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. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT) Evidence Supporting a Systolic Blood Pressure Goal of Less Than 150 mm Hg in Patients Aged 60 Years or Older: The Minority View Blood pressure and isolated systolic hypertension and the risk of coronary heart disease and mortality in elderly men (the Zutphen Elderly Study) Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project. Cardiovascular morbidity and mortality in mild hypertension: the Australian Trial. Stenting and medical therapy for atherosclerotic renal-artery stenosis. 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. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous? Cost-effectiveness and clinical effectiveness of catheter-based renal denervation for resistant hypertension. 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
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 ,
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 .