title: Long-term effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria:Ten years of follow-up of Prevention of Renal and Vascular End-stage Disease Intervention Trial (PREVEND IT). Legacy Effect of Delayed Blood Pressure-Lowering Pharmacotherapy in Middle-Aged Individuals Stratified by Absolute Cardiovascular Disease Risk: Protocol for a Systematic Review Effectiveness of blood pressure-lowering drug treatment by levels of absolute risk: post hoc analysis of the Australian National Blood Pressure Study Effects of Fosinopril and Pravastatin on Cardiovascular Events in Subjects With Microalbuminuria The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Effect of ramipril on the incidence of diabetes. Treatment of hypertension in patients 80 years of age or older. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial Effect of valsartan on the incidence of diabetes and cardiovascular events. Coronary heart disease and treatment of hypertension. Some Oslo Study data. Long-term survival in the randomized trial of drug treatment in mild to moderate hypertension of the Oslo study 1972-3. Ten-year legacy effects of baseline blood pressure ‘treatment naivety’ in the Second Australian National Blood Pressure 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. Association between chlorthalidone treatment of systolic hypertension and long-term survival. Treatment of mild hypertension: a five year controlled drug trial. The Oslo study.
abstract: BACKGROUND The PREVEND IT investigated whether treatment targeted at lowering urinary albumin excretion ( UAE ) would reduce adverse cardiovascular events . We obtained extended follow-up data to approximately 10 years to investigate the long-term effects of fosinopril 20 mg and pravastatin 40 mg on cardiovascular outcomes in subjects with UAE > 15 mg per 24 hours . METHODS The original PREVEND IT consisted of 864 participants and 839 survivors after 4 years . For every survivor , the primary end point determined by the combined incidence of cardiovascular mortality and hospitalization for cardiovascular morbidity was registered in several national data bases and electronic hospital systems . RESULTS Mean total follow-up of the extended PREVEND IT was 9.5 years ( range 9.4 - 10.7 years ) . Four years of treatment with fosinopril was not associated with a reduction in the primary end point compared with placebo ( hazard ratio 0.87 , 95 % CI 0.61 - 1.24 [ P = .42 ] ) during long-term follow-up . After 9.5 years , subjects with a baseline UAE in the upper quintile ( > 50 mg/24 hours ) had a total event rate of 29.5 % and were at a higher risk for developing cardiovascular disease compared with less UAE ( hazard ratio 2.03 , 95 % CI 1.38 - 2.97 [ P ≤ .01 ] ) . In addition , 4 years of fosinopril treatment result ed in a risk reduction of 45 % ( 95 % CI 6%-75 % [ P = .04 ] ) in this group compared with placebo . Subjects originally assigned to pravastatin had no overall risk reduction in the primary end point ( P = .99 ) . CONCLUSIONS Elevated UAE is associated with increased cardiovascular mortality and morbidity after 9.5 years of follow-up , with a doubling of the risk if the UAE is > 50 mg per 24 hours . In this group , the benefits of 4-year treatment with fosinopril were sustained during posttrial follow-up for cardiovascular mortality and morbidity . We propose that UAE be used to estimate risk in the general population and that large clinical trials be design ed to confirm the hypothesis that angiotensin-converting enzyme-inhibitor treatment may be beneficial in patients with mildly elevated UAE despite the absence of other comorbidities Background Many national and international guidelines recommend that the initiation of blood pressure (BP)-lowering drug treatment for the primary prevention of cardiovascular disease ( CVD ) should no longer be based on BP level alone , but on absolute cardiovascular risk . While BP-lowering drug treatment is beneficial in high-risk individuals at any level of elevated BP , clinicians are concerned about legacy effects on patients with low-to-moderate risk and mildly elevated BP who remain “ untreated ” . Objective We aim to investigate the legacy effect of delayed BP-lowering pharmacotherapy in middle-aged individuals ( 45 - 65 years ) with mildly elevated BP ( systolic BP 140 - 159 mmHg and /or diastolic BP 90 - 99 mmHg ) stratified by absolute risk for primary prevention of CVD , but particularly in the low-risk ( < 10 % five-year absolute risk ) group . Methods R and omized trials of BP-lowering therapy versus placebo or pretreated subjects in active comparator studies with posttrial follow-up will be identified using a 2-step process . First , r and omized trials of BP-lowering therapy will be identified by ( 1 ) retrieving the references of trials included in published systematic review s of BP-lowering therapy , ( 2 ) retrieving studies published by the Blood Pressure Lowering Treatment Trialists ’ Collaboration ( BPLTTC ) , and ( 3 ) checking studies referenced in the 1993 World Health Organization/International Society of Hypertension meeting memor and um on BP management . Posttrial follow-up studies will then be identified by forward citation search ing the r and omized trials identified in step 1 through Web of Science . The search will include r and omized controlled trials with at least 1-year in-trial period and a posttrial follow-up phase . Age is the major determinant of absolute cardiovascular risk , so the participants in our review will be restricted to middle-aged adults who are more likely to have a lower cardiovascular risk profile . The primary outcome will be all-cause mortality . Secondary outcomes will include cardiovascular mortality , fatal stroke , fatal myocardial infa rct ion , and death due to heart failure . Results The search es for existing systematic review s and BPLTTC studies were piloted and modified . The study is expected to be completed before June 2018 . Conclusions The findings of this study will contribute to the body of knowledge concerning the beneficial , neutral , or harmful effects of delayed BP-lowering drug treatment on the primary prevention of CVD in patients with mildly elevated BP and low-to-moderate CVD risk . Trial Registration PROSPERO International Prospect i ve Register of Systematic Review s : CRD42017058414 ; https://www.crd.york.ac.uk/ PROSPERO /display_record.asp?ID = CRD42017058414 ( Archived by WebCite ® at http://www.webcitation.org/6t6sa8O2Q Objectives In many current guidelines , blood pressure (BP)-lowering drug treatment for primary prevention of cardiovascular disease ( CVD ) is based on absolute risk . However , in clinical practice , therapeutic decisions are often based on BP levels alone . We sought to investigate which approach was superior by conducting a post hoc analysis of the Australian National Blood Pressure ( ANBP ) cohort , a seminal study establishing the efficacy of BP lowering in ‘ mild hypertensive ’ persons . Design A post hoc subgroup analysis of the ANBP trial results by baseline absolute risk tertile . Setting and participants 3244 participants aged 35–69 years in a community-based r and omised placebo controlled trial of blood pressure-lowering medication . Interventions Chlorothiazide500 mg versus placebo . Primary outcome measures All-cause mortality and non-fatal events ( non-fatal CVD , congestive cardiac failure , renal failure , hypertensive retinopathy or encephalopathy ) . Results Treatment effects were assessed by HR , absolute risk reduction and number needed to treat . Participants had an average 5-year CVD risk in the intermediate range ( 10.5±6.5 ) with moderately elevated BP ( mean 159/103 mmHg ) and were middle aged ( 52±8 years ) . In a subgroup analysis , the relative effects ( HR ) and absolute effects ( absolute risk reduction and number needed to treat ) did not statistically differ across the three risk groups except for the absolute benefit in all-cause mortality ( p for heterogeneity=0.04 ) . With respect to absolute benefit , drug treatment significantly reduced the number of events in the high-risk group regarding any event with a number needed to treat of 18 ( 10 to 64 ) , death from any cause with 45 ( 25 to 196 ) and major CVD events with 23 ( 12 to 193 ) . Conclusion Our analysis confirms that the benefit of treatment was substantial only in the high-risk tertile , reaffirming the rationale of treating elevated blood pressure in the setting of all risk factors rather than in isolation Background —Microalbuminuria is associated with increased risk of cardiovascular events . We assessed whether therapeutic intervention aim ed at lowering urinary albumin excretion would reduce cardiovascular events in microalbuminuric subjects ( 15 to 300 mg/24 hours ) . Methods and Results —From the Prevention of Renal and Vascular Endstage Disease ( PREVEND ) cohort ( n=8592 ) , 1439 subjects fulfilled the inclusion criteria of the PREVEND Intervention Trial ( PREVEND IT ) . Of these subjects , 864 were r and omized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo . The mean follow-up was 46 months , and the primary end point was cardiovascular mortality and hospitalization for cardiovascular morbidity . Mean age was 51±12 years ; 65 % of subjects were male , and 3.4 % had a previous cardiovascular event . Mean cholesterol level was 5.8±1.0 mmol/L , mean systolic/diastolic blood pressure was 130±18/76±10 mm Hg , and median urinary albumin excretion was 22.8 ( 15.8 to 41.3 ) mg/24 hours . The primary end point occurred in 45 subjects ( 5.2 % ) . Fosinopril  reduced urinary albumin excretion by 26 % ( P<0.001 ) . Subjects treated with fosinopril showed a 40 % lower incidence of the primary end point ( hazard ratio 0.60 [ 95 % CI 0.33 to 1.10 ] , P=0.098 , log-rank ) . Pravastatin did not reduce urinary albumin excretion , and subjects treated with pravastatin showed a 13 % lower incidence of the primary end point than subjects in the placebo group ( 0.87 [ 0.49 to 1.57 ] , P=0.649 , log-rank ) . Conclusions —In microalbuminuric subjects , treatment with fosinopril had a significant effect on urinary albumin excretion . In addition , fosinopril treatment was associated with a trend in reducing cardiovascular events  . Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND Previous studies have suggested that blockade of the renin-angiotensin system may prevent diabetes in people with cardiovascular disease or hypertension . METHODS In a double-blind , r and omized clinical trial with a 2-by-2 factorial design , we r and omly assigned 5269 participants without cardiovascular disease but with impaired fasting glucose levels ( after an 8-hour fast ) or impaired glucose tolerance to receive ramipril ( up to 15 mg per day ) or placebo ( and rosiglitazone or placebo ) and followed them for a median of 3 years . We studied the effects of ramipril on the development of diabetes or death , whichever came first ( the primary outcome ) , and on secondary outcomes , including regression to normoglycemia . RESULTS The incidence of the primary outcome did not differ significantly between the ramipril group ( 18.1 % ) and the placebo group ( 19.5 % ; hazard ratio for the ramipril group , 0.91 ; 95 % confidence interval [ CI ] , 0.81 to 1.03 ; P=0.15 ) . Participants receiving ramipril were more likely to have regression to normoglycemia than those receiving placebo ( hazard ratio , 1.16 ; 95 % CI , 1.07 to 1.27 ; P=0.001 ) . At the end of the study , the median fasting plasma glucose level was not significantly lower in the ramipril group ( 102.7 mg per deciliter [ 5.70 mmol per liter ] ) than in the placebo group ( 103.4 mg per deciliter [ 5.74 mmol per liter ] , P=0.07 ) , though plasma glucose levels 2 hours after an oral glucose load were significantly lower in the ramipril group ( 135.1 mg per deciliter [ 7.50 mmol per liter ] vs. 140.5 mg per deciliter [ 7.80 mmol per liter ] , P=0.01 ) . CONCLUSIONS Among persons with impaired fasting glucose levels or impaired glucose tolerance , the use of ramipril for 3 years does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycemia . ( Clinical Trials.gov number , NCT00095654 [ Clinical Trials.gov ] . ) BACKGROUND Whether the treatment of patients with hypertension who are 80 years of age or older is beneficial is unclear . It has been suggested that antihypertensive therapy may reduce the risk of stroke , despite possibly increasing the risk of death . METHODS We r and omly assigned 3845 patients from Europe , China , Australasia , and Tunisia who were 80 years of age or older and had a sustained systolic blood pressure of 160 mm Hg or more to receive either the diuretic indapamide ( sustained release , 1.5 mg ) or matching placebo .  The angiotensin-converting-enzyme inhibitor perindopril ( 2 or 4 mg ) , or matching placebo , was added if necessary to achieve the target blood pressure of 150/80 mm Hg . The primary end point was fatal or nonfatal stroke . RESULTS The active-treatment group ( 1933 patients ) and the placebo group ( 1912 patients ) were well matched ( mean age , 83.6 years ; mean blood pressure while sitting , 173.0/90.8 mm Hg ) ; 11.8 % had a history of cardiovascular disease . Median follow-up was 1.8 years . At 2 years , the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group . In an intention-to-treat analysis , active treatment was associated with a 30 % reduction in the rate of fatal or nonfatal stroke ( 95 % confidence interval [ CI ] , -1 to 51 ; P=0.06 ) , a 39 % reduction in the rate of death from stroke ( 95 % CI , 1 to 62 ; P=0.05 ) , a 21 % reduction in the rate of death from any cause ( 95 % CI , 4 to 35 ; P=0.02 ) , a 23 % reduction in the rate of death from cardiovascular causes ( 95 % CI , -1 to 40 ; P=0.06 ) , and a 64 % reduction in the rate of heart failure ( 95 % CI , 42 to 78 ; P<0.001 ) . Fewer serious adverse events were reported in the active-treatment group ( 358 , vs. 448 in the placebo group ; P=0.001 ) . CONCLUSIONS The results provide evidence that antihypertensive treatment with indapamide ( sustained release ) , with or without perindopril , in persons 80 years of age or older is beneficial . ( Clinical Trials.gov number , NCT00122811 [ Clinical Trials.gov ] . ) Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation  to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies Background To assess the impact of immediate versus delayed antihypertensive treatment on the outcome of older patients with isolated systolic hypertension  , we extended the double-blind placebo-controlled Systolic Hypertension in Europe ( Syst-Eur ) trial by an open-label follow-up study lasting 4 years . Methods The Syst-Eur trial included 4695 r and omized patients with minimum age of 60 years and an untreated blood pressure of 160–219 mmHg systolic and below 95 mmHg diastolic . The double-blind trial ended after a median follow-up of 2.0 years ( range 1–97 months ) . Of 4409 patients still alive , 3517 received open-label treatment consisting of nitrendipine ( 10–40 mg daily ) with the possible addition of enalapril ( 5–20 mg daily ) , hydrochlorothiazide ( 12.5–25 mg daily ) , or both add-on drugs .  Non- participants ( n = 892 ) were also followed up . Results Median follow-up increased to 6.1 years . Systolic pressure decreased to below 150 mmHg ( target level ) in 2628 participants ( 75.0 % ) . During the 4-year open-label follow-up , stroke and cardiovascular complications occurred at similar frequencies in patients formerly r and omized to placebo and those continuing active treatment . These rates were similar to those previously observed in the active-treatment group during the double-blind trial . Considering the total follow-up of 4695 r and omized patients , immediate compared with delayed antihypertensive treatment reduced the occurrence of stroke and cardiovascular complications by 28 % ( P = 0.01 ) and 15 % ( P = 0.03 ) , respectively , with a similar tendency for total mortality ( 13 % , P = 0.09 ) . In 492 diabetic patients , the corresponding estimates of long-term benefit ( P < 0.02 ) were 60 , 51 and 38 % , respectively . Conclusions Antihypertensive treatment can achieve blood pressure control in most older patients with isolated systolic hypertension . Immediate compared with delayed treatment prevented 17 strokes or 25 major cardiovascular events per 1000 patients followed up for 6 years . These findings underscore the necessity of early treatment of isolated systolic hypertension BACKGROUND It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance . METHODS In this double-blind , r and omized clinical trial with a 2-by-2 factorial design , we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan ( up to 160 mg daily ) or placebo ( and nateglinide or placebo ) in addition to lifestyle modification . We then followed the patients for a median of 5.0 years for the development of diabetes ( 6.5 years for vital status ) . We studied the effects of valsartan on the occurrence of three co primary outcomes : the development of diabetes ; an extended composite outcome of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , hospitalization for heart failure , arterial revascularization , or hospitalization for unstable angina ; and a core composite outcome that excluded unstable angina and revascularization . RESULTS The cumulative incidence of diabetes was 33.1 % in the valsartan group , as compared with 36.8 % in the placebo group ( hazard ratio in the valsartan group , 0.86 ; 95 % confidence interval [ CI ] , 0.80 to 0.92 ; P<0.001 ) . Valsartan , as compared with placebo , did not significantly reduce the incidence of either the extended cardiovascular outcome ( 14.5 % vs. 14.8 % ; hazard ratio , 0.96 ; 95 % CI , 0.86 to 1.07 ; P=0.43 ) or the core cardiovascular outcome ( 8.1 % vs. 8.1 % ; hazard ratio , 0.99 ; 95 % CI , 0.86 to 1.14 ; P=0.85 ) . CONCLUSIONS Among patients with impaired glucose tolerance and cardiovascular disease or risk factors , the use of valsartan for 5 years , along with lifestyle modification , led to a relative reduction of 14 % in the incidence of diabetes but did not reduce the rate of cardiovascular events . ( Clinical Trials.gov number , NCT00097786 . The Oslo Hypertension Study began in 1972 ; patients were followed for an average of 66 months ( range : 60 to 78 ) . A total of 785 healthy men , aged 40 to 49 , with mild hypertension was r and omly assigned to either a drug-treated group or to an untreated control group . Hydrochlorothiazide was used alone in 36 percent of patients , in combination with propranolol in 26 percent , and with methyldopa in 20 percent . Other drugs , including combinations with hydrochlorothiazide , were used in 18 percent . A total of 95 percent of patients in the drug-treated group received hydrochlorothiazide .  Complications of hypertension such as stroke and aneurysm occurred only in the control group . Coronary events were more numerous in the drug-treated group ; thus , the total incidence of cardiovascular complications did not significantly differ between the treated and untreated groups . After five and 10 years , total mortality was the same in both groups . However , the coronary heart disease mortality rate at 10 years was significantly greater in the drug-treated group than in the untreated control group ( 14 versus three , p less than 0.01 ) . This article presents possible reasons for the failure of antihypertensive drug therapy to prevent coronary heart disease . The adverse effect of diuretics and beta-adrenergic blockers , both on lipid and carbohydrate metabolism , is contrasted with the effect of the alpha-adrenergic blocker prazosin , which has been shown to have no adverse effect on the blood lipid profile . In a short-term trial that was part of the Oslo Study , prazosin was found to reduce total serum cholesterol by 9 percent , low-density lipoprotein and very-low-density lipoprotein cholesterol by 10 percent , and total triglycerides by 16 percent . All these changes are statistically significant BACKGROUND In the Oslo cardiovascular study of 1972 - 3 a 5-year r and omized trial in mild to moderate hypertension was performed . Several changes in treatment practice s have been recommended since that time . We followed the mortality patterns up to 40 years . METHODS Invited to the Oslo study screening were 25,915 middle-aged men and 16,203 ( 63 % ) participated . Reexaminations were done to select suitable participants into the trial . Men had blood pressure 150 - 179/95 - 109 mm Hg and the active group ( n=406 ) was treated with thiazides , alpha-methyldopa and propranolol versus untreated controls ( n=379 ) . Cox regression analysis was used for statistical analyses . RESULTS There was no trend towards reduction in total mortality by treatment . A nominally significant increase in risk of death at first myocardial infa rct ion was observed in the trial treatment group across the follow-up period , HR=1.51 ( 1.01 - 2.25 ) ; ( P=0.042 ) . The excess risk developed rapidly during the first 15 years , but the gap between the groups diminished to a large extent during the next 15 years , but the curves stayed at a certain distance for the last 10 years . Cerebrovascular death tended to be non-significantly reduced , HR=0.85 ( 0.52 - 1.41 ) . CONCLUSIONS Drug treatment of mild hypertensive men initiated in the 1970s did not reduce mortality at first MI or total mortality . However , during the period ( late 1980s and whole 1990s ) , when large changes in hypertension treatment practice s occurred into regimes with more use of combination therapies including metabolically neutral drugs at lower doses , beneficial effects on MI mortality could be observed Objectives : Current blood pressure ( BP ) management guidelines recommend that treatment thresholds for BP be based on absolute cardiovascular disease ( CVD ) risk rather than on elevated BP levels alone . Clinicians are concerned that delayed pharmacotherapy in individuals with high BP , but low CVD risk , may increase long-term CVD events . To investigate this , we examined differences in CVD events within the Second Australian National BP study ( ANBP2 ) for those previously on pharmacotherapy and those who were not , as well as fatal events in the 6-year post-trial period . Methods : Population consisted of ANBP2 participants without a prior CVD event . Adjusted Cox-regression hazard models were used to assess the effects of prior BP pharmacotherapy use on cardiovascular endpoints within ANBP2 . An extended 6-year follow-up analysis for cardiovascular and all-cause mortality was also conducted . Results : We found a higher in-trial CVD and all-cause mortality rate and incidence of new-onset diabetes for those on previous treatment versus those who were treatment-naive . We investigated whether this was an effect of the in-trial protocol , but this did not explain the observed differences . No difference in CVD or all-cause mortality at 10 years was observed between ‘ treatment-naive ’ and ‘ previous treatment ’ groups . Conclusion : We found no long-term adverse mortality associated with treatment naivety of elevated BP in an elderly hypertensive cohort , but this finding is likely to be confounded as seen by the lower in-trial mortality in the ‘ treatment-naive ’ group . Legacy effects need to be explored in r and omized trials of middle-aged population s where the clinical concern lies 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 CONTEXT In the Systolic Hypertension in the Elderly Program ( SHEP ) trial , conducted between 1985 and 1990 , antihypertensive therapy with chlorthalidone-based stepped-care therapy result ed in a lower rate of cardiovascular events than placebo but effects on mortality were not significant . OBJECTIVE To study the gain in life expectancy of participants r and omized to active therapy at the 22-year follow-up . DESIGN , SETTING , AND PARTICIPANTS A National Death Index ascertainment of death in the long-term follow-up of a r and omized , placebo-controlled , clinical trial ( SHEP ) of patients aged 60 years or older with isolated systolic hypertension . Recruitment was between March 1 , 1985 , and January 15 , 1988 . After the end of a 4.5-year r and omized phase of the SHEP trial , all participants were advised to receive active therapy .  The time interval between the beginning of recruitment and the ascertainment of death by National Death Index ( December 31 , 2006 ) was approximately 22 years ( 21 years 10 months ) . MAIN OUTCOME MEASURES Cardiovascular death and all-cause mortality . RESULTS At the 22-year follow-up , life expectancy gain , expressed as the area between active ( n = 2365 ) and placebo ( n = 2371 ) survival curves , was 105 days ( 95 % CI , -39 to 242 ; P = .07 ) for all-cause mortality and 158 days ( 95 % CI , 36 - 287 ; P = .009 ) for cardiovascular death . Each month of active treatment was therefore associated with approximately 1 day extension in life expectancy . The active treatment group had higher survival free from cardiovascular death vs the placebo group ( hazard ratio [ HR ] , 0.89 ; 95 % CI , 0.80 - 0.99 ; P = .03 ) but similar survival for all-cause mortality ( HR , 0.97 ; 95 % CI , 0.90 - 1.04 ; P = .42 ) . There were 1416 deaths ( 59.9 % ) in the active treatment group and 1435 deaths ( 60.5 % ) in the placebo group ( log-rank P = .38 , Wilcoxon P = .24 ) . Cardiovascular death was lower in the active treatment group ( 669 deaths [ 28.3 % ] ) vs the placebo group ( 735 deaths [ 31.0 % ] ; log-rank P = .03 , Wilcoxon P = .02 ) . Time to 70th percentile survival was 0.56 years ( 95 % CI , -0.14 to 1.23 ) longer in the active treatment group vs the placebo group ( 11.53 vs 10.98 years ; P = .03 ) for all-cause mortality and 1.41 years ( 95 % CI , 0.34 - 2.61 ; 17.81 vs 16.39 years ; P = .01 ) for survival free from cardiovascular death . CONCLUSION In the SHEP trial , treatment of isolated systolic hypertension with chlorthalidone stepped-care therapy for 4.5 years was associated with longer life expectancy at 22 years of follow-up 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
target: The effects of delayed BP lowering treatment on long-term all-cause and CVD mortality did not vary with baseline risk of CVD .
  The review showed no clinical ly adverse ‘ legacy effect ’ on mortality or major CVD event from not treating middle-aged adults at a systolic BP threshold of 140 mmHg or over .
  Although these studies are non-r and omised post-hoc analyses , they may allay concerns that early treatment of elevated systolic BP is necessary to prevent CVD events in primary prevention population
background: To investigate if there is evidence for a ‘ legacy effect ’ for blood pressure ( BP ) lowering treatment , that is , worse health outcomes from not initiating drug treatment at a systolic BP threshold of 140 mmHg in middle-age adults .