Effectiveness of blood pressure-lowering drug treatment by levels of absolute risk: post hoc analysis of the Australian National Blood Pressure Study Legacy Effect of Delayed Blood Pressure-Lowering Pharmacotherapy in Middle-Aged Individuals Stratified by Absolute Cardiovascular Disease Risk: Protocol for a Systematic Review Apparent effect on blood pressure is only partly responsible for the risk reduction due to antihypertensive treatments. Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease. Does lowering the blood pressure improve the mood? Quality-of-life results from the Hypertension Optimal Treatment (HOT) study. Non-pharmacological treatment of hypertension in primary health care: a 2-year open randomized controlled trial of lifestyle intervention against hypertension in eastern Finland Subgroup and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly. The effects of blood pressure reduction in older patients: an overview of five randomized controlled trials in elderly hypertensives. Long-Term Weight Loss and Changes in Blood Pressure: Results of the Trials of Hypertension Prevention, Phase II Therapeutic benefit of internet-based lifestyle counselling for hypertension. Blood pressure declines and less favorable outcomes in the NINDS tPA stroke study The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels. Results of the Trials of Hypertension Prevention, Phase I. Treatment of mild hypertension: a five year controlled drug trial. The Oslo study. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial EFFICACY OF ANTIHYPERTENSIVE DRUG TREATMENT ACCORDING TO AGE, SEX, BLOOD PRESSURE, AND PREVIOUS CARDIOVASCULAR DISEASE IN PATIENTS OVER THE AGE OF 60 Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous? Implications of small reductions in diastolic blood pressure for primary prevention.
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 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 The mechanism of risk reduction obtained by blood pressure-lowering pharmacological treatment remains unclear . We explored the amount of risk reduction attributable to the apparent effect of antihypertensive medicines on blood pressure by using the capture approach . Five r and omized , placebo or nil controlled trials with a total of 28,997 subjects and 1,935 cardiovascular fatal or non-fatal events from the INDANA data base met the eligibility criteria . Computations were performed on the original individual records using multiple Cox 's proportional hazard regression models design ed for meeting the assumed treatment mode of action and comparing relevant assumptions . For coronary event , the results are inconclusive essentially because the risk reduction is mild . However , for stroke the risk reduction adjusted for baseline risk factors is 34 % ( P<0.0001 ) . The part explained by the effect of treatment on systolic blood pressure is 49 % of this reduction , with 95 % confidence interval not including 100 % . This result suggests that the apparent effect on blood pressure is not the only cause of stroke risk reduction in hypertensive subjects su bmi tted to an antihypertensive medicine Blood-pressure and cholesterol lowering in persons without cardiovascular disease Elevated blood pressure and elevated low-density lipoprotein ( LDL ) cholesterol increase the risk of cardiovascular disease . Lowering both should reduce the risk of cardiovascular events substantially . This proposition is examined in this r and omised trial in which patients without cardiovascular disease were r and omised to receive such treatments compared with placebos . The combination of rosuvastatin ( 10 mg per day ) , c and esartan ( 16 mg per day ) , and hydrochlorothiazide ( 12.5 mg per day ) was associated with a significantly lower rate of cardiovascular events than dual placebo among persons at intermediate risk who did not have cardiovascular disease .  Muscle weakness and dizziness were more common in the combined therapy group , but the rate of discontinuation was similar in the two groups Nine-hundred- and -twenty-two hypertensive patients were included in a sub study to the Hypertension Optimal Treatment study , which aim ed to investigate the impact on quality of life of lowering the pressure and of intensified therapy .  Seven-hundred- and -eighty-one patients completed both baseline and follow-up question naires ( intention-to-treat population ) , while 610 patients were included in a per protocol analysis . Patients were r and omized to three diastolic BP levels ( DBPs ) , i.e. < or = 90 mmHg , < or = 85 mmHg and < or = 80 mmHg . Two self-administered vali date d question naires , the  Psychological General Well-Being index and the Subjective Symptoms Assessment Profile ( SSA-P )  were completed at baseline and after 6 months . The lower the DBP achieved , the greater the improvement in well-being ( p < 0.05 ) . The increase in well-being from baseline to 6 months was significant in target groups < or = 80 mmHg ( p < 0.01 ) and < or = 85 mmHg ( p < 0.05 ) . The SSA-P domains , cardiac symptoms and dizziness improved in all groups but the sex life score deteriorated in the < or = 80 and < or = 85 mmHg groups in male patients . In all target groups , headaches were reduced ( p < 0.001 ) , while swollen ankles ( p < 0.001 ) and dry cough in the < or = 80 mmHg group ( p < 0.001 ) increased . Although more intensive antihypertensive therapy is associated with a slight increase in subjective symptoms , it is nonetheless still associated with improvements in patients ' well-being Objective To assess whether lifestyle counselling is effective in non-pharmacological treatment of hypertension in primary health care . Design Open r and omized controlled trial . Setting Ten municipal primary health care centres in eastern Finl and . Patients Seven hundred and fifteen subjects aged 25–74 years with systolic blood pressure 140–179 mmHg and /or diastolic blood pressure 90–109 mmHg or antihypertensive drug treatment . Interventions Systematic health counselling given by local public health nurses for 2 years . Main outcome measures Blood pressure , lipids and lifestyle data were collected annually . Results Among participants with no antihypertensive drug treatment , the net reductions after 1 year both in systolic blood pressure [ −2.6 mmHg ; 95 % confidence interval ( CI ) , −4.7 to −0.5 mmHg ] and in diastolic blood pressure ( −2.7 mmHg ; 95 % CI , −4.0 to −1.4 mmHg ) were significant in favour of the intervention group . This difference in blood pressure change was maintained during the second year . In participants with antihypertensive drug treatment , no significant difference in blood pressure reduction was seen between the groups during the study . Conclusions A relatively modest , but systematic counselling in primary health care can , at least among untreated hypertensive subjects , produce reductions in blood pressure levels that are modest for the individual , but very important from the public health point of view BACKGROUND In 1989 , the European Working Party on High Blood Pressure in the Elderly started the double-blind , placebo-controlled , Systolic Hypertension in Europe Trial to test the hypothesis that antihypertensive drug treatment would reduce the incidence of fatal and nonfatal stroke in older patients with isolated systolic hypertension . This report addresses whether the benefit of antihypertensive treatment varied according to sex , previous cardiovascular complications , age , initial blood pressure ( BP ) , and smoking or drinking habits in an intention-to-treat analysis and explores whether the morbidity and mortality results were consistent in a per- protocol analysis . METHODS After stratification for center , sex , and cardiovascular complications , 4695 patients 60 years of age or older with a systolic BP of 160 to 219 mm Hg and diastolic BP less than 95 mm Hg were r and omized . Active treatment consisted of nitrendipine ( 10 - 40 mg/d ) , with the possible addition of enalapril maleate ( 5 - 20 mg/d ) and /or hydrochlorothiazide ( 12.5 - 25 mg/d ) , titrated or combined to reduce the sitting systolic BP by at least 20 mm Hg , to below 150 mm Hg . In the control group , matching placebo tablets were employed similarly . RESULTS In the intention-to-treat analysis , male sex , previous cardiovascular complications , older age , higher systolic BP , and smoking at r and omization were positively and independently correlated with cardiovascular risk . Furthermore , for total ( P = .009 ) and cardiovascular ( P = .09 ) mortality , the benefit of antihypertensive drug treatment weakened with advancing age ; for total mortality ( P = .05 ) , the benefit increased with higher systolic BP at entry , while for fatal and nonfatal stroke ( P = .01 ) , it was most evident in nonsmokers ( 92.5 % of all patients ) . In the per protocol analysis , active treatment reduced total mortality by 24 % ( P = .05 ) , reduced all fatal and nonfatal cardiovascular end points by 32 % ( P<.001 ) , reduced all strokes by 44 % ( P = .004 ) , reduced nonfatal strokes by 48 % ( P = .005 ) , and reduced all cardiac end points , including sudden death , by 26 % ( P = .05 ) . CONCLUSIONS In elderly patients with isolated systolic hypertension , stepwise antihypertensive drug treatment , starting with the dihydropyridine calcium channel blocker nitrendipine , improves prognosis . The per- protocol analysis suggested that treating 1000 patients for 5 years would prevent 24 deaths , 54 major cardiovascular end points , 29 strokes , or 25 cardiac end points . The effects of antihypertensive drug treatment on total and cardiovascular mortality may be attenuated in very old patients Direct evidence about the effects of antihypertensive treatment on vascular disease in older patients is available from five r and omized trials conducted exclusively in patients over the age of 60 years . These trials involved a total of 12,483 individuals with systolic or diastolic hypertension ( mean age = 72 years , mean entry blood pressure = 181/88 mmHg ) . Over an average follow-up period of 4.7 years , a 15/6 mmHg difference in blood pressure between study and control groups was achieved . Among those patients assigned active treatment , stroke incidence was reduced by 34 % SD6 and coronary heart disease incidence was reduced by 19 % SD7 . These proportional reductions were of similar size to those observed in trials in predominantly younger patients . However , the absolute benefits observed in older patients were more than twice as great as those observed in younger patients . The results suggest that over 10 years , treatment would prevent at least one major vascular event among every 10 elderly patients at similar risk to those enrolled in the trials Approximately one fourth of the U.S. adult population nearly 50 million peoplehas hypertension ( 1 , 2 ) . Taking a broader perspective , more than half of the adult population has higher than optimal blood pressure ( 1 ) , defined as systolic blood pressure greater than 120 mm Hg and diastolic blood pressure greater than 80 mm Hg ( 2 ) . These persons are at significantly increased risk for cardiovascular disease and stroke ( 3 ) . Although pharmacologic treatment for hypertension significantly reduces morbidity and mortality from cardiovascular diseases ( 4 , 5 ) , long-term pharmacologic therapy can have undesirable side effects and requires the expense of continuing medical supervision . Furthermore , pharmacologic therapy is not usually initiated when blood pressure is higher than optimal yet below diagnostic thresholds for hypertension . Thus , lifestyle interventions for primary prevention and initial treatment of high blood pressure remain a vital strategy for controlling this highly prevalent condition ( 2 ) . Weight loss has been shown to reduce blood pressure in overweight hypertensive patients ( 6 - 9 ) and in overweight persons with high-normal blood pressure ( 10 - 12 ) . Two review s of r and omized trials of weight reduction to reduce blood pressure examined the results of nine studies ( 13 , 14 ) . Most of these trials were small , only one had more than 500 participants ( 11 ) , and most had short-term follow-up ( 1 year or less ) . Only three studies had follow-up of 3 to 5 years ( 8 , 10 , 11 ) . Compared with controls ,  weight loss  averaged nearly 7 kg in the short-term trials and approximately 3 kg in the three longer-term trials . In almost all trials , systolic blood pressure and diastolic blood pressure were reduced in the intervention groups . Since these review s were published , the Trials of Hypertension Prevention ( TOHP ) Phase I reported mean weight reduction of 3.9 kg at 18 months in 564 overweight participants with high-normal blood pressure , result ing in significant decreases in systolic blood pressure and diastolic blood pressure compared with a usual care control group ( 12 , 15 ) . To investigate whether nonpharmacologic interventions can prevent hypertension over the long term , TOHP II was initiated . This was a r and omized , controlled trial examining the effects of  weight loss and dietary sodium reduction , alone and in combination , in reducing blood pressure in overweight adults with high-normal diastolic blood pressure ( 16 ) . This target population is at high risk for hypertension as they age . The primary outcome paper from this trial ( 17 ) provided only a brief overview of the effects of weight loss on blood pressure . Here , we provide more detailed analysis of weight loss and blood pressure in TOHP II . Of special interest are the long-term effects of weight loss on blood pressure , the magnitude of the doseresponse relationship at 36 months , the effect of patterns of weight loss on blood pressure , and the predictors of weight loss and blood pressure response . Methods Participants Participants in TOHP II were overweight adults with nonmedicated diastolic blood pressure of 83 to 89 mm Hg and systolic blood pressure less than 140 mm Hg . Other eligibility criteria included age 30 to 54 years and a body mass index of 26.1 to 37.4 kg/m2 for men and 24.4 to 37.4 kg/m2 for women , approximately 110 % to 165 % of ideal weight ( 18 ) . Principal exclusion criteria were current treatment with medications that might affect blood pressure , clinical or laboratory evidence of cardiovascular disease , diabetes mellitus , renal insufficiency ( serum creatinine concentration 150 mol/L [ 1.7 mg/dL ] for men and 132 mol/L [ 1.5 mg/dL ] for women ) , and current or planned pregnancy . Detailed descriptions of recruitment and participant characteristics have been published elsewhere ( 19 , 20 ) . The study was review ed and approved by the institutional review boards at all nine TOHP centers and the coordinating center , and all participants signed informed consent forms . Design Eligible participants were r and omly assigned with equal probability to one of four groups : weight loss only , sodium reduction only , combined weight loss and sodium reduction , or usual care ( controls ) . Measurements Age , sex , ethnicity , and years of education were obtained by question naire . Baseline blood pressure measurements were taken at three screening visits , each separated by 7 to 45 days . At each visit , three readings of systolic blood pressure and diastolic blood pressure were obtained and averaged . Certified staff obtained measurements in seated participants by using a Hawksley r and om-zero sphygmomanometer ( 21 ) . Body weight was measured to the nearest 0.2 kg ( 0.5 lb ) by using a calibrated balance-beam scale ; participants wore indoor clothing ( without shoes ) . Blood pressure and weight were measured every 6 months after r and omization to the end of follow-up at 36 , 42 , or 48 months , depending on r and omization date . Clinic staff who were blinded to study group assignment made these assessment s. Blood pressure measurements were obtained during a single visit at all follow-up points except for 18 and 36 months , when measurements were taken at a series of three visits approximately 1 week apart . Multiple measurements were taken at 18 and 36 months to provide a more precise assessment of average blood pressures at these primary outcome points . Dietary intake was assessed by 24-hour recall , and physical activity was assessed by question naire . Intervention Participants assigned to the weight loss intervention group sought to lose at least 4.5 kg ( 10 lb ) during the first 6 months of the intervention and to maintain their weight loss for the remainder of the trial . A brief description of the intervention methods is presented here ; a more detailed description has been published elsewhere ( 22 ) . The intervention started with an individual counseling session , followed by 14 weekly group meetings led by dietitians or health educators . After this 14-week intensive phase , participants attended six biweekly group meetings and then monthly group meetings . Beginning in the 18th month , participants were offered a variety of options to keep them involved in the intervention , including individual counseling sessions and special group sessions focused on selected weight loss topics . The intervention focused on self-directed behavior change ( behavioral self-management ) , nutrition education , information on physical activity , and social support for making and maintaining behavior changes . Specific behavior change techniques included self-monitoring ( food diaries and graphs of minutes of physical activity per day ) , setting explicit short-term goals and developing specific action plans to achieve those objectives , and developing alternative strategies for situations that trigger problem eating . The dietary intervention focused on reducing caloric intake by decreasing consumption of excess fat , sugar , and alcohol . Keeping daily food diaries was emphasized for monitoring intake and assessing progress . With experience , the participants determined the caloric intake that produced moderate weight loss for them . It was suggested that men not consume less than 1500 kcal/d and women not less than 1200 kcal/d . Weight loss of more than 0.9 kg ( 2 lb ) per week was discouraged . The physical activity goal was to gradually increase activity to 30 to 45 minutes per day , four to five days per week . Exercise intensity was moderate , approximately 40 % to 55 % of heart rate reserve , and consisted primarily of brisk walking . Statistical Analysis Baseline characteristics of the weight loss and usual care groups were compared overall and by sex by using t-tests for means and chi-square tests for proportions . Although weight and blood pressure data were collected every 6 months , special efforts were made to achieve high follow-up rates at 18 and 36 months ; at each of these two time points , nine blood pressure readings were collected over three visits and were averaged . For participants prescribed antihypertensive medication , follow-up blood pressure for all subsequent visits was taken to be the last study blood pressure before therapy was started . Participants receiving medications that affect blood pressure for reasons other than hypertension or who became pregnant were treated as missing at that visit . We used two- sample t-tests to compare changes in weight and blood pressure from baseline in the  weight loss intervention and usual care groups overall , by sex , by ethnicity , and by sex and ethnicity . The effects of the intervention in terms of changes in weight and blood pressure were examined overall and in subgroups defined by sex , ethnicity , and sex and ethnicity . Subgroup differences were tested by using terms for the interaction of treatment group with sex and with ethnicity in multiple linear regression models . Regression analyses were also used to analyze the doseresponse relationship between change in weight and change in blood pressure , overall and within sex and ethnicity subgroups . Differences in dose response were tested by using interaction terms in linear regression models . All regressions were adjusted for age and baseline weight . We also adjusted for baseline blood pressure in the blood pressure regression models . Change in blood pressure was also examined in relation to quintile of weight loss . Quintiles were computed by using the distribution of weight change in the weight loss intervention group . Additional multiple regression analyses were performed in which weight loss participants were categorized according to patterns of weight loss at 6 and 36 months . The PROC MIXED function of SAS software ( SAS Institute , Inc. , Cary , North Carolina ) was used to perform repeated- measures analyses that tested differences over time by pattern of weight loss . Cox proportional-hazards models were used for survival analyses , with onset of hypertension as the outcome . Results Baseline Findings The baseline characteristics of participants assigned to BACKGROUND Preventive electronic (e)-counselling has been shown to reduce cardiovascular risk factors . However , heterogeneity in outcomes is commonly reported due to differences in e- protocol s. We incorporated key features of an established behavioural therapy , motivational interviewing , to help st and ardize e-counselling in order to reduce blood pressure in patients with hypertension . METHODS Subjects ( n = 387 , mean age = 56 years , 59 % female , 72 % taking ≥ 1 antihypertensive drug ) were diagnosed with stage 1 or 2 hypertension . Subjects were r and omized to a 4-month protocol of e-counselling ( beta version of the " Blood Pressure Action Plan " , Heart and Stroke Foundation of Canada ) vs waitlist control ( general e-information on heart-healthy living ) . Outcomes were systolic , diastolic , and pulse pressures , and total lipoprotein cholesterol after treatment . RESULTS Intention to treat analysis did not find a significant group difference in outcomes due to contamination across the 2 arms of this trial . However , per protocol analysis indicated that subjects receiving ≥ 8 e-counselling messages ( a priori therapeutic dose ) vs 0 e-counselling messages ( control ) demonstrated greater reduction in systolic blood pressure ( mean , -8.9 mm Hg ; 95 % confidence interval [ CI ] , -11.5 to -6.4 vs -5.0 mm Hg ; 95 % CI , -6.7 to -3.3 , P = 0.03 ) , pulse pressure ( -6.1 mm Hg ; 95 % CI , -8.1 to -4.1 vs -3.1 mm Hg ; 95 % CI , -4.3 to -1.8 , P = 0.02 ) and total cholesterol ( -0.24 mmol/L ; 95 % CI , -0.43 to -0.06 vs 0.05 mmol/L ; 95 % CI , -0.06 to 0.16 , P = 0.03 ) , but not diastolic blood pressure . CONCLUSIONS These findings support the merit of evaluating whether e-counselling can improve blood pressure control and reduce cardiovascular risk over the long-term BACKGROUND AND PURPOSE Hypertension is the most important modifiable risk factor for secondary stroke prevention but the immediate management of blood pressure after stroke is uncertain . We evaluated outcomes in the NINDS tPA stroke study in relation to blood pressure declines during the first 24 h after r and omization . METHODS Declines in blood pressure compared to baseline and preceding time points were analyzed in relationship to favorable outcomes ( by a global test ) , poor outcomes ( Rankin scale > 3 ) and death at 3 months . RESULTS 551 patients did not receive immediate pre-r and omization anti-hypertensive treatment and had available blood pressures . Multivariate analysis showed significantly and progressively reducing likelihoods of a favorable outcome with each 10 mmHg decline in systolic blood pressure ( SBP ) > 50 mmHg compared to any preceding measurement . Poor outcomes were significantly more likely in patients with > 50 mmHg SBP reduction ( or > 30 mmHg compared to any immediately preceding measurement ) . There was an increased risk of death with blood pressure declines > 60 mmHg . tPA treatment still produced favorable outcomes compared with placebo even with blood pressure declines . The median largest SBP reduction from baseline in patients treated with tPA was 35 mmHg compared to 30 mmHg in placebo-treated patients ( p<0.01 ) . CONCLUSIONS In this post hoc analysis , progressively reducing likelihoods of a favorable outcome were seen with increasing declines in SBP . Despite a greater likelihood of favorable outcomes , tPA treatment was associated with a greater reduction in blood pressure than placebo . R and omized trials of blood pressure management are needed OBJECTIVE To test the short-term feasibility and efficacy of seven nonpharmacologic interventions in persons with high normal diastolic blood pressure . DESIGN R and omized control multicenter trials . SETTING Volunteers recruited from the community , treated and followed up at special clinics . PARTICIPANTS Of 16,821 screenees , 2182 men and women , aged 30 through 54 years , with diastolic blood pressure from 80 through 89 mm Hg were selected . Of these , 50 did not return for follow-up blood pressure measurements . INTERVENTIONS Three life-style change groups ( weight reduction , sodium reduction , and stress management ) were each compared with unmasked nonintervention controls over 18 months . Four nutritional supplement groups ( calcium , magnesium , potassium , and fish oil ) were each compared singly , in double-blind fashion , with placebo controls over 6 months . MAIN OUTCOME MEASURES Primary : change in diastolic blood pressure from baseline to final follow-up , measured by blinded observers . Secondary : changes in systolic blood pressure and intervention compliance measures . RESULTS Weight reduction intervention produced weight loss of 3.9 kg ( P less than .01 ) , diastolic blood pressure change of -2.3 mm Hg ( P less than .01 ) , and systolic blood pressure change of -2.9 mm Hg ( P less than .01 ) . Sodium reduction interventions lowered urinary sodium excretion by 44 mmol/24 h ( P less than .01 ) , diastolic blood pressure by 0.9 mm Hg ( P less than .05 ) , and systolic blood pressure by 1.7 mm Hg ( P less than .01 ) . Despite good compliance , neither stress management nor nutritional supplements reduced diastolic blood pressure or systolic blood pressure significantly ( P greater than .05 ) . CONCLUSIONS Weight reduction is the most effective of the strategies tested for reducing blood pressure in normotensive persons . Sodium reduction is also effective . The long-term effects of weight reduction and sodium reduction , alone and in combination , require further evaluation 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 Objective To explore the likely optimum blood pressure ( BP ) level for patients with a history of cerebrovascular disease . Methods The Perindopril Protection Against Recurrent Stroke Study ( PROGRESS ) was a r and omized , placebo-controlled trial that established the beneficial effects of BP lowering in 6105 patients with cerebrovascular disease . The present study comprises two series of post hoc analyses . The first was design ed to investigate the effects of r and omized treatment on recurrent stroke by baseline BP levels , and the second was a corresponding observational analysis investigating the association between achieved follow-up BP levels and recurrent stroke risk . Results Analyses of the r and omized treatment comparisons showed that BP lowering with combination therapy produced similar risk reductions in each of four subgroups defined by baseline BP of less than 120 , 120–139 , 140–159 , and 160 mmHg or greater ( P homogeneity = 0.5 ) . The effects of single-drug therapy were also comparable across these subgroups ( P homogeneity = 0.2 ) , but consistently greater benefits were observed with combination compared to single-drug therapy . The analyses of achieved follow-up BP showed that the lowest risk of recurrence was among the one-quarter of participants with the lowest follow-up BP levels ( median 112/72 mmHg ) , and that risks rose progressively with higher follow-up BP levels . Minor side-effects were progressively more common at lower BP levels ( P homogeneity = 0.04 ) , but there was no excess of serious complications ( all P homogeneity > 0.2 ) . Conclusion These analyses provide no evidence of a J-curve relationship between BP level and stroke risk among patients with cerebrovascular disease , and identify no patient group among whom more intensive BP lowering would not be expected to produce greater risk reductions Results of the European Working Party on High Blood Pressure in the Elderly ( EWPHE ) trial have been analysed in relation to age , sex , blood pressure , and previous cardiovascular disease . Cardiovascular mortality and the cardiovascular study -terminating events were significantly and independently related to treatment , age , cardiovascular complications at r and omisation , and systolic but not diastolic blood pressure . The benefits of treatment observed in the trial seemed to be independent of entry blood pressure and the presence or absence of cardiovascular complications at entry . There was some evidence that treatment effect decreases with advancing age . Little or no benefit from treatment could be demonstrated in patients over the age of 80 years , the great majority of whom were women 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 To estimate the impact of small reductions in the population distribution of diastolic blood pressure ( DBP ) , such as those potentially achievable by population -wide lifestyle modification , on incidence of coronary heart disease ( CHD ) and stroke . DESIGN Published data from the Framingham Heart Study , a longitudinal cohort study , and from the National Health and Nutrition Examination Survey II , a national population survey , were used to examine the impact of a population -wide strategy aim ed at reducing DBP by an average of 2 mm Hg in a population including normotensive subjects . SETTING / PARTICIPANTS White men and women aged 35 to 64 years in the United States . MAIN OUTCOME MEASURES Incidence of CHD and stroke , including transient ischemic attacks ( TIAs ) . RESULTS Data from overviews of observational studies and r and omized trials suggest that a 2-mm Hg reduction in DBP would result in a 17 % decrease in the prevalence of hypertension as well as a 6 % reduction in the risk of CHD and a 15 % reduction in risk of stroke and TIAs . From an application of these results to US white men and women aged 35 to 64 years , it is estimated that a successful population intervention alone could reduce CHD incidence more than could medical treatment for all those with a DBP of 95 mm Hg or higher . It could prevent 84 % of the number prevented by medical treatment for all those with a DBP of 90 mm Hg or higher . For stroke ( including TIAs ) , a population -wide 2-mm Hg reduction could prevent 93 % of events prevented by medical treatment for those with a DBP of 95 mm Hg or higher and 69 % of events for treatment for those with a DBP of 90 mm Hg or higher . A combination strategy of both a population reduction in DBP and targeted medical intervention is most effective and could double or triple the impact of medical treatment alone . Adding a population -based intervention to existing levels of hypertension treatment could prevent an estimated additional 67,000 CHD events ( 6 % ) and 34,000 stroke and TIA events ( 13 % ) annually among all those aged 35 to 64 years in the United States . CONCLUSIONS A small reduction of 2 mm Hg in DBP in the mean of the population distribution , in addition to medical treatment , could have a great public health impact on the number of CHD and stroke events prevented . Whether such DBP reductions can be achieved in the population through lifestyle interventions , in particular through sodium reduction , depends on the results of ongoing primary prevention trials as well as the cooperation of the food industry , government agencies , and health education professionals
There was no clear evidence that proportional risk reductions in major cardiovascular disease differed by baseline disease history , except for diabetes and chronic kidney disease , for which smaller , but significant , risk reductions were detected .
β blockers were inferior to other drugs for the prevention of major cardiovascular disease events , stroke , and renal failure .
Calcium channel blockers were superior to other drugs for the prevention of stroke .
For the prevention of heart failure , calcium channel blockers were inferior and diuretics were superior to other drug classes .
INTERPRETATION Blood pressure lowering significantly reduces vascular risk across various baseline blood pressure levels and comorbidities .
BACKGROUND The benefits of blood pressure lowering treatment for prevention of cardiovascular disease are well established .
However , the extent to which these effects differ by baseline blood pressure , presence of comorbidities , or drug class is less clear .
We therefore performed a systematic review and meta- analysis to clarify these differences .