with increased risk of coronary death/nonfatal myocardial infa rct ion , new symptomatic heart failure , and stroke . Conclusions — We found a grade d independent relation between higher levels of RDW and the risk of death and cardiovascular events in people with prior myocardial infa rct ion but no symptomatic heart failure at baseline
Antihypertensive drugs used to treat predominantly healthy adults aged 18 to 59 years with mild to moderate primary hypertension have a small absolute effect to reduce cardiovascular mortality and morbidity primarily due to reduction in cerebrovascular mortality and morbidity .
All-cause mortality and coronary heart disease were not reduced .
There is lack of good evidence on withdrawal due to adverse events .
BACKGROUND Hypertension is an important risk factor for adverse cardiovascular events including stroke , myocardial infa rct ion , heart failure and renal failure .
The main goal of treatment is to reduce these events .
Systematic review s have shown proven benefit of antihypertensive drug therapy in reducing cardiovascular morbidity and mortality but most of the evidence is in people 60 years of age and older .
We wanted to know what the effects of therapy are in people 18 to 59 years of age .
OBJECTIVES To quantify antihypertensive drug effects on all-cause mortality in adults aged 18 to 59 years with mild to moderate primary hypertension .
To quantify effects on cardiovascular mortality plus morbidity ( including cerebrovascular and coronary heart disease mortality plus morbidity ) , withdrawal due adverse events and estimate magnitude of systolic blood pressure ( SBP ) and diastolic blood pressure ( DBP ) lowering at one year .