Global Risk Assessment to Guide Blood Pressure Management in Cardiovascular Disease Prevention 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. Effect of age on blood pressure parameters and risk of cardiovascular death in men. Effectiveness of blood pressure-lowering drug treatment by levels of absolute risk: post hoc analysis of the Australian National Blood Pressure Study Blood pressure and isolated systolic hypertension and the risk of coronary heart disease and mortality in elderly men (the Zutphen Elderly Study) Legacy Effect of Delayed Blood Pressure-Lowering Pharmacotherapy in Middle-Aged Individuals Stratified by Absolute Cardiovascular Disease Risk: Protocol for a Systematic Review Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group. Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial. Ten-year legacy effects of baseline blood pressure ‘treatment naivety’ in the Second Australian National Blood Pressure study Selective recording in blood pressure readings may increase subsequent mortality. Blood pressure as a cardiovascular risk factor: prevention and treatment. Blood pressure and prognosis in patients with incident heart failure: the Diet, Cancer and Health (DCH) cohort study Role of Time-of-Day of Hypertension Treatment on the J-Shaped Relationship Between Blood Pressure and Cardiovascular Risk Examination of lower targets for low-density lipoprotein cholesterol and blood pressure in diabetes--the Stop Atherosclerosis in Native Diabetics Study (SANDS). A prospective study of variability in systolic blood pressure and mortality in a rural Bangladeshi population cohort. Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality Which Patients Does the SPRINT Study Not Apply To and What Are the Appropriate Blood Pressure Goals in These Populations?
Elevated blood pressure ( BP ) is a causal risk factor for cardiovascular disease ( CVD ) . Epidemiological analyses have established the grade d and continuous association between higher BP and CVD . Moreover , r and omized clinical trials among individuals with hypertension have demonstrated , in aggregate , a reduction in CVD events by 20 % , coronary heart disease ( CHD ) by 17 % , stroke by 27 % , and heart failure by 28 % for every 10 mm Hg systolic BP ( SBP ) lowering with medical therapy.1 Therefore , prevention , detection , treatment , and control of elevated BP , and its clinical correlate hypertension , is an important public health priority and a primary target for CVD prevention . Although national health surveys have demonstrated improvements in hypertension awareness and treatment , strategic opportunities to improve the efficiency and efficacy of applying BP-lowering therapy in patients most likely to benefit remain.2 Global CVD risk assessment , using multivariable prediction models that estimate absolute CVD risk from routinely measured clinical variables , has been promulgated in several CVD prevention guidelines for cholesterol management to target the most intensive preventive therapies to those at highest absolute CVD risk.3–5 Hypertension guidelines , however , have instead relied solely on isolated BP thresholds and BP goals to guide treatment initiation and intensity . In this review , we provide a rationale for incorporating global CVD risk assessment in BP treatment decision-making and propose a framework to guide its implementation in future CVD prevention guidelines . Epidemiological analyses have firmly established that CVD is a multifactorial condition and that modest increases of several CVD risk factors can often lead to greater overall risk than a severe elevation of a 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 Elevated blood pressure ( BP ) is a risk factor for cardiovascular disease ( CVD ) , but it remains unclear which component-alone or in combination-is the best predictor . We sought to determine which BP parameters are important predictors of CVD death across a wide age range . METHODS We used a prospect i ve cohort study design with 53,163 men followed for cause-specific death during a median of 5.7 years in the Physicians ' Health Study enrollment cohort . Baseline age , systolic BP and diastolic BP were collected . We calculated relative risks ( RRs ) and their 95 % confidence intervals using Cox proportional hazard models adjusting for major risk factors for CVD , and then stratified by age ( 39 to 49 , 50 to 59 , 60 to 69 , and 70 to 84 years ) . RESULTS There were 459 CVD deaths during follow-up . For each 10 mm Hg increase in systolic BP , the multivariable RRs by ascending age group were 1.46 , 1.43 , 1.24 , and 1.13 . The multivariable RRs for each 10 mm Hg increase in diastolic BP were 1.25 , 1.20 , 1.28 , and 1.07 . Compared with systolic BP , pulse pressure and mean arterial pressure were not consistent predictors across age ranges , and combining systolic BP with another parameter did not improve the model compared with using systolic BP alone in any age group ( all P > .05 ) . CONCLUSIONS In this large cohort of healthy men with no history of hypertension , systolic BP was the most consistent and significant predictor of CVD death across all ages . Diastolic BP was not as strongly associated with risk . Our results support the continuing emphasis on using systolic BP in predicting cardiovascular risk 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 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 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 To assess the combined influence of blood pressure ( BP ) , serum cholesterol level , and cigarette smoking on death from coronary heart disease ( CHD ) and to describe how these associations vary with age , data on those factors and on mortality for 316,099 men screened for the Multiple Risk Factor Intervention Trial ( MRFIT ) were examined . Vital status of participants has been determined after an average follow-up of 12 years ; 6327 deaths from CHD have been identified . Strong grade d relationships between serum cholesterol levels above 4.65 mmol/L ( 180 mg/dL ) , systolic BP above 110 mm Hg , and diastolic BP above 70 mm Hg and mortality due to CHD were evident . Smokers with serum cholesterol and systolic BP levels in the highest quintiles had CHD death rates that were approximately 20 times greater than nonsmoking men with systolic BP and cholesterol levels in the lowest quintile . Systolic and diastolic BP , serum cholesterol level , and cigarettes per day were significant predictors of death due to CHD in all age groups . Systolic BP was a stronger predictor than diastolic BP . These results , together with the findings of clinical trials , offer strong support for intensified preventive efforts in all age groups Elevated arterial pressure enhances the risk for cardiovascular ( CV ) events in patients with diabetic nephropathy . The optimal BP and the component of the elevated BP that affect the risk have not been defined . A post hoc analysis was performed to assess the impact of achieved systolic , diastolic , and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial ( IDNT ) and had a baseline serum creatinine above the normal range , up to 266 micromol/L ( 3.0 mg/dL ) , 24-h urine protein > 900 mg/d , and at least 6 mo of follow-up . Patients were r and omized to irbesartan , amlodipine , or placebo , with other antihypertensive agents to a BP goal of < or = 135/85 mmHg . Progressively lower achieved systolic BP ( SBP ) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure ( CHF ) but not myocardial infa rct ions ( MI ) . A SBP below this threshold was associated with increased risk for CV deaths and CHF events . Achieved diastolic BP < 85 mmHg was associated with a trend to increase in all-cause mortality , significant increase in MI , but decreased risk for strokes . Increased pulse pressure predicted increased all-cause mortality , CV mortality , MI , and CHF . It is concluded that achieved SBP approaching 120 mmHg and diastolic BP of 85 mmHg are associated with the best protection against CV events in these patients . BP < or = 120/85 may be associated with an increase in CV events 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 BACKGROUND Rounding blood pressure ( BP ) to the nearest 10 mmHg ( terminal digit preference ) and selecting for particular values near treatment cut-offs ( number preference ) have both been previously described . Both reduce measurement accuracy , and may have consequences for treatment and survival . AIM To check for number preference in screening for hypertension , and whether this influenced subsequent mortality . DESIGN Prospect i ve case-control screening study . METHODS In the General Practice Hypertensive Study Group ( GPHSG ) , prospect i ve case control study patients ( n=23 574 ) were screened on one occasion for high phase-IV diastolic BP ( DBP4 ) ( > or = 90 mmHg ) . Identified cases were matched with normotensive controls for age , sex , date of screen and ethnic group , and were registered for mortality follow-up ( n=6310 ) . Patients with a high DBP4 had two further readings , and were treated if it remained elevated . RESULTS For DBP4 terminal digit , ' 0 ' was over-represented ( 28.2 % vs. 20 % ) , and the number ' 88 ' was over-represented in both men and women . There was an excess adjusted death rate for females with DBP4 88 - 89 mmHg vs. 90 - 99 mmHg for both cardiovascular ( RR 2.56 , 95%CI 1.43 - 4.56 , p=0.0015 ) and all-cause ( 1.56 , 95%CI 1.06 - 2.29 , p=0.023 ) mortality . For males , the corresponding rates were non-significantly reduced : cardiovascular RR 0.69 , 95%CI 0.42 - 1.14 , p=0.15 ; all-cause RR 0.93 , 95%CI 0.68 - 1.27 , p=0.64 . DISCUSSION The quality of BP measurements should be monitored both in research studies and in clinical practice as part of clinical governance procedures OBJECTIVE - To examine the prevalence , incidence , predisposing factors for hypertension , its hazards as an ingredient of the cardiovascular risk profile , and the implication s of this information for prevention and treatment . METHODS - Prospect i ve longitudinal analysis of 36-year follow-up data from the Framingham Study of the relation of antecedent blood pressure to occurrence of subsequent cardiovascular morbidity and mortality depending on the metabolically linked burden of associated risk factors . RESULTS - Hypertension is one of the most prevalent and powerful contributors to cardiovascular diseases , the leading cause of death in the United States . There is , on average , a 20 mm Hg systolic and 10 mm Hg diastolic increment increase in blood pressure from age 30 to 65 years . Isolated systolic hypertension is the dominant variety . There is no evidence of a decline in the prevalence of hypertension over 4 decades despite improvements in its detection and treatment . Hypertension contributes to all of the major atherosclerotic cardiovascular disease outcomes increasing risk , on average , 2- to 3-fold . Coronary disease , the most lethal and common sequela , deserves highest priority . Hypertension clusters with dyslipidemia , insulin resistance , glucose intolerance , and obesity , occurring in isolation in less than 20 % . The hazard depends on the number of these associated metabolically linked risk factors present . Coexistent overt cardiovascular disease also influences the hazard and choice of therapy . CONCLUSION - The absence of a decline in the prevalence of hypertension indicates an urgent need for primary prevention by weight control , exercise , and reduced salt and alcohol intake . The urgency and choice of therapy of existing hypertension should be based on the multivariate cardiovascular risk profile that more appropriately targets hypertensive persons for treatment and prevention of cardiovascular sequelae Background Our objective was to test the hypothesis that elevated blood pressure ( BP ) is associated with increased risk of stroke , bleeding and death in patients with incident heart failure ( HF ) . Methods We conducted a prospect i ve cohort study among subjects who were participants in the Diet , Cancer and Health study , born in Denmark , aged 50–64 years at recruitment . We assessed stroke ( ischemic stroke or systemic embolic events ) , major bleeding , death and the composite endpoint according to degree of BP control in patients with incident HF .  BP  was assessed prior to HF at cohort entry . Results Of the whole cohort of 55,748 subjects , n = 2159 ( 35 % female ) had incident HF , of which 12 % had treatment for hypertension . Median follow-up after incident HF was 3.5 years . High systolic ( SBP ) , diastolic ( DBP ) and pulse ( PP ) pressures were associated with an increased risk of stroke , major bleeding and the composite endpoint . For death and stroke/death , the relation appeared U-shaped for SBP and DBP . When comparing the highest quartile group ( Q4 ) to first quartile group ( Q1 ) , SBP ( Q4 : SBP > 163 mmHg ) was associated with significantly higher adjusted hazard rate ratio ( HR ) for stroke ( HR 1.46 , 95 % CI 1.00–2.14 ) and major bleeding ( HR 1.68 , 95 % CI 1.12–2.53 ) . For DBP ( Q4 : DBP > 94 mmHg ) , adjusted HR was significantly higher for major bleeding ( HR 1.63 , 95 % CI 1.13–2.38 ) . The highest quartile of pulse pressure ( Q4 : PP > 74 mmHg ) was associated with non-significantly higher risk of stroke ( HR 1.40 , 95 % CI 0.94–2.06 ) . Conclusion We have shown for the first time that amongst a population with incident HF , higher baseline systolic , diastolic and pulse pressure levels were associated with a higher rate of adverse events . Our data support the importance for optimised BP control , as part of the holistic management of HF patients Several previous studies found that too great a reduction of clinic blood pressure ( BP ) by treatment increased cardiovascular disease ( CVD ) risk , whereas moderate reduction decreased it . Thus , it has been suggested that the relationship between BP and CVD events is J-shaped , with CVD risk decreasing as BP is lowered , and then rising as BP is further decreased . Correlation between BP level and CVD risk , however , is stronger for ambulatory BP monitoring ( ABPM ) than clinical BP measurements . We previously established that the hypertension treatment-time regimen , upon awakening versus at bedtime , exerts differential effect on BP control during the day and nighttime , which translates into a differential degree of CVD risk prevention . We , therefore , investigated the role of hypertension treatment-time scheme on the nature of the relationship between achieved clinic and ambulatory BP and CVD risk in the MAPEC ( Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares , i.e. , Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events ) study , a prospect i ve , open-label , blinded-endpoint trial on 2156 hypertensive patients ( 1044 men/1112 women ) , 55.6 ± 13.6 ( mean ± SD ) yrs of age , r and omized to ingest all prescribed once-a-day hypertension medications upon awakening or the entire daily dose of ≥1 of them at bedtime  . Ambulatory BP was measured for 48-h at baseline and annually thereafter , and more frequently ( quarterly ) when adjustment of treatment was necessary . After a median follow-up of 5.6 yrs , a J-shaped relationship was detected between total CVD events and clinic as well as awake BP mean , but only for the group of patients ingesting all medications upon awakening . The relationship was different in the group of patients who ingested ≥1 medications at bedtime ; the risk of CVD events progressively diminished in a linear , rather than J-shaped , manner with treatment-induced decrease in awake BP mean . The adjusted hazard ratio of CVD events was significantly lower with the progressive reduction in the asleep BP mean , independent of the hypertension treatment-time regimen . There was no single major event , i.e. , CVD death , myocardial infa rct ion , or stroke , in patients who achieved an asleep systolic BP mean < 103 mm Hg . Our findings indicate that bedtime hypertension treatment is not associated with a J-shaped relationship between achieved BP and CVD risk . The decreased CVD risk associated with the progressive reduction in asleep BP , more feasible by bedtime than morning hypertension treatment , has clinical implication s , in particular , the need to consider the proper timing of hypertension medications , in conjunction with ABPM for proper assessment of BP control , as an improved and potentially safer means of reducing CVD risk of hypertensive patients . ( Author correspondence : rhermida@uvigo.es Diabetes incidence is increasing rapidly in the United States . Diabetes increases the risk for cardiovascular disease , the major cause of death in diabetic individuals . The conventional cardiovascular risk factors of hyperlipidemia and hypertension worsen diabetic vascular disease . Treatment targets for low-density lipoprotein cholesterol ( LDL-C ) and blood pressure in diabetic individuals are being debated . The S AND S is a r and omized , open-label , 3-year trial to examine the effects of aggressive LDL-C ( goal < 70 mg/dL ) and blood pressure ( BP ) ( goal < 115/75 mm Hg ) reduction versus the st and ard goals of < 100 mg/dL for LDL-C and < 130/85 mm Hg for BP .  Five hundred forty-nine American-Indian men and women > 40 years old with type 2 diabetes were r and omized to 1 of 2 groups . Lipids and BP are managed using Food and Drug Administration-approved medications in an algorithmic approach . The presence and progression of atherosclerosis are evaluated by carotid ultrasonography ; echocardiography assesses cardiac function . The primary end point is the composite outcome of change in carotid artery intimal medial thickness and fatal/nonfatal cardiovascular events . These outcomes are combined by using a ranked analysis for carotid thickness and assigning a " worst rank " for a cardiovascular event . Secondary end points include carotid plaque score , left ventricular geometry and function , serum C-reactive protein , and safety measures . Unique aspects of the study design and analysis plan involve the use of a composite outcome and changes during the trial of LDL-C treatment goals for participants with baseline or incident cardiovascular disease in the conventional group because of changes in the st and ard of care . Study results will further underst and ing of the effects of aggressive risk factor reduction on atherosclerosis burden and cardiac function in diabetic individuals in US population s and will help determine optimal LDL-C and BP treatment goals for diabetic patients OBJECTIVE Limited studies suggest that blood pressure variability over time is a risk factor of long-term cardiovascular outcomes . However , most of these were in population s with pre-existing cardiovascular diseases ( CVD ) and studies in general population are lacking . METHODS The study included 11,153 participants in a population -based , prospect i ve cohort study in Araihazar , Bangladesh .  Resting blood pressure was measured at baseline and every two years thereafter . Participants were followed up for an average of 6.5 years ( 2002 - 2009 ) . RESULTS Male gender , older age , baseline systolic blood pressure ( SBP ) , and absence of betel leaf use were independently positively associated with greater SBP variability over time . There was a significant association between SBP variability and the risk of death from overall CVD , especially from major CVD events . The positive association with the risk of death from any cause and stroke in age- and sex-adjusted models was attenuated in fully-adjusted models . In addition , the hazard ratio ( HR ) of stroke mortality was greater for individuals with both high baseline and high SBP variability . Similar patterns of HRs were observed for all-cause and CVD mortalities . CONCLUSION In this rural Bangladeshi population , variability in SBP contributes to the risk of death from CVD and may further potentiate the increased mortality risk associated with high SBP 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 , The Systolic Blood Pressure Intervention Trial ( SPRINT ) is a large National Institutes of Health– sponsored multicenter r and omized controlled trial that enrolled 9361 patients with a systolic blood pressure ( SBP ) of at least 130 mm Hg . The primary goal of SPRINT was to test whether reducing SBP to a lower goal ( < 120 mm Hg ) than currently recommended ( < 140 mm Hg ) would reduce the occurrence of cardiovascular disease ( CVD ) and chronic kidney disease ( CKD ) events . Enrolled patients were 50 years or older with an SBP ≥130 mm Hg and at least one of the following : a history of CVD , stage 3 CKD ( estimated glomerular filtration rate 20–59 mL/min/1.73 m ) , an intermediate to high risk for CVD other than stroke , or age 75 years or older . A patient was defined as having CVD if they had a prior myocardial infa rct ion , percutaneous coronary intervention , coronary artery bypass grafting , carotid endarterectomy or carotid stenting , peripheral arterial disease with revascularization , acute coronary syndrome , abdominal aortic aneurysm ≥5 cm with or without repair , a coronary calcium score > 400 , or left ventricular hypertrophy . Patients were defined as at intermediate or high risk for CVD based on the following : Framingham Risk Score for 10-year CVD risk of 15 % based on laboratory work performed for lipids within the past 12 months . The primary outcome was a composite of cardiovascular events . The SPRINT study was terminated early after 3.26 years on advisory of the data safety monitoring board . The results of the SPRINT study showed a 25 % reduction in the primary combined cardiovascular outcome and a 27 % reduction in mortality in the group r and omized to SBP < 120 mm Hg . This obviously has important implication s for blood pressure ( BP ) guidelines in this population . The baseline mean systolic and diastolic BPs were 139.7 mm Hg and 78.1 mm Hg , respectively . At 1 year , the mean SBP was 121.4 mm Hg in the intensive treatment group and 136.2 mm Hg in the st and ard treatment group . The SPRINT study included 28 % of patients with CKD , 28 % of patients were older than 75 years , 36 % were women , and 20 % had prior CVD . The sample was diverse and included 29.9 % black , 10.5 % Hispanic , and 57.7 % white patients .  Importantly , SPRINT excluded many patients with hypertension . Who were these population s ? The following groups of patients with hypertension were excluded : those with a history of prior stroke , diabetes , polycystic kidney disease , any secondary cause for hypertension , glomerular filtration rate ( GFR ) < 20 cc/ min , > 1 g of proteinuria per 24 hours , glomerulonephritis treated with immunosuppressive therapy , symptomatic heart failure within the past 6 months or left ventricular ejection fraction < 35 % , expected survival less than 3 years , cancer diagnosed within the past 2 years , organ transplant , cardiovascular event , procedure or hospitalization for unstable angina within the past 3 months , and all patients younger than 50 years . Why were these patients excluded ? Patients with diabetes were excluded as it was felt that this population had already been studied in the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) BP trial , which did not show a cardiovascular advantage of lower SBP ( < 120 mm Hg ) vs st and ard BP ( < 140 mm Hg ) although there was a decreased risk of stroke .  Patients with polycystic kidney disease have also been studied separately in the HALT Progression of Polycystic Kidney Disease study , which recently showed that rigorous BP control was associated with a slower increase in total kidney volume , no overall change in the estimated GFR , a greater decline in the left ventricular mass index , and greater reduction in urinary albumin excretion .  Patients with excessive proteinuria > 1 g per 24 hours were also excluded , but , based on data from the Modification of Diet in Renal Disease ( MDRD ) , the Blood Pressure Control for Renoprotection in Patients With Nondiabetic Chronic Renal Disease ( REIN ) , and the African American Study of Kidney Disease and Hypertension ( AASK ) studies , lower BP goals ( < 130/80 mm Hg ) have been suggested and recommended by some guidelines in this patient population . Renal transplant recipients were excluded in this population . There are no r and omized controlled trials examining optimal levels of BP and this is a population that needs to be studied . BP threshold for treatment of kidney transplant recipients remains at 130/80 mm Hg , regardless of proteinuria . The Secondary Prevention of Small Subcortical Strokes ( SPS3 ) trial , which compared an SBP treatment target of < 130 mm Hg with a target of 130 mm Hg to 149 mm Hg in participants with a recent lacunar stroke , showed a nonsignificant reduction in recurrent stroke in the group r and omized to the lower target . There are no specific studies that have evaluated BP targets in patients without other comorbidities who are Address for correspondence : Debbie L. Cohen , MD , Renal , Electrolyte and Hypertension Division , Perelman School of Medicine at the University of Pennsylvania , 1 Founders Building , 3400 Spruce Street , Philadelphia , PA 19104 E-mail :
In primary prevention , the association of BP-lowering treatment with major cardiovascular events was dependent on baseline systolic BP ( SBP ) .
Conclusions and Relevance Primary preventive BP lowering is associated with reduced risk for death and CVD if baseline SBP is 140 mm Hg or higher .
At lower BP levels , treatment is not associated with any benefit in primary prevention but might offer additional protection in patients with CHD
Importance High blood pressure ( BP ) is the most important risk factor for death and cardiovascular disease ( CVD ) worldwide .
The optimal cutoff for treatment of high BP is debated .
Objective To assess the association between BP lowering treatment and death and CVD at different BP levels .