Dementia risk with antihypertensive use and blood pressure variability Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): Practical Implications Relationship of Antihypertensive Treatment Regimens and Change in Blood Pressure to Risk for Heart Failure in Hypertensive Patients Randomly Assigned to Doxazosin or Chlorthalidone: Further Analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality The 2001 Canadian recommendations for the management of hypertension: Part two--Therapy. RELATION BETWEEN INITIAL BLOOD PRESSURE AND ITS FALL WITH TREATMENT The Multifactor Primary Prevention Trial in Göteborg, Sweden Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial Effects of antihypertensive treatment after acute stroke in the Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospective, randomised, open, blinded-endpoint trial Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous? Differences in precision of dietary estimates among different population subgroups. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study The Influence of Nicardipine in Patients with High Risk of Stroke Comparison of the Effects of Antihypertensive Agents on Central Blood Pressure and Arterial Stiffness in Isolated Systolic Hypertension Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Physical activity for the prevention and treatment of major chronic disease: an overview of systematic reviews QUALITY OF LIFE BEFORE AND DURING ANTIHYPERTENSIVE TREATMENT: A COMPARATIVE STUDY OF CELIPROLOL AND ATENOLOL Comparison of the Efficacy of Morning Versus Evening Administration of Telmisartan in Essential Hypertension Community-based education classes for hypertension control. A 1.5-year randomized controlled trial. Blood Pressure Reduction: An Added Benefit of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Predictors of antihypertensive drug responses: initial data from a placebo-controlled, randomized, cross-over study with four antihypertensive drugs (The GENRES Study). Practitioner's Trial on the Efficacy of Antihypertensive Treatment in the Elderly Hypertension (The PATE-Hypertension Study) in Japan.
Objective : To determine the association between discrete antihypertensive drug classes and incident dementia controlling for blood pressure variability ( BPV ) in the preceding 4 years . Methods : A total of 6,537 participants ( mean age 79 years , 62 % women ) in a prospect i ve population -based cohort were followed up for incident dementia . A 4-year time lag period was created to classify drug exposure and measure blood pressure . BPV ( percent coefficient of variation [ CV ] ) was regressed against 9 antihypertensive drug classes ( BPVreg ) . Cox regression models were employed to determine hazard ratios ( HRs ) for incident dementia thereafter according to drug class , adjusted for mean blood pressure , covariates , and BPV or BPVreg . Results : Over a median 8.4 years follow-up ( interquartile range 6.7–9.0 ) , lower dementia risk was associated with nondihydropyridine calcium channel blocker ( HR 0.56 ; 95 % confidence interval [ CI ] 0.31–1.00 , p = 0.05 ) and loop diuretics ( HR 0.45 ; 95 % CI 0.22–0.93 , p = 0.03 ) after adjusting for CV-BPV . Similar findings were obtained in analyses restricted to antihypertensive drug users for nondihydropyridine calcium channel blocker ( HR 0.52 ; 95 % CI 0.28–0.95 , p = 0.03 ) and loop diuretics ( HR 0.40 ; 95 % CI 0.19–0.83 , p = 0.01 ) . All systolic BPV × antihypertensive drug interaction terms were not different from p < 0.05 . Conclusions : Nondihydropyridine calcium channel blocker and loop diuretics were associated with a reduced dementia risk independent of CV-BPV in the preceding 4 years . Systolic BPV was not the primary mechanism through which antihypertensive drug classes lower dementia risk Objective Hypertension guidelines recommend initial treatment with a β-blocker or diuretic and adding the other drug where blood pressure is not controlled . We hypothesized that systematic rotation through the major classes of antihypertensive drugs would demonstrate substantial differences in the pattern of an individual patient 's response , and suggest a more rational approach to choosing best treatment . Design Thirty-four young hypertensives ( age 28–55 , median 47 ) rotated in a double-blind , Latin-square , crossover fashion through 6 weeks of treatment each with amlodipine , doxazosin , lisinopril , bisoprolol , bendrofluazide and placebo . Blood pressure was measured at each visit . ‘ Best ’ drug , defined by efficacy and tolerability , was repeated at the end . Results Rotation doubled the number of patients reaching target blood pressure ( systolic < 140 mmHg ) on one drug ( P = 0.03 ) . All five drugs were represented among the ‘ best ’ drugs . In six patients , the blood pressure on ‘ best ’ drug was at least 10 mmHg lower than on any other . Response to the ‘ best ’ drug was highly correlated ( r = 0.79 ) with its previous administration . By contrast , there were only weak correlations between responses to pairs of drugs , except for angiotensin-converting enzyme ( ACE ) inhibitor ( A ) with β-blocker ( B ) , and calcium blocker ( C ) with diuretic ( D ) – each r = 0.71 , P < 0.005 ) . In these young patients , the majority of patients ( 23/34 ) responded best to a drug suppressing the renin system ( A and B ) . Conclusions Patients vary reproducibly in their response to initial treatment , and switching among drugs can increase the efficacy of monotherapy . The results support an AB/CD scheme for choosing therapy , in which the first drug is taken from one of these pairs , and uncontrolled patients switch to one of the other pair The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , sponsored by the National Heart , Lung , and Blood Institute ( NHLBI ) , is the largest outcome trial of antihypertensive treatment ever carried out and the only large blood pressure ( BP ) trial to be carried out in a US population in the past decade.1 The rationale for ALLHAT , which was design ed in the early 1990s , was the urgent need to determine which of the several classes of antihypertensive drugs that had been developed and released for clinical use was most effective in preventing coronary heart disease ( CHD ) , defined as fatal CHD and nonfatal myocardial infa rct ion.2 The only r and omized trials that had previously compared representatives of the antihypertensive drug classes , the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents3 and the Treatment of Mild Hypertension Study (TOMHS),4 showed BP reductions with all classes but were not powered to evaluate CHD outcomes . Further , prior outcome trials had shown that the reduction in CHD event rates with antihypertensive treatment was less than expected based on epidemiologic data .5 Adverse effects of study drugs , particularly diuretics , including hypokalemia , hypomagnesemia , hyperuricemia , hyperlipidemia , insulin resistance , and ventricular ectopic activity , had been adduced to account for the disappointing outcomes of earlier trials by off setting the beneficial effects of BP reduction.6,7 To further complicate the picture , benefits beyond BP reduction had been attributed to some antihypertensive drug classes , ie , improved survival and reduced morbidity in persons with heart failure or left ventricular dysfunction treated with angiotensin-converting enzyme ( ACE ) inhibitors8–10 and improved insulin sensitivity and lipid profiles with α-blocker treatment.11 In contrast , another antihypertensive drug class , the dihydropyridine calcium channel blockers ( CCBs ) , had been associated with unfavorable outcomes in patients with acute myocardial infa rct ion or unstable angina.12 There were no data Context Previously published results of this r and omized , double-blind trial showed that hypertensive patients treated with doxazosin rather than chlorthalidone more often developed heart failure . Did differences in blood pressure control or treatment with other drugs explain these findings ? Contribution This analysis shows that the slightly worse blood pressure control achieved with doxazosin did not explain higher risks for heart failure . Risks with doxazosin versus chlorthalidone were highest among patients who received monotherapy ( relative risk , 3.10 ) and lowest among patients who received stepped care with additional drugs ( relative risk , 1.42 ) . Implication s Increased risks for heart failure with doxazosin versus chlorthalidone are attenuated but not eliminated when additional antihypertensive drugs are used . The Editors The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , multicenter clinical trial including 42 418 participants at 623 clinical sites , is design ed to determine whether treatment begun with a calcium-channel blocker ( amlodipine ) , an angiotensin-converting enzyme inhibitor ( lisinopril ) , or an -adrenergic blocker ( doxazosin ) compared to treatment with a diuretic ( chlorthalidone ) reduces the incidence of fatal coronary heart disease or nonfatal myocardial infa rct ion in high-risk patients with hypertension ( 1 ) . Secondary end points are all-cause mortality , stroke , and other cardiovascular events . A lipid-lowering trial in a subset of 10 356 participants is design ed to determine whether decreasing cholesterol levels with a hydroxymethyl glutamyl coenzyme A reductase inhibitor ( pravastatin ) compared with usual care reduces all-cause mortality in older , moderately hypercholesterolemic patients . In January 2000 , the doxazosin arm of the trial was discontinued ( 2 ) because major cardiovascular disease ( relative risk , 1.25 [ 95 % CI , 1.17 to 1.33 ] ; P < 0.001 ) , especially heart failure ( relative risk , 2.04 [ 95 % CI , 1.79 to 2.32 ] ; P < 0.001 ) , was significantly increased compared with the chlorthalidone arm . Equally important , a low probability existed that doxazosin would show benefit over chlorthalidone for the primary end point by the scheduled study end , given the lack of difference ( relative risk , 1.02 [ 95 % CI , 0.90 to 1.17 ] ; P > 0.2 ] at that time . These intention-to-treat analyses compared patients assigned to chlorthalidone with patients assigned to doxazosin . In this article , we analyze how treatment changes may have affected the comparison of doxazosin with chlorthalidone in terms of heart failure . Our major objectives are to ascertain to what extent the relative risk with doxazosin versus chlorthalidone depends on 1 ) whether the assigned drugs were used as monotherapy or in combination with other agents and 2 ) the difference in decreases in systolic and diastolic blood pressure . Methods Study Design The rationale and design of ALLHAT are described in detail elsewhere ( 1 ) . In brief , eligible participants were men and women 55 years of age or older who had systolic or diastolic hypertension ( 140/90 mm Hg or hypertension controlled with medication ) plus at least one additional risk factor for coronary heart disease events . The risk factors included previous ( > 6 months ) myocardial infa rct ion or stroke , left ventricular hypertrophy on electrocardiography or echocardiography , history of type 2 diabetes , current cigarette smoking , and a low high-density lipoprotein cholesterol level . Persons with a history of hospitalized or treated symptomatic heart failure or a known ejection fraction less than 0.35 were excluded . Unless the drug regimen required tapering for safety , participants who had been taking antihypertensive medications continued to do so until the day of r and omization , at which point they stopped taking all previous medications . On the day after r and omization , treatment with the study drug was initiated . Enrollment occurred from February 1994 through January 1998 . The original reported number of 42 448 participants and 625 sites changed because 30 patients with poor documentation of informed consent were excluded ( 2 ) . Participants were assigned by a computer-generated r and omization schedule in a ratio of 1.7:1 to receive chlorthalidone or doxazosin . R and omization was stratified by center and blocked over time to maintain the ratio . All participants gave written informed consent , and all centers obtained institutional review board approval . Ascertainment of Outcomes At each clinic visit , occurrence of study end points was assessed by the clinical investigator . A hospital discharge summary was required for each hospitalized study outcome , and a death certificate was required for each death . ALLHAT defined symptomatic heart failure as clear-cut signs or symptoms of left or right ventricular dysfunction that can not be attributed to other causes . A patient had to have at least one symptom ( paroxysmal nocturnal dyspnea , dyspnea at rest , New York Heart Association class III dyspnea or other symptoms [ on less than ordinary exertion ] , or orthopnea ) and one sign ( rales , ankle edema , tachycardia , cardiomegaly or characteristic pulmonary pattern on chest radiography , S3 gallop , or jugular venous distention ) ( 3 ) . Symptoms and signs were determined by the clinic investigator through patient history , chart review , or consultation with the treating physician , but such data were not collected central ly . A one-time sample of 24 hospitalized or fatal heart failure events was review ed in a blinded manner by the ALLHAT Endpoints Subcommittee ; 20 of 24 ( 83 % ) were deemed to have complete data for a definitive diagnosis . Of the 20 cases , the agreement rate between the subcommittee and the clinic investigators was 90 % ( 18 of 20 ) and similar in both treatment groups . Details on the validity of diagnosis of heart failure will be provided in a future report . Measurement and Treatment of Blood Pressure The ALLHAT protocol specified a stepped-care treatment program for hypertension . Trained observers using st and ardized techniques measured blood pressures during the trial ( 1 , 2 ) . All blood pressures were calculated as the average of two measurements obtained with a 30-second interval between them . The blood pressure goal in all four study arms was less than 140/90 mm Hg . This level was to be achieved with the lowest possible dose of blinded first-line drug , with addition of second- and third-line open-label therapy as needed after reaching the maximal dose of first-line drug . Chlorthalidone and doxazosin were to be taken once daily in the morning . By design , doses were selected to achieve equivalent blood pressure control in the treatment groups . The first , second , and third dosage levels were 12.5 mg/d , 12.5 mg/d ( sham titration ) , and 25 mg/d , respectively , for chlorthalidone and 2 mg/d , 4 mg/d , and 8 mg/d for doxazosin . Double-blinded 1-mg and 12.5-mg doses of doxazosin and chlorthalidone , respectively , were used for the first week to minimize the frequency of postural hypotension associated with doxazosin . The identity of drugs was masked at each dosage level , but dosage level was not . After r and omization , patients were seen for dose titration as needed at 1 and 3 months per the protocol , but they could return more often until target blood pressure was reached . Subsequently , required visits occurred at 3-month intervals during the first year and at 4-month intervals thereafter . Open-label second-step drugs were added as needed and tolerated . These agents were reserpine ( 0.05 to 0.2 mg/d ) , clonidine ( 0.1 to 0.3 mg twice daily ) , and atenolol ( 25 to 100 mg/d ) . The choice of second-step drug was at the discretion of the treating clinician-investigator . The third-step agent was hydralazine ( 25 to 100 mg twice daily ) . Details of these therapies are provided elsewhere ( 1 ) . Investigators could choose to prescribe open-label antihypertensive drugs other than those provided by the study . However , use of the drug classes under study thiazide diuretics , calcium antagonists , angiotensin-converting enzyme inhibitors , and -adrenergic blockerswas strongly discouraged to avoid dilution of treatment comparisons . When clinical conditions other than uncontrolled hypertension ( for example , angina or heart failure ) were present , drugs from any study class could be used . If a step 1 drug was specifically required for blood pressure control while blinded drug treatment was continued , the step 1 drug could be added as open-label therapy but the dose could not exceed one half the maximum recommended by the Fifth Joint National Committee ( 4 ) . In most such cases , unblinding the patient or the investigator to treatment assignment was not necessary . ( Overall , < 1 % of drug identities were provided to either participant or investigator . ) Any of nine possible open-label drug typesdiuretic , calcium-channel blocker , angiotensin-converting enzyme inhibitor , -adrenergic blocker , atenolol , reserpine , clonidine , hydralazine , and other antihypertensive drug ( which could include nonatenolol -blockers , although drug name was not logged)could be recorded at each visit . Because diuretics , angiotensin-converting enzyme inhibitors , and -blockers are beneficial in preventing or treating heart failure , we call these antihypertensive heart failure drugs . Data on  antihypertensive drug use before study enrollment were collected , but not by drug class . Statistical Analysis Data were analyzed for use of additional drugs according to participants ' r and omized treatment assignments and regardless of continuation of blinded study treatment . The outcomes all heart failure ( treated outside hospital , hospitalized , or fatal ) and hospitalized or fatal heart failure were examined by treatment group for the entire cohort . The time to event for the previously published as-r and omized analyses was the interval from r and omization to first diagnosis of heart failure for patients who had an outcome , or from r and omization to 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 , OBJECTIVE To provide up date d , evidence -based recommendations for the therapy of hypertension in adults . OPTIONS For patients with hypertension , a number of antihypertensive agents may control blood pressure . R and omized trials evaluating first-line therapy with thiazides , beta-adrenergic antagonists , angiotensin-converting enzyme inhibitors , calcium channel blockers , alpha-blockers , central ly acting agents or angiotensin II receptor antagonists were review ed . OUTCOMES The health outcomes that were considered were changes in blood pressure , cardiovascular morbidity , and cardiovascular and /or all-cause mortality rates . Economic outcomes were not considered due to insufficient evidence . EVIDENCE MEDLINE was search ed for the period March 1999 to October 2001 to identify studies not included in the 2000 revision of the Canadian Recommendations for the Management of Hypertension . Reference lists were scanned , experts were polled , and the personal files of the subgroup members and authors were used to identify other published studies . All relevant articles were review ed and appraised , using prespecified levels of evidence , by content experts and method ological experts . VALUES A high value was placed on the avoidance of cardiovascular morbidity and mortality . BENEFITS , HARMS AND COSTS Various antihypertensive agents reduce the blood pressure of patients with sustained hypertension . In certain setting s , and for specific classes of drugs , blood-pressure lowering has been associated with reduced cardiovascular morbidity and /or mortality . RECOMMENDATIONS The present document contains detailed recommendations pertaining to treatment thresholds , target blood pressures , and choice of agents in various setting s in patients with hypertension . The main changes from the 2000 Recommendations are the addition of a section on the treatment of hypertension in patients with diabetes mellitus , the amalgamation of the previous sections on treatment of hypertension in the young and old into one section , increased emphasis on the role of combination therapies over repeated trials of single agents and expansion of the section on the treatment of hypertension after stroke . Implicit in the recommendations for therapy is the principle that treatment for an individual patient should take into consideration global cardiovascular risk , the presence and /or absence of target organ damage , and comorbidities . VALIDATION All recommendations were grade d according to strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group . Individuals with potential conflicts of interest relative to any specific recommendation were excluded from voting on that recommendation . Only those recommendations achieving high levels of consensus are reported here . These guidelines will continue to be up date d annually The relation between pre-treatment  blood-pressure and the fall in pressure after treatment was examined for most classes of  antihypertensive drugs . Positive correlations were demonstrated for all drugs , for placebo , and for bed rest . This suggests that for all manoeuvres response is related to the height of the pretreatment pressure . Substitution of the pre-treatment and achieved pressures by r and om numbers reveals that positive correlations are mathematically inevitable and do not indicate any action on a basic mechanism of essential hypertension . After statistical correction for mathematical associations between the variables the apparent effects were generally lost . A correlation between the pre-treatment value of any variable and its change after a therapeutic intervention thus may not be valid Summary All male inhabitants of the city of Göteborg , who were born between 1915–1922 and 1924–1925 were included in the trial , and were 47 to 55 years of age on entry to the study in 1970 to 1973 . One-third of these men were r and omly allocated to an intervention group , whilst the other two-thirds acted as controls  . Men of all social classes , employed as wellas unemployed , health conscious as well as careless , were invited , with 75 % of these responding to the invitation . The intervention group contained 10,000 men and the control group 20,000 men . The intervention group were given advice on diet , both individually and in groups , the type of advice depending upon serum cholesterol level . Smokers were advised to stop smoking , and men with elevated blood pressure were treated with antihypertensive drugs . Due to the large size of the groups and because they formed a r and om population sample , it was assumed that they had similar characteristics at the start of the trial . Risk factors were only measured in the intervention group at this time , followed by intervention . This design feature solved several ethical problems with regard to no treatment in the control group . These men were , however , subjected to health examinations and treatment as well as general health advice . Risk factor levels were measured in the intervention group , and also in r and om sub sample s ( 11 % ) of the control group after 4 and 10 years . Serum cholesterol , blood pressure and smoking decreased among men in both groups , and only slightly more in the intervention group . Antihypertensive drug treatment was given to 26 % of the intervention group and 20 % of the control group participants after 10 years . No significant effect on total or cardiovascular mortality , or on the incidence of myocardial infa rct ion or stroke was found . However , the effect of this intensive antihypertensive treatment on mortality and morbidity is indicated when the present results are compared to those of a previous population study in the same city . A markedly higher mortality in the group of non- participants diluted the results considerably , and some characteristics of this group will be discussed in view of future possibilities of prevention efforts in the whole community Summary Background High blood pressure is associated with poor outcome after stroke . Whether blood pressure should be lowered early after stroke , and whether to continue or temporarily withdraw existing antihypertensive drugs , is not known . We assessed outcomes after stroke in patients given drugs to lower their blood pressure . Methods In our multicentre , partial-factorial trial , we r and omly assigned patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised systolic blood pressure ( systolic 140–220 mm Hg ) to 7 days of transdermal glyceryl trinitrate ( 5 mg per day ) , started within 48 h of stroke onset , or to  no glyceryl trinitrate ( control group ) . A subset of patients who were taking antihypertensive drugs before their stroke were also r and omly assigned to continue or stop taking these drugs . The primary outcome was function , assessed with the modified Rankin Scale at 90 days by observers masked to treatment assignment . This study is registered , number IS RCT N99414122 . Findings Between July 20 , 2001 , and Oct 14 , 2013 , we enrolled 4011 patients .  Mean blood pressure was 167 ( SD 19 ) mm Hg/90 ( 13 ) mm Hg at baseline ( median 26 h [ 16–37 ] after stroke onset ) , and was significantly reduced on day 1 in 2000 patients allocated to glyceryl trinitrate compared with 2011 controls ( difference −7·0 [ 95 % CI −8·5 to −5·6 ] mm Hg/–3·5 [ –4·4 to −2·6 ] mm Hg ; both p<0·0001 ) , and on day 7 in 1053 patients allocated to continue antihypertensive drugs compared with 1044 patients r and omised to stop them ( difference −9·5 [ 95 % CI −11·8 to −7·2 ] mm Hg/–5·0 [ –6·4 to −3·7 ] mm Hg ; both p<0·0001 ) . Functional outcome at day 90 did not differ in either treatment comparison — the adjusted common odds ratio ( OR ) for worse outcome with glyceryl trinitrate versus no glyceryl trinitrate was 1·01 ( 95 % CI 0·91–1·13 ; p=0·83 ) , and with continue versus stop antihypertensive drugs OR was 1·05 ( 0·90–1·22 ; p=0·55 ) . Interpretation In patients with acute stroke and high blood pressure , transdermal glyceryl trinitrate lowered blood pressure and had acceptable safety but did not improve functional outcome . We show no evidence to support continuing prestroke antihypertensive drugs in patients in the first few days after acute stroke . Funding UK Medical Research Council BACKGROUND Up to 50 % of patients with acute stroke are taking antihypertensive drugs on hospital admission . However , whether such treatment should be continued during the immediate post-stroke period is unclear . We therefore aim ed to assess the efficacy and safety of continuing or stopping pre-existing antihypertensive drugs in patients who had recently had a stroke . METHODS The Continue or Stop Post-Stroke Antihypertensives Collaborative Study ( COSSACS ) was a UK multicentre , prospect i ve , r and omised , open , blinded-endpoint trial . Patients were recruited at 49 UK National Institute for Health Research Stroke Research Network centres from January 1 , 2003 , to March 31 , 2009 . Patients aged over 18 years who were taking antihypertensive drugs were enrolled within 48 h of stroke and the last dose of antihypertensive drug . Patients were r and omly assigned ( 1:1 ) by secure internet central r and omisation to either continue or stop pre-existing antihypertensive drugs for 2 weeks . Patients and clinicians who r and omly assigned patients were unmasked to group allocation . Clinicians who assessed 2-week outcomes and 6-month outcomes were masked to group allocation . The primary endpoint was death or dependency at 2 weeks , with dependency defined as a modified Rankin scale score greater than 3 points . Analysis was by intention to treat . This trial is registered with the International St and ard R and omised Controlled Trial Register , number IS RCT N89712435 . FINDINGS 763 patients were assigned to continue ( n=379 ) or stop ( n=384 ) pre-existing antihypertensive drugs . 72 of 379 patients in the continue group and 82 of 384 patients in the stop group reached the primary endpoint ( relative risk 0.86 , 95 % CI 0.65 - 1.14 ; p=0.3 ) . The difference in systolic blood pressure at 2 weeks between the continue group and the stop group was 13 mm Hg ( 95 % CI 10 - 17 ) and the difference in diastolic blood pressure was 8 mm Hg ( 6 - 10 ; difference between groups p<0.0001 ) . No substantial differences were observed between groups in rates of serious adverse events , 6-month mortality , or major cardiovascular events . INTERPRETATION Continuation of antihypertensive drugs did not reduce 2-week death or dependency , cardiovascular event rate , or mortality at 6 months . Lower blood pressure levels in those who continued antihypertensive treatment after acute mild stroke were not associated with an increase in adverse events . These neutral results might be because COSSACS was underpowered owing to early termination of the trial , and support the continuation of ongoing research trials . FUNDING The Health Foundation and The Stroke Association 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 Population s vary in consistency of diets . The precision of estimates ( E ) of  nutrient  intake depends both on the ratio ( R ) of intraindividual to interindividual variances , as well as on the number of days of dietary intake recorded ( k ) . We present baseline data from 872 participants in the Trial of Antihypertensive Interventions and Management ( T AIM ) , a r and omized clinical trial of diet and drug treatment for mild hypertension . There is wide variation in R among different demographic groups and for different nutrients . This has implication s for the ability to estimate the correlations between the nutrient and a physiologic variable such as blood pressure , as well as for power calculations to compare group means on nutrient intake . For example , to achieve the same degree of precision ( E = 0.80 ) in estimating the correlation between sodium intake and blood pressure for whites in New York , 7 days of food records would be required , compared to 2 days for whites in Alabama . Tables are presented indicating within- and between-person variances for different groups and different nutrients . Methods of calculating E , determining k , and calculating sample s size are provided . Investigators design ing nutritional epidemiologic studies should take into account ratios of intraindividual to interindividual variances of different population subgroups and different nutrients in order to determine the number of daily food records that must be obtained and the sample size for group comparisons BACKGROUND The efficacy of new antihypertensive drugs has been question ed . We compared the effects of conventional and newer antihypertensive drugs on cardiovascular mortality and morbidity in elderly patients . METHODS We did a prospect i ve , r and omised trial in 6614 patients aged 70 - 84 years with hypertension ( blood pressure > or = 180 mm Hg systolic , > or = 105 mm Hg diastolic , or both ) . Patients were r and omly assigned conventional antihypertensive drugs ( atenolol 50 mg , metoprolol 100 mg , pindolol 5 mg , or hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily ) or newer drugs ( enalapril 10 mg or lisinopril 10 mg , or felodipine 2.5 mg or isradipine 2 - 5 mg daily ) . We assessed fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease . Analysis was by intention to treat . FINDINGS Blood pressure was decreased similarly in all treatment groups . The primary combined endpoint of fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease occurred in 221 of 2213 patients in the conventional drugs group ( 19.8 events per 1000 patient-years ) and in 438 of 4401 in the newer drugs group ( 19.8 per 1000 ; relative risk 0.99 [ 95 % CI 0.84 - 1.16 ] , p=0.89 ) . The combined endpoint of fatal and non-fatal stroke , fatal and non-fatal myocardial infa rct ion , and other cardiovascular mortality occurred in 460 patients taking conventional drugs and in 887 taking newer drugs ( 0.96 [ 0.86 - 1.08 ] , p=0.49 ) . INTERPRETATION Old and new antihypertensive drugs were similar in prevention of cardiovascular mortality or major events . Decrease in blood pressure was of major importance for the prevention of cardiovascular events Blood pressure and clinical status of 1,736 patients with cerebrovascular disease were observed during 12 months of treatment with nicardipine . The most common diagnoses were chronic cerebral ischemia ( 53.2 % ) , transient ischemic attacks ( TIA ; 25.1 % ) , and cerebral infa rct ( 8.7 % ) ; 50.1 % of patients were classed as hypertensive [ systolic blood pressure ( SBP ) ≥ 160 mm Hg or diastolic blood pressure ( DBP ) ≥ 90 mm Hg ] . Most patients ( 91.2 % ) received a daily dose of 60 mg nicardipine . Additional treatments included diuretics ( 37 % ) , β-blockers ( 11.5 % ) , other antihypertensive drugs ( 15.8 % ) , platelet antiaggregants ( 25.1 % ) , and cardiotonic drugs ( 15.1 % ) . A total of 282 patients ( 16.2 % ) were lost to follow-up , 21 ( 1.2 % ) patients withdrew due to side effects , 32 ( 1.8 % ) died , and 9 ( 0.5 % ) patients had treatment interrupted due to concomitant illness . In the hypertensive subgroup , blood pressure ( SBP/ DBP ) was reduced from a mean baseline value of 175 ± 22/97 ± 14 mm Hg to 152 ± 17/85 ± 11 mm Hg at 3 months and 149 ± 23/81 ± 11 mm Hg after 12 months of treatment . The incidence of TIA or stroke among these patients was reduced from 29 cases ( 3.5 % ) during the first 3 months to 11 cases ( 1.54 % ) during months 4–12 ( p < 0.01 ) . In normotensive patients there were 18 ( 2.15 % ) cases during months 1–3 and 13 ( 1.55 % ) cases during months 4–12 ( difference not significant ) . In the 280 patients treated  with nicardipine alone , the most frequent side effects during the first month were facial flushing ( 6.8 % ) , gastrointestinal problems ( 5 % ) , dizziness ( 3.2 % ) , headache ( 3.2 % ) , drowsiness ( 3.2 % ) , and hypotension ( 1.1 % ) . Most of these side effects were transient . These results demonstrate that nicardipine lowered blood pressure over the 12 months of observation . This may have contributed to the reduction in the incidence of TIA or stroke among hypertensive patients during months 4–12 Isolated systolic hypertension is an important risk factor for cardiovascular disease and results primarily from elastic artery stiffening . Although various drug therapies are used to lower peripheral blood pressure ( BP ) in patients with isolated systolic hypertension , the effects of the 4 major classes of antihypertensive agents on central BP , pulse pressure ( PP ) amplification , and arterial stiffness in this condition are not clear . Fifty-nine patients over the age of 60 years with untreated isolated systolic hypertension ( systolic BP ≥140 mm Hg and diastolic BP ≤90 mm Hg ) were r and omly assigned to receive 1 of the following 4 antihypertensive agents : perindopril , atenolol , lercanidipine , or bendrofluazide  . BP was measured using a mercury sphygmomanometer , and augmentation index and carotid-femoral ( aortic ) pulse wave velocity were measured at baseline , after 2 weeks of placebo therapy , and at the end of 10 weeks of active therapy . Peripheral systolic BP and peripheral PP were reduced similarly after treatment with all 4 classes of drug . However , central PP was only reduced significantly by perindopril , lercanidipine , and bendrofluazide , whereas atenolol had no effect . Lercanidipine reduced the augmentation index , whereas atenolol increased it . Aortic pulse wave velocity was not changed by any of the drugs . In summary , despite similar reductions in peripheral systolic and PPs with the 4 classes of drug , changes in central pressure and augmentation index varied . Because central PP and increased wave reflections are considered important risk factors in patients with isolated systolic hypertension , the choice of therapy may be influenced by these findings in the future CONTEXT Blood pressure control ( < 140/90 mm Hg ) rates for hypertension fall far short of the US national goal of 50 % or more . Achievable control rates in varied practice setting s and geographic regions and factors that predict improved blood pressure control are not well identified . OBJECTIVE To determine the success and predictors of blood pressure control in a large hypertension trial involving a multiethnic population in diverse practice setting s. DESIGN The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial is a r and omized , double-blind , active-controlled clinical trial with a mean follow-up of 4.9 years . Participant enrollment began in February 1994 and follow-up was completed in March 2002 . SETTING A total of 623 centers in the United States , Canada , and the Caribbean . PARTICIPANTS A total of 33,357 participants ( aged > or = 55 years ) with hypertension and at least one other coronary heart disease risk factor . INTERVENTIONS Participants were r and omly assigned to receive ( double-blind ) chlorthalidone , 12.5 - 25 mg/d ( n=15,255 ) , amlodipine 2.5 - 10 mg/d ( n=9048 ) , or lisinopril 10 - 40 mg/d ( n=9054 ) after other medication was discontinued . Doses were increased within these ranges and additional drugs from other classes were added as needed to achieve blood pressure control ( < 140/90 mm Hg ) . MAIN OUTCOME MEASURES The outcome measures for this report are systolic and diastolic blood pressure , the proportion of participants achieving blood pressure control ( < 140/90 mm Hg ) , and the number of drugs required to achieve control in all three groups combined . RESULTS Mean age was 67 years , 47 % were women , 35 % black , 36 % diabetic ; 90 % were on antihypertensive drug treatment at entry . At the first of two pre-r and omization visits , blood pressure was < 140/90 mm Hg in only 27.4 % of participants . After 5 years of follow-up , the percent controlled improved to 66 % . Systolic blood pressure was < 140 mm Hg in 67 % of participants , diastolic blood pressure was < 90 mm Hg in 92 % , the mean number of drugs prescribed was 2.0+/-1.0 , and the percent on > or = 2 drugs was 63 % . Blood pressure control varied by geographic regions , practice setting s , and demographic and clinical characteristics of participants . CONCLUSIONS These data demonstrate that blood pressure may be controlled in two thirds of a multiethnic hypertensive population in diverse practice setting s. Systolic blood pressure is more difficult to control than diastolic blood pressure , and at least two antihypertensive medications are required for most patients to achieve blood pressure control . It is likely that the majority of people with hypertension could achieve a blood pressure < 140/90 mm Hg with the antihypertensive medications available today Background The evidence that higher levels of physical activity and /or lower levels of physical inactivity are associated with beneficial health-related outcomes stems mainly from observational studies . Findings from these studies often differ from r and omised controlled trials and systematic review s currently demonstrate mixed results , due partly to heterogeneity in physical activity interventions , method ologies used and population s studied . As a result , translation into clinical practice has been difficult . It is therefore essential that an overview is carried out to compare and contrast systematic review s , and to identify those physical activity interventions that are the most effective in preventing and /or treating major chronic disease . This protocol has been registered on PROSPERO 2013 : CRD42013003523 . Methods We will carry out an overview of Cochrane systematic review s. We will search the Cochrane Data base of Systematic Review s for systematic review s of r and omised controlled trials that have a primary focus on disease-related outcomes . We will restrict review s to those in selected major chronic diseases . Two authors will independently screen search outputs , select studies , extract data and assess the quality of included review s using the assessment of multiple systematic review s tool ; all discrepancies will be resolved by discussing and reaching a consensus , or by arbitration with a third author . The data extraction form will summarise key information from each review , including details of the population ( s ) ( for example , disease condition ) , the context ( for example , prevention , treatment or management ) , the participants , the intervention(s ) , the comparison(s ) and the outcomes . The primary outcomes of interest are the prevention of chronic disease and /or improved outcomes , in the treatment or management of chronic disease . These outcomes will be summarised and presented for individual chronic diseases ( for example , any change in blood pressure in hypertension or glucose control in diabetes ) . Secondary outcomes of interest are to describe the structure and delivery of physical activity interventions  across chronic disease conditions and adverse events associated with physical activity . Discussion We anticipate that our results could inform research ers , guideline groups and policymakers of the most efficacious physical activity interventions in preventing and /or managing major chronic disease Hypertensive patients may be adversely affected by complications and other concomitant processes such as anxiety , sedation , and drug side effects . It has been suggested that some recently developed antihypertensive agents do not affect quality of life by causing adverse effects . We compared the effects of two antihypertensive drugs on quality of life : atenolol , a st and ard cardioselective β-blocker , and celiprolol , one of a new class of selective β-blockers with vasodilatory properties . One hundred thirty-two patients with mild-to-moderate hypertension were eligible to enter a 28-week , double-blind , parallel-group study . The study protocol consisted of a 4-week period on placebo and a 24-week period of dosage-adjusted treatment with either atenolol or celiprolol . We assessed both systolic and diastolic blood pressure and quality of life perception by a selected test battery that included the Bulpitt and Fletcher Quality of Life Question naire . Supine blood pressure fell from 167/101 ( range 120/95 to 200/116 ) to 150/92 mm Hg ( p < 0.0001 ) during celiprolol treatment . This antihypertensive effect was at least as good with celiprolol as with atenolol  . Quality of life perception was comparable for the two drugs although adverse effects were seen more frequently with atenolol than with celiprolol , particularly after prolonged treatment . Patient compliance was better for celiprolol than for atenolol . Our results show that the selective β-blocker with vasodilatory property celiprolol is at least as effective as atenolol and that it is more advantageous in terms of some quality of life variables Valsartan administration at bedtime as opposed to on wakening improves the sleep time – relative blood pressure decline toward a more dipper pattern without loss in 24-hour efficacy . Yet to be determined is whether this administration time-dependent efficacy is a class-related feature , characteristic of all angiotensin receptor blockers or specific only to valsartan . Terminal half-life is a major difference between angiotensin receptor blockers , being largest ( ≈24 hours ) for telmisartan . This trial investigated the administration time-dependent antihypertensive efficacy of telmisartan . We studied 215 patients with hypertension ( 114 men and 101 women ) , 46.4±12.0 years of age , r and omly assigned to receive telmisartan ( 80 mg/d ) as a monotherapy either on awakening or at bedtime . Blood pressure was measured for 48 hours before and after 12 weeks of treatment . The significant blood pressure reduction after treatment was similar for both groups . Bedtime administration of telmisartan , however , was more efficient than morning dosing in reducing the nocturnal blood pressure mean . The sleep time – relative blood pressure decline was slightly reduced after telmisartan on awakening but significantly increased with bedtime dosing , thus reducing the prevalence of nondipping from baseline by 76 % . Telmisartan administered at bedtime , as opposed to morning dosing , improved the sleep time – relative blood pressure decline toward a more dipper pattern without loss in 24-hour efficacy . Nocturnal BP regulation is significantly better achieved with bedtime dosing of telmisartan . Results from this prospect i ve trial suggest that these beneficial features of bedtime dosing may be class related for angiotensin receptor blockers . These results should be taken into account when prescribing this class of antihypertensive medication for treatment of essential hypertension Community-based hypertension control is important for primary prevention of cardiovascular disease . In this study , untreated men and women aged 35 to 69 years were r and omly assigned to an  intervention ( n=56 ) or control ( n=55 ) group in a 1.5-year community-based education program .  Subjects had no evidence of hypertensive end-organ defects and had screening blood pressures of 140 to 179 mm Hg systolic and /or 90 to 109 mm Hg diastolic , with no difference in mean blood pressure between groups ( 148 to 150 mm Hg for mean systolic and 83 to 84 mm Hg for mean diastolic pressures ) . The intervention group took four education classes in the first 6 months and four classes during the next year , and the control group took two classes . Health education focused on reduced dietary sodium and increased milk intake , brisk walking , and , if necessary , reduction of alcohol and sugar intakes . Antihypertensive medication was started less often in the intervention than in the control group at 1.5 years ( 9 % versus 24 % , P < .05 ) . Mean systolic pressure was 5 to 6 mm Hg less in the intervention than in the control group at both 6 months and 1.5 years ( P < .05 ) , with or without inclusion of those subjects who began antihypertensive medication . Diastolic pressure and body mass index did not change significantly between groups . Urinary sodium excretion declined in the intervention but not in the control group ( differences between groups : P=.04 at 6 months and P=.07 at 1.5 years ) . According to a behavioral question naire , sodium reduction and milk increase were greater in the intervention than the control group ( sodium : P < .01 at 6 months and P=.08 at 1.5 years ; milk : P < .001 at 6 months and P < .01 at 1.5 years ) . Mean ethanol intake was reduced in the intervention but not the control group ( P=.04 at 1.5 years ) . This community-based hypertension control program was effective in reducing systolic pressure levels by nonpharmacological means during the first 6 months and maintaining the reduction for 1.5 years Sodium – glucose cotransporter 2 ( SGLT2 ) inhibitors are a newly approved class of glucose-lowering medications with a novel mechanism of action . These agents increase glycosuria , which leads to improved glucose control . They also produce an osmotic diuresis that , in part , contributes to blood pressure reduction and calorie loss secondary to glycosuria leading to weight loss ( 1,2 ) . A recent review of SGLT2 inhibitors focuses on the blood pressure – lowering effects of the two approved glucose-lowering agents , dapagliflozin and canagliflozin ( 3 ) . While not approved as antihypertensive agents , they may potentially aid in lowering blood pressure in patients with diabetes . A review of studies in both hypertensive and normotensive patients with type 2 diabetes demonstrates a 4–10 mmHg reduction of systolic blood pressure ( 3 ) . In this issue of Diabetes Care , Tikkanen et al. ( 4 ) investigate the effectiveness and safety of the newest agent in this class , empagliflozin , on blood pressure using 24-h ambulatory blood pressure monitoring . This study r and omized over 800 subjects with type 2 diabetes , mean age of 60 years , and good kidney function ( i.e. , a mean estimated glomerular filtration rate [ eGFR ] of 84 mL/min/1.73 m2 ) . These subjects either were normotensive ( < 140/90 mmHg ) or had stage 1 hypertension ( ≥140/90 < 160/99 mmHg ) . They were r and omized to either empagliflozin 10 mg daily , empagliflozin 25 mg BACKGROUND Only a minority of hypertensive individuals is adequately controlled for their hypertension , partially because reliable predictors for efficient antihypertensive drug therapy are lacking . METHODS In a prospect i ve , r and omized , double-blind , cross-over , placebo-controlled study ( The GENRES Study ) , 208 moderately hypertensive Finnish men ( aged 35 to 60 years ) were treated for 4 weeks with antihypertensive drugs from four different classes : amlodipine ( 5 mg ) , bisoprolol ( 5 mg ) , hydrochlorothiazide ( 25 mg ) , or losartan ( 50 mg ) daily . Each individual received each of the four monotherapies in a r and omized order . Four-week placebo periods were included before and between drug treatment periods . Antihypertensive responses were assessed with 24-h ambulatory and office measurements and analyzed according to age , body mass index , triceps skin fold thickness , waist-to-hip ratio , duration of hypertension , number of previous antihypertensive drugs , number of affected parents , and blood pressure ( BP ) levels , and profiles during placebo periods . RESULTS The median BP responses in 24-h ambulatory recordings ( systolic/diastolic ) were 11/8 mm Hg for bisoprolol , 9/6 mm Hg for losartan , 7/5 mm Hg for amlodipine , and 5/2 mm Hg for hydrochlorothiazide . The highest pairwise within-subject correlations in BP responses were seen for the combinations of bisoprolol-losartan and amlodipine-hydrochlorothiazide . The BP responses to bisoprolol and losartan did not vary according to the variables .  Amlodipine and hydrochlorothiazide responses were positively correlated with age , placebo BP level , and lower night-time dipping on placebo . CONCLUSIONS Baseline clinical and BP parameters may be used to predict the efficacy of antihypertensive therapies . The GENRES Study material should provide an excellent platform for future pharmacogenetic analyses of antihypertensive drug responsiveness Patients aged 60 years and older with essential hypertension were treated with an angiotensin-converting enzyme inhibitor ( ACE-I ) , delapril ( Adecut ) or a long-acting calcium (Ca)-antagonist , manidipine ( Calslot ) for 3 years . The incidences of cardiovascular events as well as drug-related side effects were compared between the two groups to investigate whether both classes of antihypertensive drugs are beneficial in elderly hypertensive patients . There were no significant differences in characteristics of patients between the two intervention groups , except for slightly lower blood pressure ( P = .08 ) in the Ca-antagonist group at the initiation of the study . There were no significant differences in total death between the two groups . Cardiovascular events ( both fatal and nonfatal ) were noted in 34 of 699 patients ( 22.5/1000 patient-years ) in the ACE-I group and 50 of 1049 patients ( 19.7/1000 patient-years ) in the Ca-antagonist group , with no significant difference found between the two groups . The correlation between cardiovascular incidence and the blood pressure attained during treatment showed a J-shaped phenomenon and suggests that an excessive reduction less than 120 mm Hg in systolic blood pressure ( SBP ) is unnecessary and may be harmful in certain cases . Side effects were more frequent in the ACE-I group than in the Ca-antagonist group ( P = .01 ) . Cough was the major adverse event , occurring in 5.0 % of patients in the ACE-I group . In conclusion , the study indicates that both ACE-I ( delapril ) and Ca-antagonist ( manidipine ) were equally beneficial for reducing cardiovascular morbidity and mortality in elderly hypertensive patients . However , tolerability of ACE-I was lower due to the adverse event of coughing
INTERPRETATION Drug-class effects on interindividual variation in blood pressure can account for differences in effects of antihypertensive drugs on risk of stroke independently of effects on mean SBP .
INTRODUCTION Unexplained differences between classes of antihypertensive drugs in their effectiveness in preventing stroke might be due to class effects on intraindividual variability in blood pressure .
We did a systematic review to assess any such effects in r and omised controlled trials .