Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomized trial. The role of diastolic blood pressure when treating isolated systolic hypertension. Combining Multiple Approaches for the Secondary Prevention of Vascular Events After Stroke: A Quantitative Modeling Study Subgroup and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly. Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous? Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. MIDAS: Hypertension and Atherosclerosis A Trial of the Effects of Antihypertensive Drug Treatment on Atherosclerosis Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality Cardiovascular Outcomes in High-Risk Hypertensive Patients Stratified by Baseline Glomerular Filtration Rate Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the CATIS randomized clinical trial. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial of cardiovascular events in hypertension. Rationale and design. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial Aspirin, Statins, or Both Drugs for the Primary Prevention of Coronary Heart Disease Events in Men: A CostUtility Analysis Pioglitazone Exerts Protective Effects Against Stroke in Stroke-Prone Spontaneously Hypertensive Rats, Independently of Blood Pressure
BACKGROUND AND OBJECTIVES The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown ; neither is it clear whether in patients with a previous cardiovascular event , the optimal values are lower than in the low-to-moderate risk hypertensive patients , or a more cautious blood pressure ( BP ) reduction should be obtained . Because of the uncertainty whether ' the lower the better ' or the ' J-curve ' hypothesis is correct , the European Society of Hypertension and the Chinese Hypertension League have promoted a r and omized trial comparing antihypertensive treatment strategies aim ing at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack . As the optimal level of low-density lipoprotein cholesterol ( LDL-C ) level is also unknown in these patients , LDL-C-lowering has been included in the design . PROTOCOL DESIGN The European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment trial is a prospect i ve multinational , r and omized trial with a 3 × 2 factorial design comparing : three different SBP targets ( 1 , < 145 - 135 ; 2 , < 135 - 125 ; 3 , < 125 mmHg ) ; two different LDL-C targets ( target A , 2.8 - 1.8 ; target B , < 1.8 mmol/l ) . The trial is to be conducted on 7500 patients aged at least 65 years ( 2500 in Europe , 5000 in China ) with hypertension and a stroke or transient ischaemic attack 1 - 6 months before r and omization .  Antihypertensive and statin treatments will be initiated or modified using suitable registered agents chosen by the investigators , in order to maintain patients within the r and omized SBP and LDL-C windows . All patients will be followed up every 3 months for BP and every 6 months for LDL-C. Ambulatory BP will be measured yearly . OUTCOMES Primary outcome is time to stroke ( fatal and non-fatal ) . Important secondary outcomes are : time to first major cardiovascular event ; cognitive decline ( Montreal Cognitive Assessment ) and dementia . All major outcomes will be adjudicated by committees blind to r and omized allocation . A Data and Safety Monitoring Board has open access to data and can recommend trial interruption for safety . SAMPLE SIZE CALCULATION It has been calculated that 925 patients would reach the primary outcome after a mean 4-year follow-up , and this should provide at least 80 % power to detect a 25 % stroke difference between SBP targets and a 20 % difference between LDL-C targets OBJECTIVE To assess the role of treated diastolic blood pressure ( DBP ) level in stroke , coronary heart disease ( CHD ) , and cardiovascular disease ( CVD ) in patients with isolated systolic hypertension ( ISH ) . DESIGN An analysis of the 4736 participants in the Systolic Hypertension in the Elderly Program ( SHEP ) was undertaken . The SHEP was a r and omized multicenter double-blind outpatient clinical trial of the impact of treating ISH in men and women aged 60 years and older . MAIN OUTCOME MEASURES Cox proportional hazards regression analysis , with DBP and systolic blood pressure ( SBP ) as time-dependent covariables . RESULTS After adjustment for the baseline risk factors of race ( black vs other ) , sex , use of antihypertensive medication before the study , a composite variable ( diabetes , previous heart attack , or stroke ) , age , and smoking history ( ever vs never ) and adjustment for the SBP as a time-dependent variable , we found , for the active treatment group only , that a decrease of 5 mm Hg in DBP increased the risk for stroke ( relative risk , [ RR ] , 1.14 ; 95 % confidence interval [ CI ] , 1.05 - 1.22 ) , for CHD ( RR , 1.08 ; 95 % CI , 1.00 - 1.16 ) , and for CVD ( RR , 1.11 ; 95 % CI , 1.05 - 1.16 ) . CONCLUSIONS Some patients with ISH may be treated to a level that uncovers sub clinical disease , and some may be overtreated . Further studies need to determine whether excessively low DBP can be prevented by more careful titration of antihypertensive therapy while maintaining SBP control . It is reassuring that patients receiving treatment for ISH never perform worse than patients receiving placebo in terms of CVD events Background and Purpose — Numerous effective strategies for the secondary prevention of cardiovascular events in high-risk patients have now been established . We sought to calculate the cumulative benefit of combining multiple strategies for preventing recurrent events in patients with a history of ischemic stroke or transient ischemic attack . Methods — A comprehensive literature search was undertaken to identify meta-analyses of r and omized controlled trials reporting on the efficacy of secondary prevention strategies . The baseline incidence of vascular events was modeled from the Life Long After Cerebral Ischemia study . Strategies were combined on a multiplicative scale and cumulative risk reductions were computed over a 5-year interval . Results — The combination of 5 proven strategies applied to survivors of an initial stroke or transient ischemic attack — dietary modification , exercise , aspirin , a statin , and an antihypertensive agent — could result in a cumulative relative risk reduction of 80 % . Given a 5-year major cardiovascular event rate of 24 % , this translates to a number needed to treat of about 5 . Further gains would result from applying multimodality therapy over longer intervals and enriching the base strategy with dual antiplatelet therapy , high-dose statins , and more intensive blood pressure – lowering . Even more benefit would be present in high-risk subgroups with the addition , where appropriate , of carotid endarterectomy , moderate intensity oral anticoagulants , glycemic control , and smoking cessation . Conclusions — At least four-fifths of recurrent vascular events in patients with cerebrovascular disease might be prevented by application of a comprehensive , multifactorial approach 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 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 BACKGROUND Blood pressure is a determinant of the risk of stroke among both hypertensive and non-hypertensive individuals with cerebrovascular disease . However , there is uncertainty about the efficacy and safety of blood-pressure-lowering treatments for many such patients . The perindopril protection against recurrent stroke study ( PROGRESS ) was design ed to determine the effects of a blood-pressure-lowering regimen in hypertensive and non-hypertensive patients with a history of stroke or transient ischaemic attack . METHODS 6105 individuals from 172 centres in Asia , Australasia , and Europe were r and omly assigned active treatment ( n=3051 ) or placebo ( n=3054 ) . Active treatment comprised a flexible regimen based on the angiotensin- converting-enzyme inhibitor perindopril ( 4 mg daily ) , with the addition of the diuretic indapamide at the discretion of treating physicians . The primary outcome was total stroke ( fatal or non-fatal ) . Analysis was by intention to treat . FINDINGS Over 4 years of follow up , active treatment reduced blood pressure by 9/4 mm Hg . 307 ( 10 % ) individuals assigned active treatment suffered a stroke , compared with 420 ( 14 % ) assigned placebo ( relative risk reduction 28 % [ 95 % CI 17 - 38 ] , p<0.0001 ) . Active treatment also reduced the risk of total major vascular events ( 26 % [ 16 - 34 ] ) . There were similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups ( all p<0.01 ) . Combination therapy with perindopril plus indapamide reduced blood pressure by 12/5 mm Hg and stroke risk by 43 % ( 30 - 54 ) . Single-drug therapy reduced blood pressure by 5/3 mm Hg and produced no discernable reduction in the risk of stroke . INTERPRETATION This blood-pressure-lowering regimen reduced the risk of stroke among both hypertensive and non-hypertensive individuals with a history of stroke or transient ischaemic attack . Combination therapy with perindopril and indapamide produced larger blood pressure reductions and larger risk reductions than did single drug therapy with perindopril alone . Treatment with these two agents should now be considered routinely for patients with a history of stroke or transient ischaemic attack , irrespective of their blood pressure OBJECTIVE To assess the ability of antihypertensive drug treatment to reduce the risk of nonfatal and fatal ( total ) stroke in isolated systolic hypertension . DESIGN Multicenter , r and omized , double-blind , placebo-controlled . SETTING Community-based ambulatory population in tertiary care centers . PARTICIPANTS 4736 persons ( 1.06 % ) from 447,921 screenees aged 60 years and above were r and omized ( 2365 to active treatment , 2371 to placebo ) . Systolic blood pressure ranged from 160 to 219 mm Hg and diastolic blood pressure was less than 90 mm Hg . Of the participants , 3161 were not receiving antihypertensive medication at initial contact , and 1575 were . The average systolic blood pressure was 170 mm Hg ; average diastolic blood pressure , 77 mm Hg . The mean age was 72 years , 57 % were women , and 14 % were black . INTERVENTIONS -- Participants were stratified by clinical center and by antihypertensive medication status at initial contact . For step 1 of the trial , dose 1 was chlorthalidone , 12.5 mg/d , or matching placebo ; dose 2 was 25 mg/d . For step 2 , dose 1 was atenolol , 25 mg/d , or matching placebo ; dose 2 was 50 mg/d . MAIN OUTCOME MEASURES Primary . Nonfatal and fatal ( total ) stroke . Secondary . Cardiovascular and coronary morbidity and mortality , all-cause mortality , and quality of life measures . RESULTS Average follow-up was 4.5 years . The 5-year average systolic blood pressure was 155 mm Hg for the placebo group and 143 mm Hg for the active treatment group , and the 5-year average diastolic blood pressure was 72 and 68 mm Hg , respectively . The 5-year incidence of total stroke was 5.2 per 100 participants for active treatment and 8.2 per 100 for placebo . The relative risk by proportional hazards regression analysis was 0.64 ( P = .0003 ) . For the secondary end point of clinical nonfatal myocardial infa rct ion plus coronary death , the relative risk was 0.73 . Major cardiovascular events were reduced ( relative risk , 0.68 ) . For deaths from all causes , the relative risk was 0.87 . CONCLUSION In persons aged 60 years and over with isolated systolic hypertension , antihypertensive stepped-care drug treatment with low-dose chlorthalidone as step 1 medication reduced the incidence of total stroke by 36 % , with 5-year absolute benefit of 30 events per 1000 participants . Major cardiovascular events were reduced , with 5-year absolute benefit of 55 events per 1000 Although clinical trials of the efficacy of antihypertensive treatment have demonstrated impressive reductions in the incidence of stroke , the reduction in coronary artery disease mortality has been less impressive . It may be that the antihypertensive drugs used in these trials induced metabolic disturbances , or produced inadequate regression of left ventricular hypertrophy , thus blunting the reduction in risk of coronary artery disease expected with blood pressure-lowering . Isradipine , a dihydropyridine calcium antagonist known to be an effective antihypertensive agent , has also displayed pronounced antiatherogenic effects in animals . Thus , a reasonable hypothesis could be that isradipine not only reduces the level of blood pressure , but also may have a positive effect on the evolution of atherosclerotic plaque in coronary and carotid arteries , thereby leading to prevention of clinical sequelae of atherosclerosis . On this basis , a 3-year clinical trial is being carried out in the United States – the Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS)–to establish the efficacy of isradipine in inhibiting atherogenesis and retarding the progression of atherosclerosis in carotid arteries of hypertensive patients . The primary end point of the study is intima-media thickness and the extent of atherosclerotic plaque in the carotid arteries , as measured by B-mode ultrasonography 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 , Context Long-term outcomes of patients with a reduced glomerular filtration rate ( GFR ) who are treated for hypertension are not well-known . Contribution This analysis of a large multicenter trial found that coronary heart disease ( CHD ) was much more common than end-stage renal disease ( 15 % vs. 6 % ) in hypertensive patients with moderate to severe reductions in GFR who were followed for 6 years . Lower baseline GFR was associated with higher risk for CHD independent of other risk factors . Neither amlodipine nor lisinopril is superior to chlorthalidone in preventing CHD , stroke , or combined CVD , and chlorthalidone is superior to both for preventing heart failure , independent of level of renal function . Caution s These are post hoc subgroup findings , and proteinuria was not measured . The Editors It is estimated that more than 10 million Americans have chronic kidney disease ( 1 , 2 ) . The prevalence of chronic kidney disease is particularly high in older adults ; it is estimated to be greater than 25 % in persons older than 70 years of age . Patients with chronic kidney disease are at very high risk for cardiovascular disease ( CVD ) ( 3 - 8 ) . However , the long-term outcomes of older patients who have a mild or moderate reduction in glomerular filtration rate ( GFR )  , particularly with regard to CVD , are not well-known . Because of the large population of older adults with chronic kidney disease , it is important , from a public health and a clinical st and point , to quantify and underst and the comparative risks for CVD and renal disease in these patients . Management of hypertension is an important aspect of management in patients with chronic kidney disease ; in patients with proteinuria , drugs that inhibit the reninangiotensin axis have been shown to be superior to conventional antihypertensive drug therapy for preservation of renal function ( 1 , 9 , 10 ) . However , it is uncertain whether the choice of antihypertensive drug therapy affects risk for CVD in patients with chronic kidney disease ( 11 , 12 ) . The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) is a large clinical trial design ed to compare the efficacy of treatment with different first-line antihypertensive agents on CVD outcomes in high-risk patients with hypertension who are older than 55 years of age ( 13 - 15 ) . The objectives of this report from the ALLHAT data are to 1 ) compare rates of cardiovascular events with rates of development of end-stage renal disease ( ESRD ) in high-risk older adults with hypertension who have reduced GFR ; 2 ) determine whether reduced GFR is independently associated with an increased risk for CVD after adjusting for traditional cardiovascular risk factors ; and 3 ) report the efficacy of first-step treatment with a calcium-channel blocker ( amlodipine ) or an angiotensin-converting enzyme ( ACE ) inhibitor ( lisinopril ) , each compared with a diuretic ( chlorthalidone ) , in modifying CVD outcomes in high-risk patients with hypertension who are stratified by baseline GFR . Methods The rationale and design of ALLHAT have been presented in detail elsewhere ( 13 ) . The study received institutional review board approval , and participants provided written informed consent . Participants were men and women 55 years of age or older who had hypertension with at least 1 additional risk factor for coronary heart disease ( CHD ) . The risk factors included previous ( > 6 months ) myocardial infa rct ion ( MI ) or stroke , left ventricular hypertrophy demonstrated by electrocardiography or echocardiography , history of type 2 diabetes , current cigarette smoking , high-density lipoprotein cholesterol level of less than 0.91 mmol/L ( < 35 mg/dL ) , and documentation of other atherosclerotic CVD . Exclusion criteria included a history of symptomatic heart failure and /or a known left ventricular ejection fraction of less than 0.35 and a serum creatinine level greater than 176.8 mol/L ( > 2 mg/dL ) as reported by the investigator . Participants ( n= 33 357 ) were recruited at 623 centers in the United States , Canada , Puerto Rico , and the U.S. Virgin Isl and s between February 1994 and January 1998 ( Appendix Figure 1 ) . Appendix Figure 1 . R and omization and follow-up of participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) by treatment group . Block r and omization was stratified by center . Participants were r and omly assigned in a double-blind manner and in a 1.7:1:1 ratio to chlorthalidone , amlodipine , or lisinopril . A fourth arm of the study using the -blocker doxazosin was stopped early and is not considered in this report ( 16 ) . The goal blood pressure in each r and omly assigned group was less than 140/90 mm Hg , to be achieved by titrating the assigned study drug ( step 1 ) and by adding study -supplied , open-label agents ( atenolol , clonidine , or reserpine [ step 2 ] or hydralazine [ step 3 ] ) when necessary , at the physician 's discretion ( 16 , 17 ) . Nonpharmacologic lifestyle approaches to treatment of hypertension were recommended according to national guidelines . Other drugs , including low doses of open-label step 1 drug classes , were permitted if clinical ly indicated . Follow-up visits were at 1 month ; 3 , 6 , 9 , and 12 months ; and every 4 months thereafter . Levels of serum creatinine were measured in a single central laboratory using VITROS ( Ortho Clinical Diagnostics , Rochester , New York ) , which had a coefficient of variation of approximately 2 % . Creatinine measurements were calibrated to the Modification of Diet in Renal Disease ( MDRD ) laboratory , and no additional correction was found to be necessary ( 18 ) . A total of 1460 participants ( 4.4 % ) were missing creatinine values , and thus estimated GFR , at baseline . The simplified MDRD Study equation was used to estimate GFR ( mL/min per 1.73 m2 ) according to the following formula : 186.3 ( serum creatinine in mg/dL 1.154 ) ( age in years 0.203 ) 1.212 ( if black ) 0.742 ( if female ) ( 19 ) . Patients were classified into 3 baseline categories of GFR consistent with recommendations in the National Kidney Foundation Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines on Chronic Kidney Disease : normal or increased ( 90 mL/min per 1.73 m2 ) , mild reduction ( 60 to 89 mL/min per 1.73 m2 ) , and moderate or severe reduction ( < 60 mL/min per 1.73 m2 ) ( 1 ) . Because a serum creatinine level of greater than 176.8 mol/L ( > 2 mg/dL ) was an exclusion criterion , the percentage of patients with severe chronic kidney disease ( estimated GFR 29 mL/min per 1.73 m2 ) at baseline was very small ( 0.6 % ) . Therefore , as in another study ( 6 ) , these participants were considered along with those with moderate chronic kidney disease ( GFR 30 to 59 mL/min per 1.73 m2 ) . Patients were also classified as diabetic or not diabetic by baseline history of diabetes . The primary outcome was fatal CHD or nonfatal MI . Combined CVD was defined as a composite of the primary outcome , coronary revascularization , hospitalized angina , stroke , other treated angina , heart failure ( fatal , hospitalized , or treated nonhospitalized ) , and peripheral arterial disease . Coronary revascularization included coronary artery bypass grafting , percutaneous angioplasty , insertion of stents , and atherectomy . Peripheral vascular disease included intermittent claudication or arterial disease of the lower extremities leading to procedures , such as revascularizations , angioplasty of peripheral arteries , or amputation . End-stage renal disease included death from kidney disease , kidney transplantation , and start of long-term kidney dialysis . Study outcomes were defined in the ALLHAT Manual of Operations ( available from the authors on request ) , were assessed by site investigators at follow-up visits , and were reported to the Clinical Trials Center . Medical review ers from the Clinical Trials Center review ed all events for concordance with study criteria . More detailed information was collected on a r and om ( 10 % ) subset of CHD and stroke events and was review ed by the Endpoints Subcommittee to vali date the procedure of using physician diagnoses . Statistical Analyses Data were analyzed according to the participants ' r and omly assigned treatments regardless of their subsequent medications ( intention-to-treat analysis ) . Baseline characteristics were compared across treatments and the 3 GFR groups by using the Z-test for continuous covariates and contingency table analyses for categorical data . Cox proportional hazards models were used to obtain hazard ratios and 95 % CIs for time to CHD , combined CVD , and stroke to assess the effects of treatment within each of the 3 GFR strata . Because baseline characteristics are similar across treatment groups , no adjustment was deemed necessary . Additional models were used to assess the impact of baseline GFR ( using deciles ) on CHD and combined CVD . Baseline characteristics are not expected to be similar across the various GFR groups defined by deciles ; therefore , adjustments are necessary . Cox test assumptions were examined using loglog plots and tests of treatment by time ( time-dependent ) interaction terms . Because the assumptions were violated in the case of heart failure , logistic models were used to estimate odds ratios for this end point . The consistency of treatment effects across subgroups was examined in the Cox and logistic models by calculating the differences in the log likelihood for models with and without the interaction terms . Treatment effects by GFR subgroup were also analyzed for participants with a history of diabetes by using the aforementioned methods . A P value less than 0.05 indicated statistical significance for the results . Role of the Funding Sources This study was supported by contract NO1-HC-35130 from the National Heart , Lung , and Blood Institute ( NHLBI ) ; the NHLBI was involved in the collection , analysis , and interpretation of the data and the decision to su bmi t the manuscript for publication but was not involved in the direct operations of the study centers . Study medications were supplied by IMPORTANCE Although the benefit of reducing blood pressure for primary and secondary prevention of stroke has been established , the effect of antihypertensive treatment in patients with acute ischemic stroke is uncertain . OBJECTIVE To evaluate whether immediate blood pressure reduction in patients with acute ischemic stroke would reduce death and major disability at 14 days or hospital discharge . DESIGN , SETTING , AND PARTICIPANTS The China Antihypertensive Trial in Acute Ischemic Stroke , a single-blind , blinded end-points r and omized clinical trial , conducted among 4071 patients with nonthrombolysed ischemic stroke within 48 hours of onset and elevated systolic blood pressure . Patients were recruited from 26 hospitals across China between August 2009 and May 2013 . INTERVENTIONS Patients ( n = 2038 ) were r and omly assigned to receive antihypertensive treatment ( aim ed at lowering systolic blood pressure by 10 % to 25 % within the first 24 hours after r and omization , achieving blood pressure less than 140/90 mm Hg within 7 days , and maintaining this level during hospitalization ) or to discontinue all antihypertensive medications ( control ) during hospitalization ( n = 2033 ) . MAIN OUTCOMES AND MEASURES Primary outcome was a combination of death and major disability ( modified Rankin Scale score ≥3 ) at 14 days or hospital discharge . RESULTS Mean systolic blood pressure was reduced from 166.7 mm Hg to 144.7 mm Hg ( -12.7 % ) within 24 hours in the antihypertensive treatment group and from 165.6 mm Hg to 152.9 mm Hg ( -7.2 % ) in the control group within 24 hours after r and omization ( difference , -5.5 % [ 95 % CI , -4.9 to -6.1 % ] ; absolute difference , -9.1 mm Hg [ 95 % CI , -10.2 to -8.1 ] ; P < .001 ) . Mean systolic blood pressure was 137.3 mm Hg in the antihypertensive treatment group and 146.5 mm Hg in the control group at day 7 after r and omization ( difference , -9.3 mm Hg [ 95 % CI , -10.1 to -8.4 ] ; P < .001 ) . The primary outcome did not differ between treatment groups ( 683 events [ antihypertensive treatment ] vs 681 events [ control ] ; odds ratio , 1.00 [ 95 % CI , 0.88 to 1.14 ] ; P = .98 ) at 14 days or hospital discharge . The secondary composite outcome of death and major disability at 3-month posttreatment follow-up did not differ between treatment groups ( 500 events [ antihypertensive treatment ] vs 502 events [ control ] ; odds ratio , 0.99 [ 95 % CI , 0.86 to 1.15 ] ; P = .93 ) . CONCLUSION AND RELEVANCE Among patients with acute ischemic stroke , blood pressure reduction with antihypertensive medications , compared with the absence of hypertensive medication , did not reduce the likelihood of death and major disability at 14 days or hospital discharge . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01840072 Essential hypertension is a major Public Health issue . Although the number of treated hypertensive patients has increased , only 25 % of treated patients have their blood pressure levels under control . The benefit of treating hypertension has been proven , but cardiovascular morbidity and mortality rates remain high . The ideal antihypertensive drug should not only normalize blood pressure levels , but also reduce the associated cardiovascular morbidity and mortality rates . The role of angiotensin II in systemic hypertension and its complications has been recently redefined . The potent trophic effects of angiotensin II on blood vessels and on cardiac cells have been well demonstrated , especially the role of angiotensin II in left ventricular hypertrophy , vascular hypertrophy , endothelial dysfunction , and congestive heart failure . Of all ongoing mortality and morbidity trials in systemic hypertension , VALUE ( Valsartan Antihypertensive Long-term Use Evaluation ) is the only one comparing an angiotensin II antagonist ( valsartan ) with a third-generation calcium channel blocker ( amlodipine ) . The main hypothesis of the VALUE trial is that , for an equivalent decrease in blood pressure , valsartan will be more effective than amlodipine in decreasing cardiac mortality and morbidity . VALUE is a prospect i ve , multinational , multicentre , double-blind , r and omized , active-controlled , 2-arm parallel group comparison with a response-dependent dose titration scheme . VALUE involves 14,400 patients in over 30 countries , who will be followed for 4 years or until 1450 patients experience a primary endpoint . The population to be included in VALUE consists of hypertensive men and women , aged 50 years or older , and at a relatively high risk of sustaining a cardiovascular event . The high risk profile is defined taking into account age , gender , and a list of cardiovascular risk factors and disease factors . Risk factors are cigarette smoking , hypercholesterolaemia , diabetes mellitus , uncomplicated left ventricular hypertrophy , proteinuria , and high serum creatinine . Disease factors include documented history of myocardial infa rct ion , peripheral vascular disease , stroke or transient ischaemic attack , or the presence of left ventricular hypertrophy with strain on the ECG . A unique feature of VALUE is the assessment of the predictive power of this cardiovascular risk factor scale in a large population of treated hypertensive patients . The trial started on 10 September 1997 BACKGROUND Observational epidemiological studies have shown a positive association between hypertension and risk of incident dementia ; however , the effects of antihypertensive therapy on cognitive function in controlled trials have been conflicting , and meta-analyses of the trials have not provided clear evidence of whether antihypertensive treatment reduces dementia incidence . The Hypertension in the Very Elderly trial ( HYVET ) was design ed to assess the risks and benefits of treatment of hypertension in elderly patients and included an assessment of cognitive function . METHODS Patients with hypertension ( systolic pressure 160 - 200 mm Hg ; diastolic pressure < 110 mm Hg ) who were aged 80 years or older were enrolled in this double-blind , placebo-controlled trial . Participants were r and omly assigned to receive 1.5 mg slow release indapamide , with the option of 2 - 4 mg perindopril , or placebo . The target systolic blood pressure was 150 mm Hg ; the target diastolic blood pressure was 80 mm Hg . Participants had no clinical diagnosis of dementia at baseline , and cognitive function was assessed at baseline and annually with the mini-mental state examination ( MMSE ) . Possible cases of incident dementia ( a fall in the MMSE score to < 24 points or a drop of three points in 1 year ) were assessed by st and ard diagnostic criteria and expert review . The trial was stopped in 2007 at the second interim analysis after treatment result ed in a reduction in stroke and total mortality . Analysis was by intention to treat . The trial is registered with Clinical Trials.gov , number NCT00122811 . FINDINGS 3336 HYVET participants had at least one follow-up assessment ( mean 2.2 years ) and were included : 1687 participants were r and omly assigned to the treatment group and 1649 to the placebo group . Only five reports of adverse effects were attributed to the medication : three in the placebo group and two in the treatment group . The mean decrease in systolic blood pressure between the treatment and placebo groups at 2 years was systolic -15 mm Hg , p<0.0001 ; and diastolic -5.9 mm Hg , p<0.0001 . There were 263 incident cases of dementia . The rates of incident dementia were 38 per 1000 patient-years in the placebo group and 33 per 1000 patient-years in the treatment group . There was no significant difference between treatment and placebo groups ( hazard ratio [ HR ] 0.86 , 95 % CI 0.67 - 1.09 ) ; however , when these data were combined in a meta- analysis with other placebo-controlled trials of antihypertensive treatment , the combined risk ratio favoured treatment ( HR 0.87 , 0.76 - 1.00 , p=0.045 ) . INTERPRETATION Antihypertensive treatment  in elderly patients does not statistically reduce incidence of dementia . This negative finding might have been due to the short follow-up , owing to the early termination of the trial , or the modest effect of treatment . Nevertheless , the HYVET findings , when included in a meta- analysis , might support antihypertensive treatment to reduce incident dementia Context National guidelines recommend aspirin or statin drugs individually to reduce first coronary heart disease ( CHD )  events , but there are no guidelines about taking both . Contribution The authors used a Markov model to estimate the cost-effectiveness of aspirin , statins , both drugs , or neither in men . In patients with a 10-year risk for CHD of 7.5 % , aspirin alone reduced costs and lengthened life compared with no treatment . Adding a statin cost $ 56200 per additional quality -adjusted life-year at a 7.5 % risk but only $ 42500 at a 10 % risk . Caution s The authors ' analysis was limited to men . Implication s Therapy with aspirin alone is effective and cost-effective in men with an average level of risk for CHD . The addition of a statin is more cost-effective as risk increases . The Editors Aspirin and statin drugs have been shown to be effective for preventing first coronary heart disease ( CHD ) events ( 1 - 3 ) . Systematic review s and meta-analyses suggest that the relative risk reductions with both forms of therapy are similar in magnitude and seem to be independent and relatively constant across the range of underlying risk for CHD ( 2 - 5 ) . The absolute benefit from these treatments seems to be proportional to the patient 's underlying risk for CHD . National treatment guidelines recommend aspirin and statin drugs individually for the primary prevention of cardiovascular events in men who are at increased risk ( 4 , 6 , 7 ) . However , no U.S. guidelines have addressed how these drugs should be used together , and we are unaware of any previous analyses that have reported the cost-effectiveness of these drugs when used in combination for CHD prevention . To help inform clinical and policy decisions about primary CHD prevention , we performed a costutility analysis that examined the use of aspirin therapy , statin therapy , or combination therapy with both drugs in men with various underlying levels of risk for CHD . Methods To examine the cost and utility associated with aspirin and with statin use , we used Microsoft Excel 2002 for Windows ( Microsoft Corp. , Redmond , Washington ) to develop a Markov state-transition model . The model was design ed to simulate cohorts of initially healthy middle-aged men with no history of cardiovascular events and with various levels of 10-year risk for CHD ( Figure 1 ) . Figure 1 . General structure of the Markov model . Base-Case Scenario In our base-case scenario , we compared the effectiveness of 10 years of aspirin therapy , statin therapy , combination therapy with both drugs , and no therapy in 45-year-old men with a 10-year risk for CHD of 7.5 % . After 10 years , both groups adopted the treatment used in the intervention group . Although the differences in therapy were maintained for only 10 years , we examined the effects of these therapies over a lifetime . Model Assumptions All persons were initially healthy and progressed through the model in annual cycles . In each cycle , an individual remained healthy , had an initial cardiovascular event ( angina , myocardial infa rct ion , or stroke ) , experienced adverse effects from therapy ( gastrointestinal bleeding from aspirin or myopathy from statins ) , or died . We assumed that those who had cardiovascular events or adverse events stayed in the subacute state for the remainder of that cycle and then entered a postevent state . Adherence to treatment was assumed to be 100 % in the absence of adverse effects , although the treatment efficacy data were based on the actual rates of adherence in the clinical trials . Persons who had adverse effects from therapy stopped taking the offending medication ; their procession through the model was similar to that of healthy patients after the initial cycle . All costs and outcomes were discounted at 3 % in accordance with current consensus recommendations ( 8) . Model Parameters Model parameters , including base-case values , ranges , and references , are shown in Table 1 ( 1 - 3 , 9 - 29 ) . Table 1 . Base-Case Estimates and Ranges Used in Sensitivity Analyses Noncardiovascular Mortality Age-dependent noncardiovascular mortality rates were estimated from the National Vital Statistics life tables ( 31 ) . Rates were adjusted as the cohort aged over the time horizon of the analysis . Cardiovascular Event Rates Baseline risks for initial cardiovascular events ( myocardial infa rct ion , stroke , angina , and death from CHD ) were drawn from Framingham risk equations by using hypothetical scenarios of nonsmoking , nonhypertensive , nondiabetic men at different levels of risk for CHD ( Appendix Table ) ( 32 ) . Assuming an exponential distribution , we translated these 10-year risks into annual event-related transition probabilities . These probabilities were allowed to change over time to reflect increasing risk for CHD over the time horizon of the analysis . Appendix Table . Sample Baseline Characteristics of 45-Year-Old Men by Risk Level Because we were interested in primary prevention , we did not simulate or examine the details of a patient 's course after a primary , nonfatal event . Instead , we assigned them an increased risk for death , increased costs , and decreased utilities by using data from the literature regarding the average experience of patients after an initial event . The increased relative risk for death after an initial event ( Table 1 ) was drawn from population -based studies in the United Kingdom ( 12 , 16 ) and applied to the general mortality rates from the U.S. life tables to generate the estimated postevent mortality rates . We modified these event rates by assuming that all patients received optimal secondary prevention . Adverse Effects The excess risks for gastrointestinal bleeding with aspirin use and for myopathy with statin use were drawn from systematic review s of r and omized trials and a recent secondary data analysis ( 2 , 26 , 27 ) . Risks for gastrointestinal bleeding and myopathy in untreated patients were assumed to be zero so that only treatment-induced adverse events were counted . Because better data were not available , we estimated the risks for death from aspirin-related gastrointestinal bleeding and statin-induced myopathy and varied them in sensitivity analysis . Patients who had nonfatal adverse effects were not given therapy with alternate agents for primary prevention of CHD . Modeling Stroke Because many r and omized trials of aspirin prophylaxis did not distinguish by stroke type , we had difficulty estimating the precise effect of aspirin on ischemic and hemorrhagic strokes ( 30 ) . To account for this limitation , we used 2 approaches to model the effect of aspirin on stroke . In the base-case analysis , we followed the approach that was used in a recent meta- analysis ( 9 ) by including hemorrhagic stroke and ischemic stroke together in 1 estimate of the effect of aspirin on total stroke ( relative risk for stroke with aspirin , 1.06 ) . In an alternate scenario , we modeled hemorrhagic stroke and ischemic stroke as separate health states . We assumed that aspirin was associated with an excess annual risk of 20 hemorrhagic strokes per 100000 users on the basis of published meta-analyses and that one third of these hemorrhagic strokes would be fatal ( 19 , 30 , 33 ) . We conservatively assumed that aspirin had no effect on ischemic stroke ( 30 ) . The costs and utilities of ischemic stroke and hemorrhagic stroke were also considered separately . Treatment Efficacy We used summary relative risk estimates from existing meta-analyses or relative risks from individual trials to estimate the efficacy of aspirin and statin therapy , either alone or in combination , for preventing CHD events ( 3 , 24 , 29 ) . Where data were limited , we made conservative assumptions . The efficacy of the combined use of aspirin and statins was assumed to be independent on the basis of data from secondary prevention trials ( 5 ) . We did not model the effect of aspirin or statins on initial use of revascularization procedures in the absence of a cardiovascular event . All patients who survived an initial cardiovascular event were assumed to have received secondary preventive therapy with aspirin and a statin or with an alternate agent if  they could not tolerate  aspirin  or  statins . The effect of treatments on all-cause mortality was estimated from meta-analyses of secondary prevention trials ( 18 - 20 ) . Costs We conducted our analysis from the perspective of a third-party payer . State costs ( Table 1 ) , which were derived from data from the published literature and several recent national data bases , are expressed in 2003 dollars . To estimate the costs during the year in which an event occurred , we estimated acute care costs by drawing on data regarding hospital charges from the Healthcare Utilization Project data base and by converting these values to costs . To convert hospital charges to costs , we used the 1999 cost-to-charge ratio value of 0.4501 , which was derived from the Medicare Provider Analysis and Review of short-stay hospitals ( 28 ) . We then used the Medical Consumer Price Index to generate an inflation factor of 1.195 , which was applied to the 1999 cost figure to convert 1999 dollars to 2003 dollars ( 17 ) . In addition to the acute care costs , we assumed that each patient who survived an acute event would also incur one half of the estimated ongoing annual costs of care for the first year . Costs for subsequent years were based on ongoing costs of care that were drawn from the medical literature ( 22 - 25 ) . Drug costs were obtained from the 2003 Red Book average wholesale prices ( 21 ) . For our base-case analysis , we set the annual  statin cost to $ 730 by averaging the Red Book prices of simvastatin ( $ 922 for 10 mg/d ) and lovastatin ( $ 503 for 10 mg/d ) . The base-case cost of aspirin was based on an annual cost of $ 16 for Bayer aspirin ( Bayer Healthcare LLC , Morristown , New Jersey ) . The annual cost of generic aspirin  was estimated at approximately $ 6 ( 21 ) . We varied the costs of each drug over wide ranges in sensitivity analysis . To check our cost estimates , we compared our derived values with other cost estimates Background and Purpose — Very recent subgroup analysis from the PROspect i ve pioglitAzone Clinical Trial In macroVascular Events has shown that pioglitazone reduces the risk of recurrent stroke in type 2 diabetic patients . However , the underlying mechanism of stroke prevention by pioglitazone is unknown . Our aim was to examine the effect of pioglitazone on hypertension-based stroke in rats . Methods — Pioglitazone ( 1 mg · kg−1 · d−1 ) was orally administered to stroke-prone spontaneously hypertensive rats ( SHRSP ) to examine the effect on incidental stroke , cerebrovascular injury , brain inflammation , oxidative stress , and vascular endothelial dysfunction induced by hypertension . Results — Treatment of SHRSP  with pioglitazone for 4 weeks , without affecting blood pressure and blood glucose values , improved vascular endothelial dysfunction ( P<0.05 ) , suppressed remodeling of the middle cerebral artery ( P<0.05 ) and brain microvessels ( P<0.05 ) , and inhibited brain macrophage infiltration ( P<0.05 ) and the upregulation of brain monocyte chemoattractant protein-1 and tumor necrosis factor-&agr ; expression ( P<0.01 ) . Furthermore , pioglitazone treatment significantly delayed the onset of stroke signs and death in SHRSP ( P<0.05 ) . These beneficial effects of pioglitazone on cerebrovascular injury and stroke in SHRSP were associated with a reduction of brain and vascular superoxide via the inhibition of NADPH oxidase activity . Conclusions — Our work provides the first evidence that pioglitazone significantly protects against hypertension-induced cerebrovascular injury and stroke by improving vascular endothelial dysfunction , inhibiting brain inflammation , and reducing oxidative stress . These beneficial effects of pioglitazone were independent of blood pressure or blood sugar values . Thus , pioglitazone appears to be a potential therapeutic agent for stroke in type 2 diabetes with hypertension
CONCLUSION Despite recent large trials showing no significant effect , in patients that have experienced a TIA or stroke , blood pressure lowering agents reduced the occurrence of subsequent stroke and cardiovascular events .
The rate of myocardial infa rct ion and all-cause mortality was unchanged
BACKGROUND While hypertension is a leading risk factor for an initial stroke , the role of blood pressure lowering to prevent subsequent stroke is less clear .
The results of recent large clinical trials investigating effects of antihypertensive agents in patients with a history of stroke have not shown a significant benefit ; findings that are at odds with previous data .
Our meta- analysis systematic ally evaluates the available , relevant trials to examine the role of antihypertensive drugs in preventing recurrent stroke .