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Background and Purpose: In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients., Methods: Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150-180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130-140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) treatment. All patients were followed up for functional status and serious adverse events to 90 days. Logistic regression models were used to analyze 3 SBP summary measures postrandomization: attained (mean), variability (SD) in 1-24 hours, and magnitude of reduction in 1 hour. The primary outcome was a favorable shift on the modified Rankin Scale. The key safety outcome was any intracranial hemorrhage., Results: Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71-0.82]; P <0.001 and 0.86 [95% CI, 0.76-0.98]; P =0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93-1.04]; P =0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06-1.31]; P =0.002 and 1.34 [1.11-1.62]; P =0.002) but not with magnitude of SBP reduction (1.05 [0.98-1.14]; P =0.184)., Conclusions: Attaining early and consistent low levels in SBP <140 mm Hg, even as low as 110 to 120 mm Hg, over 24 hours is associated with better outcomes in thrombolyzed acute ischemic stroke patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01422616.

[Figure: see text].

Background: Randomised evidence on the efficacy of blood pressure (BP)-lowering treatment to reduce cardiovascular risk in patients with atrial fibrillation (AF) is limited. Therefore, this study aimed to compare the effects of BP-lowering drugs in patients with and without AF at baseline., Methods and Findings: The study was based on the resource provided by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC), in which individual participant data (IPD) were extracted from trials with over 1,000 patient-years of follow-up in each arm, and that had randomly assigned patients to different classes of BP-lowering drugs, BP-lowering drugs versus placebo, or more versus less intensive BP-lowering regimens. For this study, only trials that had collected information on AF status at baseline were included. The effects of BP-lowering treatment on a composite endpoint of major cardiovascular events (stroke, ischaemic heart disease or heart failure) according to AF status at baseline were estimated using fixed-effect one-stage IPD meta-analyses based on Cox proportional hazards models stratified by trial. Furthermore, to assess whether the associations between the intensity of BP reduction and cardiovascular outcomes are similar in those with and without AF at baseline, we used a meta-regression. From the full BPLTTC database, 28 trials (145,653 participants) were excluded because AF status at baseline was uncertain or unavailable. A total of 22 trials were included with 188,570 patients, of whom 13,266 (7%) had AF at baseline. Risk of bias assessment showed that 20 trials were at low risk of bias and 2 trials at moderate risk. Meta-regression showed that relative risk reductions were proportional to trial-level intensity of BP lowering in patients with and without AF at baseline. Over 4.5 years of median follow-up, a 5-mm Hg systolic BP (SBP) reduction lowered the risk of major cardiovascular events both in patients with AF (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.83 to 1.00) and in patients without AF at baseline (HR 0.91, 95% CI 0.88 to 0.93), with no difference between subgroups. There was no evidence for heterogeneity of treatment effects by baseline SBP or drug class in patients with AF at baseline. The findings of this study need to be interpreted in light of its potential limitations, such as the limited number of trials, limitation in ascertaining AF cases due to the nature of the arrhythmia and measuring BP in patients with AF., Conclusions: In this meta-analysis, we found that BP-lowering treatment reduces the risk of major cardiovascular events similarly in individuals with and without AF. Pharmacological BP lowering for prevention of cardiovascular events should be recommended in patients with AF., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KR is an academic editor on PLOS Medicine’s editorial board and has in the past received personal fees as Speciality Consulting Editor for PLOS Medicine. KR is also in receipt of personal fees as Associate Editor for BMJ Heart.MW reports personal fees from Amgen, Kyowa Kirin, and Freeline outside the submitted work; JS reports ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer, Bayer, Pfizer and AstraZeneca, outside the submitted work. Group authors listed in the acknowledgements have no known competing interests.

Objectives: Evidence about sex differences in blood pressure (BP) at the time of acute stroke presentation is scarce. We aimed to summarize available data on sex differences in BP at the time of acute stroke presentation, including stratification by prior history of hypertension and stroke subtype., Methods: We performed a systematic literature search across MEDLINE and Embase, from inception to 21 December 2018, to identify all population-based observational studies that reported BP at the time of acute stroke presentation. We extracted data on patient demographics, stroke-type (ischaemic or haemorrhagic), stroke severity, vascular risk factors, and SBP and DBP at the time of stroke presentation. Wherever possible, data were pooled for meta-analysis with weighted mean difference (WMD) and corresponding 95% confidence intervals (CI) using random effects meta-analysis., Results: We included 128 138 stroke patients from 43 studies. Women had higher SBP at presentation than men (WMD, 1.46; 95% CI, 0.65-2.26); this difference was significant in ischaemic stroke (1.49; 0.25-2.72 mmHg), but not in intracerebral haemorrhage (0.19; -4.21 to 4.59 mmHg). Meta regression show that sex differences in SBP were consistent with increasing age, stroke severity, other comorbidities and medication history., Conclusion: This systematic review and meta-analysis indicates that women have higher SBP at the time of presentation with acute stroke. These differences are consistent with sex differences in hypertension patterns in older age, and may be explained by the fact that women are more likely to have a premorbid hypertension. This highlights the need for effective sex-specific blood pressure control in patients at high risk for stroke.

Background and Purpose: An early elevation in blood pressure (BP) is common after spontaneous intracerebral hemorrhage (ICH), has various potential causes, and is predictive of poor outcome. We aimed to determine the predictors of this phenomenon, in pooled analyses of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials [INTERACT1 (n = 404) and INTERACT2 (n = 2829)]., Methods: INTERACT trials were international, open, blinded endpoint, randomized controlled trials of patients with spontaneous ICH (<6 h) and elevated SBP (150-220 mmHg) assigned to intensive (target SBP < 140 mmHg) or guideline-recommended (SBP < 180 mmHg) treatment. Multivariable linear and logistic regression models were used to determine associations between baseline variables and the high admission BP, with continuous and binary SBP measures, respectively., Results: Among 3233 patients (mean age 63 years; 37% female; baseline mean SBP 179 mmHg), both analytic approaches showed significant positive associations of high admission BP with history of hypertension, admission hyperglycemia at least 6.5 mmol/l, elevated heart rate, and greater neurological severity (National Institutes of Health Stroke Scale scores); and significant negative associations with prior use of antithrombotic agents and longer time from onset to randomization., Conclusion: The high admission BP of mild-to-moderate acute ICH is related to autonomic nervous system activated 'stress' rather than hematoma location and mass effect., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00226096 and NCT00716079.

The optimal blood pressure (BP) goal in patients with diabetes mellitus remains controversial. We examined whether benefits and risks of intensified antihypertensive therapy in diabetes mellitus are influenced by either baseline BP or cardiovascular disease (CVD) risk. We studied 10 948 people with diabetes mellitus, at moderate-to-high risk, in the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation). Cox models were used to determine whether baseline BP category or CVD risk modified the outcomes of combination perindopril-indapamide treatment, compared with placebo. During 4.3 years of follow-up, treatment with perindopril-indapamide versus placebo reduced mortality and major vascular (macrovascular or microvascular) events. There was no evidence of differences in these effects, regardless of baseline systolic BP (evaluated down to <120 mm Hg; P for heterogeneity, 0.85), diastolic BP (evaluated down to <70 mm Hg; P=0.49), or whether 10-year CVD risk was ≥20% or <20% ( P=0.08). The effects of randomized treatment on discontinuation of treatment because of cough or hypotension/dizziness were also statistically consistent across subgroups defined by baseline BP and CVD risk (all P ≥0.08). Adults with diabetes mellitus appear to benefit from more intensive BP treatment even at levels of BP and CVD risk that some guidelines do not currently recommend for intervention. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00751972.

Background: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke., Methods: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616., Findings: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome., Interpretation: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group., Funding: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Discontinuation of angiotensin-converting enzyme (ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum creatinine after starting this therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum creatinine are unclear. In the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), 11 140 diabetes mellitus patients were randomly assigned to perindopril-indapamide or placebo after a 6-week active run-in period. The current study included 11 066 participants with 2 serum creatinine measurements recorded before and during the active run-in period (3 weeks apart). Acute increase in creatinine was determined using these 2 measurements and classified into 4 groups: increases in serum creatinine of <10%, 10% to 19%, 20% to 29%, and ≥30%. The primary study outcome was the composite of major macrovascular events, new or worsening nephropathy, and all-cause mortality. An acute increase in serum creatinine was associated with an elevated risk of the primary outcome ( P for trend <0.001). The hazard ratios were 1.11 (95% CI, 0.97-1.28) for those with an increase of 10% to 19%, 1.34 (1.07-1.66) for 20% to 29%, and 1.44 (1.15-1.81) for ≥30%, compared with <10%. However, there was no evidence of heterogeneity in the benefit of randomized treatment effects on the outcome across subgroups defined by acute serum creatinine increase ( P for heterogeneity=0.94). Acute increases in serum creatinine after starting perindopril-indapamide were associated with greater risks of subsequent major clinical outcomes. However, the continuation of angiotensin-converting enzyme inhibitor-based therapy reduced the long-term risk of major clinical outcomes, irrespective of acute increase in creatinine. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00145925.

Objective: To determine the concordance in the prevalence of hypertension and pharmacological antihypertensive treatment recommendations for U.S. adults with diabetes using definitions from the 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guideline and the 2017 American Diabetes Association (ADA) diabetes and hypertension position statement., Research Design and Methods: We analyzed data for U.S. adults with diabetes in the U.S. National Health and Nutrition Examination Survey (NHANES), 2011-2016 ( n = 2,266). Diabetes was defined by treatment with glucose-lowering medication, glycosylated hemoglobin ≥6.5%, fasting serum glucose ≥126 mg/dL, or nonfasting serum glucose ≥200 mg/dL. BP was measured three times and antihypertensive medication use was self-reported., Results: The prevalence (95% CI) of hypertension among U.S. adults with diabetes was 77.1% (73.9, 80.0) and 66.3% (63.4, 69.1) according to the ACC/AHA and ADA definitions, respectively. Also, 22.9% (20.0, 26.1) did not have hypertension according to either definition, and the concordance in hypertension status was 89.2% (87.2, 91.0). Among U.S. adults with diabetes not taking antihypertensive medication, 52.8% (47.7, 57.8) were not recommended to initiate antihypertensive medication by either the ACC/AHA or the ADA document and 22.4% (19.2, 25.9) were recommended to initiate it by both documents (overall concordance 75.2% [70.4, 79.4]). Among those taking antihypertensive medication, 45.3% (41.3, 49.4) and 50.4% (46.5, 54.2) had BP above the goal in neither and both documents, respectively (overall concordance 95.7% [93.4, 97.2])., Conclusions: A high percentage of U.S. adults with diabetes are provided identical antihypertensive treatment recommendations by the ACC/AHA BP guideline and the ADA diabetes and hypertension position statement., (© 2018 by the American Diabetes Association.)

Background: Clinical practice guidelines have traditionally recommended blood pressure treatment based primarily on blood pressure thresholds. In contrast, using predicted cardiovascular risk has been advocated as a more effective strategy to guide treatment decisions for cardiovascular disease (CVD) prevention. We aimed to compare outcomes from a blood pressure-lowering treatment strategy based on predicted cardiovascular risk with one based on systolic blood pressure (SBP) level., Methods and Findings: We used individual participant data from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) from 1995 to 2013. Trials randomly assigned participants to either blood pressure-lowering drugs versus placebo or more intensive versus less intensive blood pressure-lowering regimens. We estimated 5-y risk of CVD events using a multivariable Weibull model previously developed in this dataset. We compared the two strategies at specific SBP thresholds and across the spectrum of risk and blood pressure levels studied in BPLTTC trials. The primary outcome was number of CVD events avoided per persons treated. We included data from 11 trials (47,872 participants). During a median of 4.0 y of follow-up, 3,566 participants (7.5%) experienced a major cardiovascular event. Areas under the curve comparing the two treatment strategies throughout the range of possible thresholds for CVD risk and SBP demonstrated that, on average, a greater number of CVD events would be avoided for a given number of persons treated with the CVD risk strategy compared with the SBP strategy (area under the curve 0.71 [95% confidence interval (CI) 0.70-0.72] for the CVD risk strategy versus 0.54 [95% CI 0.53-0.55] for the SBP strategy). Compared with treating everyone with SBP ≥ 150 mmHg, a CVD risk strategy would require treatment of 29% (95% CI 26%-31%) fewer persons to prevent the same number of events or would prevent 16% (95% CI 14%-18%) more events for the same number of persons treated. Compared with treating everyone with SBP ≥ 140 mmHg, a CVD risk strategy would require treatment of 3.8% (95% CI 12.5% fewer to 7.2% more) fewer persons to prevent the same number of events or would prevent 3.1% (95% CI 1.5%-5.0%) more events for the same number of persons treated, although the former estimate was not statistically significant. In subgroup analyses, the CVD risk strategy did not appear to be more beneficial than the SBP strategy in patients with diabetes mellitus or established CVD., Conclusions: A blood pressure-lowering treatment strategy based on predicted cardiovascular risk is more effective than one based on blood pressure levels alone across a range of thresholds. These results support using cardiovascular risk assessment to guide blood pressure treatment decision-making in moderate- to high-risk individuals, particularly for primary prevention.

Objective: To assess the relationship between risk factor clusters and cardiovascular disease (CVD) incidence in Asian and Caucasian populations and to estimate the burden of CVD attributable to each cluster., Setting: Asia Pacific Cohort Studies Collaboration., Participants: Individual participant data from 34 population-based cohorts, involving 314 024 participants without a history of CVD at baseline., Outcome Measures: Clusters were 11 possible combinations of four individual risk factors (current smoking, overweight, blood pressure (BP) and total cholesterol). Cox regression models were used to obtain adjusted HRs and 95% CIs for CVD associated with individual risk factors and risk factor clusters. Population-attributable fractions (PAFs) were calculated., Results: During a mean follow-up of 7 years, 6203 CVD events were recorded. The ranking of HRs and PAFs was similar for Australia and New Zealand (ANZ) and Asia; clusters including BP consistently showed the highest HRs and PAFs. The BP-smoking cluster had the highest HR for people with two risk factors: 4.13 (3.56 to 4.80) for Asia and 3.07 (2.23 to 4.23) for ANZ. Corresponding PAFs were 24% and 11%, respectively. For individuals with three risk factors, the BP-smoking-cholesterol cluster had the highest HR (4.67 (3.92 to 5.57) for Asia and 3.49 (2.69 to 4.53) for ANZ). Corresponding PAFs were 13% and 10%., Conclusions: Risk factor clusters act similarly on CVD risk in Asian and Caucasian populations. Clusters including elevated BP were associated with the highest excess risk of CVD., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Both sodium reduction and the Dietary Approaches to Stop Hypertension (DASH) diet lower blood pressure (BP); however, the patterns of their effects on BP over time are unknown. In the DASH-Sodium trial, adults with pre-/stage 1 hypertension, not using antihypertensive medications, were randomly assigned to either a typical American diet (control) or DASH. Within their assigned diet, participants randomly ate each of 3 sodium levels (50, 100, and 150 mmol/d, at 2100 kcal) over 4-week periods. BP was measured weekly for 12 weeks; 412 participants enrolled (57% women; 57% black; mean age, 48 years; mean systolic BP [SBP]/diastolic BP [DBP], 135/86 mm Hg). For those assigned control, there was no change in SBP/DBP between weeks 1 and 4 on the high-sodium diet (weekly change, -0.04/0.06 mm Hg/week) versus a progressive decline in BP on the low-sodium diet (-0.94/-0.70 mm Hg/week; P interactions between time and sodium <0.001 for SBP and DBP). For those assigned DASH, SBP/DBP changed -0.60/-0.16 mm Hg/week on the high- versus -0.42/-0.54 mm Hg/week on the low-sodium diet ( P interactions between time and sodium=0.56 for SBP and 0.10 for DBP). When comparing DASH to control, DASH changed SBP/DBP by -4.36/-1.07 mm Hg after 1 week, which accounted for most of the effect observed, with no significant difference in weekly rates of change for either SBP ( P interaction=0.97) or DBP ( P interaction=0.70). In the context of a typical American diet, a low-sodium diet reduced BP without plateau, suggesting that the full effects of sodium reduction are not completely achieved by 4 weeks. In contrast, compared with control, DASH lowers BP within a week without further effect thereafter., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000608., (© 2017 American Heart Association, Inc.)

Background: Mitral regurgitation in people without prior cardiac disease is considered a degenerative disease with no established risk factors for its prevention. We aimed to test the hypothesis that elevated systolic blood pressure (SBP) across its usual spectrum is associated with higher risk of mitral regurgitation., Methods and Findings: We used linked electronic health records from the United Kingdom Clinical Practice Research Datalink (CPRD) from 1 January 1990 to 31 December 2015. CPRD covers approximately 7% of the current UK population and is broadly representative of the population by age, sex, and ethnicity. About 5.5 million UK patients with no known cardiovascular or valve disease at baseline were included in this cohort study. We investigated the relationship between blood pressure (BP) and risk of mitral regurgitation using Cox regression models. Our primary exposure variable was SBP and our primary outcome was incident reports of mitral regurgitation, which were identified from hospital discharge reports or primary care records. Of the 5,553,984 patients in the CPRD that met our inclusion criteria, during the 10-year follow-up period, 28,655 (0.52%) were diagnosed with mitral regurgitation and a further 1,262 (0.02%) were diagnosed with mitral stenosis. SBP was continuously related to the risk of mitral regurgitation with no evidence of a nadir down to 115 mmHg (p < 0.001). Each 20 mmHg increment in SBP was associated with a 26% higher risk of mitral regurgitation (hazard ratio [HR] 1.26; CI 1.23, 1.29). The observed association was partially mediated by diseases affecting the left ventricle during follow-up (myocardial infarction [MI], ischaemic heart disease [IHD], cardiomyopathy, and heart failure). However, the percentage of excess risk mediated (PERM) by these proximate causes of secondary mitral regurgitation was only 13% (CI 6.1%, 20%), and accounting for them had little effect on the long-term association between SBP and mitral regurgitation (mediator-adjusted HR 1.22; CI 1.20, 1.25; p < 0.001). Associations were similar for each 10 mmHg increment in diastolic blood pressure (DBP) (p < 0.001) or each 15 mmHg increment in pulse pressure (PP) (p < 0.001). By contrast, there was no association between SBP and risk of mitral stenosis (HR per 20 mmHg higher SBP 1.03; CI 0.93, 1.14; p = 0.58). These analyses are based on routinely collected data from health records which may be sensitive to measurement errors, and the observed associations may not be generalizable to less severe and subclinical cases of mitral regurgitation., Conclusions: Long-term exposure to elevated BP across its whole spectrum is associated with an increased risk of primary and secondary mitral regurgitation. These findings suggest that BP control may be of importance in the prevention of mitral regurgitation.

There is a critical need for blood pressure-lowering strategies that have greater efficacy and minimal side effects. Low-dose combinations hold promise in this regard, but there are few data on very-low-dose therapy. We, therefore, conducted a systematic review and meta-analysis of randomized controlled trials with at least one quarter-dose and one placebo and standard-dose monotherapy arm. A search was conducted of Medline, Embase, Cochrane Registry, Food and Drug Administration, and European Medicinal Agency websites. Data on blood pressure and adverse events were pooled using a fixed-effect model, and bias was assessed using Cochrane risk of bias. The review included 42 trials involving 20 284 participants. Thirty-six comparisons evaluated quarter-dose with placebo and indicated a blood pressure reduction of -4.7/-2.4 mm Hg ( P <0.001). Six comparisons were of dual quarter-dose therapy versus placebo, observing a -6.7/ -4.4 mm Hg ( P <0.001) blood pressure reduction. There were no trials of triple quarter-dose combination versus placebo, but one quadruple quarter-dose study observed a blood pressure reduction of -22.4/-13.1 mm Hg versus placebo ( P <0.001). Compared with standard-dose monotherapy, the blood pressure differences achieved by single (37 comparisons), dual (7 comparisons), and quadruple (1 trial) quarter-dose combinations were +3.7/+2.6 ( P <0.001), +1.3/-0.3 (NS), and -13.1/-7.9 ( P <0.001) mm Hg, respectively. In terms of adverse events, single and dual quarter-dose therapy was not significantly different from placebo and had significantly fewer adverse events compared with standard-dose monotherapy. Quarter-dose combinations could provide improvements in efficacy and tolerability of blood pressure-lowering therapy., (© 2017 American Heart Association, Inc.)

Background: Although elevated blood pressure is associated with an increased risk of atrial fibrillation (AF), it is unclear if this association varies by individual characteristics. Furthermore, the associations between AF and a range of different vascular events are yet to be reliably quantified., Methods: Using linked electronic health records, we examined the time to first diagnosis of AF and time to first diagnosis of nine vascular events in a cohort of 4.3 million adults, aged 30 to 90 years, in the UK., Results: : A 20-mmHg higher usual systolic blood pressure was associated with a higher risk of AF [hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.19, 1.22]. The strength of the association declined with increasing age, from an HR of 1.91 (CI 1.75, 2.09) at age 30-40 to an HR of 1.01 (CI 0.97, 1.04) at age 80-90 years. AF without antithrombotic use at baseline was associated with a greater risk of any vascular event than AF with antithrombotic usage ( P interaction < 0.0001). AF without baseline antithrombotic usage was associated with an increased risk of ischaemic heart disease (HR 2.52, CI 2.23, 2.84), heart failure (HR 3.80, CI 3.50, 4.12), ischaemic stroke (HR 2.72, CI 2.19, 3.38), unspecified stroke (HR 2.59, CI 2.25, 2.99), haemorrhagic stroke, chronic kidney disease, peripheral arterial disease and vascular dementia, but not aortic aneurysm., Conclusions: The association between elevated blood pressure and AF attenuates with increasing age. AF without antithrombotic usage is associated with an increased risk of eight vascular events., (© The Author 2016. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Ephrin B2 (EFNB2) is a ligand for erythropoietin-producing hepatocellular kinases (EPH), the largest family of receptor tyrosine kinases. It has critical functions in many biological systems, but is not known to regulate blood pressure. We generated mice with a smooth muscle cell (SMC)-specific deletion of EFNB2 and investigated its roles in blood pressure regulation and vascular SMC (VSMC) contractility. Male Efnb2 knockout (KO) mice presented reduced blood pressure, whereas female KO mice had no such reduction. Both forward signaling from EFNB2 to EPHs and reverse signaling from EPHs to EFNB2 were involved in regulating VSMC contractility, with EPHB4 serving as a critical molecule for forward signaling, based on crosslinking studies. We also found that a region from aa 313 to aa 331 in the intracellular tail of EFNB2 was essential for reverse signaling regulating VSMC contractility, based on deletion mutation studies. In a human genetic study, we identified five SNPs in the 3' region of the EFNB2 gene, which were in linkage disequilibrium and were significantly associated with hypertension for male but not female subjects, consistent with our findings in mice. The coding (minor) alleles of these five SNPs were protective in males. We have thus discovered a previously unknown blood pressure-lowering mechanism mediated by EFNB2 and identified EFNB2 as a gene associated with hypertension risk in humans.

Background and Purpose: Vascular dementia is the second most common form of dementia but reliable evidence on age-specific associations between blood pressure (BP) and risk of vascular dementia is limited and some studies have reported negative associations at older ages., Methods: In a cohort of 4.28 million individuals, free of known vascular disease and dementia and identified from linked electronic primary care health records in the United Kingdom (Clinical Practice Research Datalink), we related BP to time to physician-diagnosed vascular dementia. We further determined associations between BP and dementia in a prospective population-based cohort of incident transient ischemic attack and stroke (Oxford Vascular Study)., Results: For a median follow-up of 7.0 years, 11 114 initial presentations of vascular dementia were observed in the primary care cohort after exclusion of the first 4 years of follow-up. The association between usual systolic BP and risk of vascular dementia decreased with age (hazard ratio per 20 mm Hg higher systolic BP, 1.62; 95% confidence interval, 1.13-2.35 at 30-50 years; 1.26, 1.18-1.35 at 51-70 years; 0.97, 0.92-1.03 at 71-90 years; P trend=0.006). Usual systolic BP remained predictive of vascular dementia after accounting for effect mediation by stroke and transient ischemic attack. In the population-based cohort, prior systolic BP was predictive of 5-year risk of dementia with no evidence of negative association at older ages., Conclusions: BP is positively associated with risk of vascular dementia, irrespective of preceding transient ischemic attack or stroke. Previous reports of inverse associations in old age could not be confirmed., (© 2016 American Heart Association, Inc.)

Background: Recent hypertension guidelines have reversed previous recommendations for lower blood pressure targets in high-risk patients, such as those with cardiovascular disease, renal disease, or diabetes. This change represents uncertainty about whether more intensive blood pressure-lowering strategies are associated with greater reductions in risk of major cardiovascular and renal events. We aimed to assess the efficacy and safety of intensive blood pressure-lowering strategies., Methods: For this updated systematic review and meta-analysis, we systematically searched MEDLINE, Embase, and the Cochrane Library for trials published between Jan 1, 1950, and Nov 3, 2015. We included randomised controlled trials with at least 6 months' follow-up that randomly assigned participants to more intensive versus less intensive blood pressure-lowering treatment, with different blood pressure targets or different blood pressure changes from baseline. We did not use any age or language restrictions. We did a meta-analysis of blood pressure reductions on relative risk (RR) of major cardiovascular events (myocardial infarction, stroke, heart failure, or cardiovascular death, separately and combined), and non-vascular and all-cause mortality, end-stage kidney disease, and adverse events, as well as albuminuria and progression of retinopathy in trials done in patients with diabetes., Findings: We identified 19 trials including 44,989 participants, in whom 2496 major cardiovascular events were recorded during a mean 3·8 years of follow-up (range 1·0-8·4 years). Our meta-analysis showed that after randomisation, patients in the more intensive blood pressure-lowering treatment group had mean blood pressure levels of 133/76 mm Hg, compared with 140/81 mm Hg in the less intensive treatment group. Intensive blood pressure-lowering treatment achieved RR reductions for major cardiovascular events (14% [95% CI 4-22]), myocardial infarction (13% [0-24]), stroke (22% [10-32]), albuminuria (10% [3-16]), and retinopathy progression (19% [0-34]). However, more intensive treatment had no clear effects on heart failure (15% [95% CI -11 to 34]), cardiovascular death (9% [-11 to 26]), total mortality (9% [-3 to 19]), or end-stage kidney disease (10% [-6 to 23]). The reduction in major cardiovascular events was consistent across patient groups, and additional blood pressure lowering had a clear benefit even in patients with systolic blood pressure lower than 140 mm Hg. The absolute benefits were greatest in trials in which all enrolled patients had vascular disease, renal disease, or diabetes. Serious adverse events associated with blood pressure lowering were only reported by six trials and had an event rate of 1·2% per year in intensive blood pressure-lowering group participants, compared with 0·9% in the less intensive treatment group (RR 1·35 [95% CI 0·93-1·97]). Severe hypotension was more frequent in the more intensive treatment regimen (RR 2·68 [1·21-5·89], p=0·015), but the absolute excess was small (0·3% vs 0·1% per person-year for the duration of follow-up)., Interpretation: Intensive blood pressure lowering provided greater vascular protection than standard regimens. In high-risk patients, there are additional benefits from more intensive blood pressure lowering, including for those with systolic blood pressure below 140 mmHg. The net absolute benefits of intensive blood pressure lowering in high-risk individuals are large., Funding: National Health and Medical Research Council of Australia., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Several simple clinical grading scores have been developed for intracerebral hemorrhage, primarily to predict 30-day mortality., Aims: We aimed to determine the accuracy of three popular scores (original intracerebral hemorrhage, modified intracerebral hemorrhage, and intracerebral hemorrhage grading scale) on 30-day mortality and 90-day death or major disability, and whether the magnitude of benefit varies according to prognosis graded by the three predictive scores., Methods: Data from the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial which included 2839 intracerebral hemorrhage patients (<6 hours) and elevated systolic blood pressure (150-220 mmHg), randomized to intensive (target systolic blood pressure <140 mmHg) or guideline-based (<180 mmHg) blood pressure management. Discrimination of scales for predicting death and poor outcome (modified Rankin scale 3-6) was evaluated in area under receiver operator characteristic curves., Results: Among 2556 (90%) participants with available data, the modified intracerebral hemorrhage had the highest discrimination (receiver operator characteristic 0·75) for 90-day poor outcome compared with the original intracerebral hemorrhage (receiver operator characteristic 0·68) and intracerebral hemorrhage grading scale (receiver operator characteristic 0·69). All scores had good positive predictive value (approximately 80-90%) for poor outcome but poor sensitivity and positive predictive value for death. The scores do not clearly discriminate a patient group most likely to benefit from blood pressure lowering., Conclusions: Intracerebral hemorrhage prognostic scores are not useful in defining patients at high probability of early death, but they are reliable for predicting poor outcome, defined by death or major disability. Potential benefits of early intensive blood pressure lowering are broadly applicable across grades of severity defined by such scores., (© 2015 World Stroke Organization.)

Objectives: To determine the subgroup specific associations between usual blood pressure and risk of peripheral arterial disease, and to examine the relation between peripheral arterial disease and a range of other types of vascular disease in a large contemporary cohort., Design: Cohort study., Setting: Linked electronic health records from 1990 to 2013 in the United Kingdom., Participants: 4,222,459 people aged 30-90 years, registered at a primary care practice for at least one year and with a blood pressure measurement., Main Outcome Measures: Time to first diagnosis of new onset peripheral arterial disease and time to first diagnosis of 12 different vascular events., Results: A 20 mm Hg higher than usual systolic blood pressure was associated with a 63% higher risk of peripheral arterial disease (hazard ratio 1.63, 95% confidence interval 1.59 to 1.66). The strength of the association declined with increasing age and body mass index (P<0.001 for interaction) but was not modified by sex or smoking status. Peripheral arterial disease was associated with an increased risk of 11 different vascular events, including ischaemic heart disease (1.68, 1.58 to 1.79), heart failure (1.63, 1.52 to 1.75), aortic aneurysm (2.10, 1.79 to 2.45), and chronic kidney disease (1.31, 1.25 to 1.38), but not haemorrhagic stroke. The most common initial vascular event among those with peripheral arterial disease was chronic kidney disease (24.4% of initial events), followed by ischaemic heart disease (18.5% of initial events), heart failure (14.7%), and atrial fibrillation (13.2%). Overall estimates from this cohort were consistent with those derived from traditional studies when we pooled the findings in two meta-analyses., Conclusions: Raised blood pressure is a strong risk factor for peripheral arterial disease in a range of patient subgroups. Furthermore, clinicians should be aware that those with established peripheral arterial disease are at an increased risk of a range of other vascular events, including chronic kidney disease, ischaemic heart disease, heart failure, atrial fibrillation, and stroke., (© Emdin et al 2015.)

Unlabelled: Evidence supports early intensive blood pressure (BP) lowering in acute intracerebral hemorrhage, but uncertainty persists over whether potential benefits and harms vary according to the magnitude of BP reduction. We aimed to determine whether larger systolic BP (SBP) reductions were associated with better outcomes in participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). INTERACT2 was an international, open, blinded end point, randomized controlled trial of patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated SBP (150-220 mm Hg) assigned to intensive (target SBP <140 mm Hg) or guideline-recommended (SBP <180 mm Hg) treatment. Associations of BP reduction (baseline minus average of achieved SBP) during 3 time periods post randomization (15-60 minutes, 1-24 hours, and 2-7 days) on poor outcome (death or major disability) at 90 days were analyzed in multivariable logistic regression models with odds ratios and 95% confidence intervals. Larger SBP reductions within the first hour after randomization were associated with lower risks of poor outcome: compared with minimal reduction (<10 mm Hg), odds ratios were 0.80 (95% confidence interval, 0.63-1.02) for moderate (10-20 mm Hg) and 0.65 (0.52-0.82) for large (≥20 mm Hg) reductions (P trend <0.01). Similar associations were also observed for SBP reductions during 1 to 24 hours (P<0.01) and 2 to 7 days (P 0.02). No heterogeneity in associations for patients above or below baseline SBP 180 mm Hg was reported (P>0.30). Optimal recovery from intracerebral hemorrhage was observed in hypertensive patients who achieved the greatest SBP reductions (≥20 mm Hg) in the first hour and maintained for 7 days., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00716079., (© 2015 American Heart Association, Inc.)

Objectives: To investigate the effects of intensive blood pressure (BP) lowering according to baseline BP levels and optimal achieved BP levels in patients with acute intracerebral hemorrhage (ICH)., Methods: INTERACT2 was an open, blinded endpoint, randomized controlled trial in 2,839 patients with ICH within 6 hours of onset and elevated systolic BP (SBP) (150-220 mm Hg) who were allocated to receive intensive (target SBP <140 mm Hg within 1 hour, with lower limit of 130 mm Hg for treatment cessation) or guideline-recommended (target SBP <180 mm Hg) BP-lowering treatment. Outcome was physical function across all 7 levels of the modified Rankin Scale at 90 days., Results: Analysis of the randomized comparisons showed that intensive BP lowering produced comparable benefits on physical function at 90 days in 5 subgroups defined by baseline SBP of <160, 160-169, 170-179, 180-189, and ≥190 mm Hg (p homogeneity = 0.790). Analyses of achieved BP showed linear increases in the risk of physical dysfunction for achieved SBP above 130 mm Hg for both hyperacute (1-24 hours) and acute (2-7 days) phases while modest increases were also observed for achieved SBP below 130 mm Hg., Conclusions: Intensive BP lowering appears beneficial across a wide range of baseline SBP levels, and target SBP level of 130-139 mm Hg is likely to provide maximum benefit in acute ICH., Classification of Evidence: This study provides Class I evidence that the effect of intensive BP lowering on physical function is not influenced by baseline BP., (© 2014 American Academy of Neurology.)

Background and Purpose: Early intensive blood pressure (BP) lowering has been shown to improve functional outcome in acute intracerebral hemorrhage (ICH), but the treatment effect is modest and without a clearly defined underlying explanatory mechanism. We aimed at more reliably quantifying the benefits of this treatment according to different time periods in the recovery of participants in the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) studies., Methods: Pooled analysis of the pilot INTERACT1 (n = 404) and main INTERACT2 (n = 2,839) involving patients with spontaneous ICH (<6 h) and elevated systolic BP (SBP 150-220 mm Hg) who were randomized to intensive (target SBP <140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) BP lowering treatment. Treatment effects were examined according to repeated measures analysis of an ordinal ('shift') across all 7 levels of the modified Rankin Scale (mRS) assessed during follow-up at 7, 28, and 90 days, post-randomization., Clinical Trial Registration Information: http://www.clinicaltrials.gov, NCT00226096 and NCT00716079., Results: Intensive BP lowering resulted in a significant favorable distribution of mRS scores for better functioning (odds ratio 1.13, 95% confidence interval 1.00-1.26; p = 0.042) over 7, 28 and 90 days, and the effect was consistency for early (7-28 days) and later (28-90 days) time periods (p homogeneity 0.353). Treatment effects were also consistent across several pre-specified patient characteristic subgroups, with trends favoring those randomized early, and with higher SBP and milder neurological severity at baseline., Conclusions: Intensive BP lowering provides beneficial effects on physical functioning that manifests consistently through the early and later phases of recovery from ICH., (© 2015 S. Karger AG, Basel.)

Unlabelled: Blood pressure-lowering treatment reduces cardiovascular risk in patients with diabetes mellitus, but the effect varies between individuals. We sought to identify which patients benefit most from such treatment in a large clinical trial in type 2 diabetes mellitus. In Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) participants (n=11 140), we estimated the individual patient 5-year absolute risk of major adverse cardiovascular events with and without treatment by perindopril-indapamide (4/1.25 mg). The difference between treated and untreated risk is the estimated individual patient's absolute risk reduction (ARR). Predictions were based on a Cox proportional hazards model inclusive of demographic and clinical characteristics together with the observed relative treatment effect. The group-level effect of selectively treating patients with an estimated ARR above a range of decision thresholds was compared with treating everyone or those with a blood pressure >140/90 mm Hg using net benefit analysis. In ADVANCE, there was wide variation in treatment effects across individual patients. According to the algorithm, 43% of patients had a large predicted 5-year ARR of ≥1% (number-needed-to-treat [NNT5] ≤100) and 40% had an intermediate predicted ARR of 0.5% to 1% (NNT5=100-`200). The proportion of patients with a small ARR of ≤0.5% (NNT5≥200) was 17%. Provided that one is prepared to treat at most 200 patients for 5 years to prevent 1 adverse outcome, prediction-based treatment yielded the highest net benefit. In conclusion, a multivariable treatment algorithm can identify those individuals who benefit most from blood pressure-lowering therapy in terms of ARR of major adverse cardiovascular events and may be used to guide treatment decisions in individual patients with diabetes., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00145925., (© 2014 American Heart Association, Inc.)

Objective: There is ongoing controversy regarding a 'J-curve' phenomenon such that low and high blood pressure (BP) levels are associated with increased risks of recurrent stroke. We aimed to determine whether large treatment-related BP reductions are associated with increased risks of recurrent stroke., Design: Data are from the PROGRESS trial, where 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril ± indapamide) or placebo(s). There were no BP criteria for entry. BP was measured at every visit, and participant groups defined by reduction in systolic BP (SBP) from baseline were used for the analyses. Outcome was recurrent stroke., Results: During a mean follow-up of 3.9 years, 727 recurrent strokes were observed. There were clear associations between the magnitude of SBP reduction and the risk of recurrent stroke. After adjustment for cardiovascular risk factors and randomised treatment, annual incidence was 2.08%, 2.10%, 2.31% and 2.96% for participant groups defined by SBP reductions of ≥ 20, 10-19, 0-9 and <0 mm Hg, respectively (p=0.0006 for trend)., Conclusions: The present analysis provided no evidence of an increase in recurrent stroke associated with larger reductions in SBP produced by treatment among patients with cerebrovascular disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: High blood pressure is a prognostic factor for acute stroke, but blood pressure variability might also independently predict outcome. We assessed the prognostic value of blood pressure variability in participants of INTERACT2, an open-label randomised controlled trial (ClinicalTrials.gov number NCT00716079)., Methods: INTERACT2 enrolled 2839 adults with spontaneous intracerebral haemorrhage (ICH) and high systolic blood pressure (150-220 mm Hg) without a definite indication or contraindication to early intensive treatment to reduce blood pressure. Participants were randomly assigned to intensive treatment (target systolic blood pressure <140 mm Hg within 1 h using locally available intravenous drugs) or guideline-recommended treatment (target systolic blood pressure <180 mm Hg) within 6 h of onset of ICH. The primary outcome was death or major disability at 90 days (modified Rankin Scale score ≥3) and the secondary outcome was an ordinal shift in modified Rankin Scale scores at 90 days, assessed by investigators masked to treatment allocation. Blood pressure variability was defined according to standard criteria: five measurements were taken in the first 24 h (hyperacute phase) and 12 over days 2-7 (acute phase). We estimated associations between blood pressure variability and outcomes with logistic and proportional odds regression models. The key parameter for blood pressure variability was standard deviation (SD) of systolic blood pressure, categorised into quintiles., Findings: We studied 2645 (93·2%) participants in the hyperacute phase and 2347 (82·7%) in the acute phase. In both treatment cohorts combined, SD of systolic blood pressure had a significant linear association with the primary outcome for both the hyperacute phase (highest quintile adjusted OR 1·41, 95% CI 1·05-1·90; ptrend=0·0167) and the acute phase (highest quintile adjusted OR 1·57, 95% CI 1·14-2·17; ptrend=0·0124). The strongest predictors of outcome were maximum systolic blood pressure in the hyperacute phase and SD of systolic blood pressure in the acute phase. Associations were similar for the secondary outcome (for the hyperacute phase, highest quintile adjusted OR 1·43, 95% CI 1·14-1·80; ptrend=0·0014; for the acute phase OR 1·46, 95% CI 1·13-1·88; ptrend=0·0044)., Interpretation: Systolic blood pressure variability seems to predict a poor outcome in patients with acute intracerebral haemorrhage. The benefits of early treatment to reduce systolic blood pressure to 140 mm Hg might be enhanced by smooth and sustained control, and particularly by avoiding peaks in systolic blood pressure., Funding: National Health and Medical Research Council of Australia., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

There is unequivocal evidence that increased sodium intake is associated with increased blood pressure, and that increased blood pressure leads to increased risk of vascular diseases. Unfortunately, the published evidence directly linking sodium intake to vascular risk is inconsistent and confusing. This review, emphasising recent developments in national and international settings, considers why this is the case and how vested interests - particularly the food industry - have exploited the vacuum. We argue that legislation is the only tool that is likely to reverse the current situation wherein many millions of lives are put at risk through an unnecessary dietary additive, the reduction of which would be eminently feasible and have no conceivable disadvantage to health.

Background: Recent evidence suggests that visit-to-visit variability in systolic blood pressure (SBP) and maximum SBP are predictors of cardiovascular disease. However, it remains uncertain whether these parameters predict the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus., Methods and Results: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was a factorial randomized controlled trial of blood pressure lowering and blood glucose control in patients with type 2 diabetes mellitus. The present analysis included 8811 patients without major macrovascular and microvascular events or death during the first 24 months after randomization. SBP variability (defined as standard deviation) and maximum SBP were determined during the first 24 months after randomization. During a median 2.4 years of follow-up from the 24-month visit, 407 major macrovascular (myocardial infarction, stroke, or cardiovascular death) and 476 microvascular (new or worsening nephropathy or retinopathy) events were observed. The association of major macrovascular and microvascular events with SBP variability was continuous even after adjustment for mean SBP and other confounding factors (both P<0.05 for trend). Hazard ratios (95% confidence intervals) for the highest tenth of SBP variability were 1.54 (0.99-2.39) for macrovascular events and 1.84 (1.19-2.84) for microvascular events in comparison with the lowest tenth. For maximum SBP, hazard ratios (95% confidence intervals) for the highest tenth were 3.64 (1.73-7.66) and 2.18 (1.04-4.58), respectively., Conclusion: Visit-to-visit variability in SBP and maximum SBP were independent risk factors for macrovascular and microvascular complications in type 2 diabetes mellitus., Clinical Trial Registration Url: http://www.clinicaltrials.gov.

Aims: To asses differences in treatment effects of a fixed combination of perindopril-indapamide on major clinical outcomes in patients with type 2 diabetes across subgroups of cardiovascular risk., Methods: 11,140 participants with type 2 diabetes, from the ADVANCE trial, were randomized to perindopril-indapamide or matching placebo. The Framingham equation was used to calculate 5-year CVD risk and to divide participants into two risk groups, moderate-high risk (<25% and no history of macrovascular disease), very high risk (>25% and/or history of macrovascular disease). Endpoints were macrovascular and microvascular events., Results: The mean age of participants was 66 years (42.5% female). 1000 macrovascular and 916 microvascular events were recorded over follow-up of 4.3 years. Relative treatment effects were similar across risk groups, (all P-values for heterogeneity ≥0.38). Hazard ratios for combined macro- and microvascular events were 0.89 (0.77-1.03) for the moderate-high risk and 0.92 (0.81-1.03) for the very high risk. Absolute treatment effects tended to be greater in the high risk groups although differences were not statistically significant (P>0.05)., Conclusions: Relative effects of blood pressure lowering with perindopril-indapamide on cardiovascular outcomes were similar across risk groups whilst absolute effects trended to be greater in the high risk group., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: Few data have linked socioeconomic status (SES) to incident hypertension, and little information on the relationship between SES and hypertension are available from developing countries. We thus investigated the long-term effects of SES on incident hypertension and changes in blood pressure in Thailand., Methods: In 1985, baseline data were collected from 3499 participants in the Electricity Generating Authority of Thailand study. Participants were re-examined in 1997, 2002 and 2007. Logistic regression models, Cox-proportional hazard models and time-dependent covariates were used to calculate the relationship between SES and prevalent hypertension in 1985, incident hypertension in 1997 and 2007, respectively., Results: The prevalence of hypertension was 20% and the level of income, but not education, was inversely related to prevalent hypertension. Adjusting for several risk factors, compared to those who had tertiary education, participants who had primary education had 30% increased risk of incident hypertension in 1997 [hazard ratio 1.30, 95% confidence interval (CI) 1.09-1.54] and 20% in 2007 (1.20, 1.05-1.37); both P for trend was less than 0.01. Participants who had higher education also had substantially lower increments in SBP and DBP across 22 years (P < 0.0001 for SBP and P = 0.015 for DBP). Level of income was similarly negatively related to the progression of SBP, with a 3.6 mmHg difference between the highest income group and the lowest (P < 0.0001)., Conclusion: Hypertensive counseling and surveillance should be emphasized within socioeconomically disadvantaged populations.

Background and Purpose: Observational studies demonstrate strong associations between blood pressure and bleeding complications of antithrombotic therapy. The objective was to determine whether blood pressure lowering reduces risks of bleeding in patients on antithrombotic therapy., Methods: This is a subsidiary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial. A total of 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril ± indapamide) or placebo(s). The outcomes were intracranial and extracranial bleeding., Results: There were 4876 (80%) patients on antithrombotic therapy at baseline. Over a mean follow-up of 3.9 years, 119 intracranial and 123 extracranial bleeding events were observed. Among patients with and without antithrombotic therapy, active treatment lowered blood pressure by 8.9/4.0 and 9.3/3.8 mm Hg and reduced the risks of intracranial bleeding by 46% (95% CI, 7%-69%) and 70% (39%-85%), respectively. However, active treatment did not reduce the risks of extracranial bleeding significantly in either group. Among patients on antithrombotic therapy, the lowest risk of intracranial bleeding was observed in participants with the lowest follow-up systolic blood pressure levels (median, 113 mm Hg)., Conclusions: Blood pressure lowering provides protection against intracranial bleeding among patients with cerebrovascular disease including those receiving antithrombotic therapy.

Background and Purpose: Elevated blood pressure and excess body mass index (BMI) are established risk factors for cardiovascular disease (CVD) but controversy exists as to whether, and how, they interact., Methods: The interactions between systolic blood pressure and BMI on coronary heart disease, ischemic and hemorrhagic stroke and CVD were examined using data from 419 448 participants (≥ 30 years) in the Asia-Pacific region. BMI was categorized into 5 groups, using standard criteria, and systolic blood pressure was analyzed both as a categorical and continuous variable. Cox proportional hazard models, stratified by sex and study, were used to estimate hazard ratios, adjusting for age and smoking and the interaction was assessed by likelihood ratio tests., Results: During 2.6 million person-years of follow-up, there were 10 877 CVD events. Risks of CVD and subtypes increased monotonically with increasing systolic blood pressure in all BMI subgroups. There was some evidence of a decreasing hazard ratio, per additional 10 mm Hg systolic blood pressure, with increasing BMI, but the differences, although significant, are unlikely to be of clinical relevance. The hazard ratio for CVD was 1.34 (95% CI, 1.32-1.36) overall with individual hazard ratios ranging between 1.28 and 1.36 across all BMI groups. For coronary heart disease, ischemic stroke, and hemorrhagic stroke, the overall hazard ratios per 10 mm Hg systolic blood pressure were 1.24, 1.46, and 1.65, respectively., Conclusions: Increased blood pressure is an important determinant of CVD risk irrespective of BMI. Although its effect tends to be weaker in people with relatively high BMI, the difference is not sufficiently great to warrant alterations to existing guidelines.

Background: Guidelines recommend intensive blood pressure (BP) lowering in patients at high risk. While placebo-controlled trials have demonstrated 22% reductions in coronary heart disease (CHD) and stroke associated with a 10-mmHg difference in systolic BP, it is unclear if more intensive BP lowering strategies are associated with greater reductions in risk of CHD and stroke. We did a systematic review to assess the effects of intensive BP lowering on vascular, eye, and renal outcomes., Methods and Findings: We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and July 2011. We included trials that randomly assigned individuals to different target BP levels. We identified 15 trials including a total of 37,348 participants. On average there was a 7.5/4.5-mmHg BP difference. Intensive BP lowering achieved relative risk (RR) reductions of 11% for major cardiovascular events (95% CI 1%-21%), 13% for myocardial infarction (0%-25%), 24% for stroke (8%-37%), and 11% for end stage kidney disease (3%-18%). Intensive BP lowering regimens also produced a 10% reduction in the risk of albuminuria (4%-16%), and a trend towards benefit for retinopathy (19%, 0%-34%, p = 0.051) in patients with diabetes. There was no clear effect on cardiovascular or noncardiovascular death. Intensive BP lowering was well tolerated; with serious adverse events uncommon and not significantly increased, except for hypotension (RR 4.16, 95% CI 2.25 to 7.70), which occurred infrequently (0.4% per 100 person-years)., Conclusions: Intensive BP lowering regimens provided greater vascular protection than standard regimens that was proportional to the achieved difference in systolic BP, but did not have any clear impact on the risk of death or serious adverse events. Further trials are required to more clearly define the risks and benefits of BP targets below those currently recommended, given the benefits suggested by the currently available data.

Background and Purpose: Despite clear evidence that blood pressure (BP) lowering is effective for prevention of cardiovascular events among patients with isolated systolic hypertension and systolic-diastolic hypertension, there is ongoing uncertainty about its effects in those with isolated diastolic hypertension. The objective of the present analysis is to determine whether BP lowering provides benefits to patients with isolated diastolic hypertension., Methods: Patients with cerebrovascular disease and hypertension at baseline (n=4283) were randomly assigned to either active treatment (perindopril in all participants plus indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo(s). The primary outcome was total major vascular events., Results: There were 1923 patients with isolated systolic hypertension (systolic BP ≥ 140 mm Hg and diastolic BP < 90 mm Hg), 315 with isolated diastolic hypertension (systolic BP <140 mm Hg and diastolic BP ≥ 90 mm Hg), and 2045 with systolic-diastolic hypertension (systolic BP ≥ 140 mm Hg and diastolic BP ≥ 90 mm Hg) at baseline. Active treatment reduced the relative risk of major vascular events by 27% (95% CI, 10% to 41%) among patients with isolated systolic hypertension, by 28% (-29% to 60%) among those with isolated diastolic hypertension, and by 32% (17% to 45%) among those with systolic-diastolic hypertension. There was no evidence of differences in the magnitude of the effects of treatment among different types of hypertension (P homogeneity=0.89)., Conclusions: BP lowering is likely to provide a similar level of protection against major vascular events for patients with isolated diastolic hypertension as for those with isolated systolic hypertension and systolic-diastolic hypertension. Clinical Trial Registration Information- This trial was not registered because patients were enrolled before July 1, 2005.

Background: The benefits of reducing blood pressure are well established, but there remains uncertainty about whether the magnitude of the effect varies with the initial blood pressure level. The objective was to compare the risk reductions achieved by different blood pressure-lowering regimens among individuals with different baseline blood pressures., Methods: Thirty-two randomized controlled trials were included and seven comparisons between different types of treatments were made. For each comparison, the primary prespecified analysis included calculation of summary estimates of effect using random-effects meta-analysis for major cardiovascular events in four groups defined by baseline SBP (<140, 140-159, 160-179, and ≥ 180 mmHg)., Results: There were 201 566 participants among whom 20 079 primary outcome events were observed. There was no evidence of differences in the proportionate risk reductions achieved with different blood pressure-lowering regimens across groups defined according to higher or lower levels of baseline SBP (all P for trend > 0.17). This finding was broadly consistent for comparisons of different regimens, for DBP categories, and for commonly used blood pressure cut-points., Conclusion: It appears unlikely that the effectiveness of blood pressure-lowering treatments depends substantively upon starting blood pressure level. As the majority of patients in the trials contributing to these overviews had a history of hypertension or were receiving background blood pressure-lowering therapy, the findings suggest that additional blood pressure reduction in hypertensive patients meeting initial blood pressure targets will produce further benefits. More broadly, the data are supportive of the utilization of blood pressure-lowering regimens in high-risk patients with and without hypertension.

The pilot phase of the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT) showed that rapid blood pressure (BP) lowering can attenuate hematoma growth in acute intracerebral hemorrhage. We sought to define the systolic BP level associated with greatest attenuation of hematoma growth. INTERACT included 404 patients with computed tomographic-confirmed intracerebral hemorrhage, elevated systolic BP (150 to 220 mm Hg), and capacity to commence BP lowering treatment within 6 hours of onset. Computed tomography was done at baseline and at 24 hours using standardized techniques, with digital images analyzed centrally, blinded to clinical data. Associations of baseline and achieved on-treatment (mean during the first 24 hours) systolic BP levels with the primary outcome of increase in hematoma volume were explored. There were 346 patients with duplicate computed tomographic scans. There was no significant association between baseline systolic BP levels and either the absolute or proportional growth in hematoma volume (P trend=0.26 and 0.12, respectively). By contrast, achieved on-treatment systolic BP levels in the first 24 hours were clearly associated with both absolute and proportional hematoma growth (both P trend=0.03). Maximum reduction in hematoma growth occurred in the one third of participants with the lowest on-treatment systolic BP levels (median: 135 mm Hg). Intensive BP reduction to systolic levels between 130 and 140 mm Hg is likely to provide the maximum protection against hematoma growth after intracerebral hemorrhage.

Objective: The efficacy and safety of blood pressure lowering in elderly patients have not been sufficiently investigated in patients with diabetes. Using data from the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation study, we assessed the efficacy and safety of routine blood pressure lowering to prevent major clinical outcomes in elderly patients with type 2 diabetes., Methods: Eleven thousand one hundred and forty patients aged at least 55 years with type 2 diabetes (mean 66+/-6 years) were randomly assigned to perindopril-indapamide or placebo. The primary endpoint was a composite of major macrovascular and microvascular disease. The effects of active treatment on outcomes were estimated in subgroups according to age: below 65, 65-74 and at least 75 years., Results: During a mean 4.3-year follow-up, 1799 (16.1%) patients experienced a major event. Active treatment produced similar relative risk reductions for the primary outcome, major macrovascular disease, death and renal events across age groups (all P heterogeneity >0.3). Over 5 years, active treatment was estimated to prevent one primary outcome in every 21, 71 and 118 patients of at least 75, 65-74 and below 65 years, respectively. Similar patterns of benefits were observed for secondary outcomes. There were no differences in the tolerability between randomized allocations across age groups (all P heterogeneity >0.6), Conclusion: Routine administration of perindopril-indapamide lowers blood pressure safely and reduces the risk of major clinical outcomes in patients of at least 75 years with type 2 diabetes. The greater absolute benefits in older patients in this age group were not offset by an increased risk of side effects.

Chronic kidney disease is a major worldwide public health problem that causes substantial morbidity and mortality. Studies from the Asia-Pacific region have reported some of the highest chronic kidney disease prevalence rates in the world, but access to dialysis is limited in many countries, making it imperative to identify high-risk individuals. We performed a participant-level data overview of prospective studies conducted in the Asia-Pacific region to quantify the magnitude and direction of the associations between putative risk factors and renal death. Age- and sex-adjusted Cox proportional hazards models were applied to pooled data from 35 studies to calculate hazard ratios (95% CIs) for renal death associated with a standardized change in risk factors. Among 560 352 participants followed for a median of 6.8 years, a total of 420 renal deaths were observed. Continuous and positive associations among systolic blood pressure, diastolic blood pressure, fasting blood glucose, and total cholesterol levels with renal death were observed, as well as a continuous but inverse association with high-density lipoprotein cholesterol. Systolic blood pressure was the strongest risk factor for renal death with each SD increase in systolic blood pressure (19 mm Hg) associated with >80% higher risk (hazard ratio: 1.84; 95% CI: 1.60 to 2.12). Neither cigarette smoking nor excess weight was related to the risk of renal death (P>0.10). The results were similar for cohorts in Asia and Australia. These results suggest that primary prevention strategies for renal disease should focus on individuals with elevated blood pressure, diabetes mellitus, and dyslipidemia.

BP is an important determinant of kidney disease among patients with diabetes. The recommended thresholds to initiate treatment to lower BP are 130/80 and 125/75 mmHg for people with diabetes and nephropathy, respectively. We sought to determine the effects of lowering BP below these currently recommended thresholds on renal outcomes among 11,140 patients who had type 2 diabetes and participated in the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study. Patients were randomly assigned to fixed combination perindopril-indapamide or placebo, regardless of their BP at entry. During a mean follow-up of 4.3 yr, active treatment reduced the risk for renal events by 21% (P < 0.0001), which was driven by reduced risks for developing microalbuminuria and macroalbuminuria (both P < 0.003). Effects of active treatment were consistent across subgroups defined by baseline systolic or diastolic BP. Lower systolic BP levels during follow-up, even to <110 mmHg, was associated with progressively lower rates of renal events. In conclusion, BP-lowering treatment with perindopril-indapamide administered routinely to individuals with type 2 diabetes provides important renoprotection, even among those with initial BP <120/70 mmHg. We could not identify a BP threshold below which renal benefit is lost.

Background and Purpose: Smoking and increased levels of blood pressure (BP) substantially increase the risk of cardiovascular diseases (CVD). If these 2 risk factors have a synergistic impact on cardiovascular events, lowering BP and quitting smoking will contribute more to reducing CVD than would be expected from ignoring their interaction., Methods: Individual participant data were combined from 41 cohorts, involving 563 144 participants (82% Asian). During a median of 6.8 years follow-up, 4344 coronary heart disease (CHD) and 5906 stroke events were recorded. Repeat measures of systolic blood pressure (SBP) were used to adjust for regression dilution bias. Hazard ratios (HRs) and 95% confidence intervals (CIs) for SBP by cigarette smoking status were estimated from Cox proportional hazard models adjusted for age and stratified by study and sex., Results: Data suggested a log-linear relationship between SBP and all subtypes of CVD. The HRs relating SBP to both CHD and ischemic stroke were broadly similar irrespective of smoking status (P>/=0.1). For hemorrhagic stroke (intracerebral hemorrhage), the HRs (95% CIs) for an additional 10 mm Hg increment in SBP were 1.81 (1.73 to 1.90) for present smokers and 1.66 (1.59 to 1.73) for nonsmokers (P=0.003). For every subtype of cardiovascular events, similar results were found for analyses involving only fatal events., Conclusions: Smoking exacerbated the impact of SBP on the risk of hemorrhagic stroke. Although quitting smoking and lowering BP are both crucial for prevention of CVD, combining the 2 could be expected to have extra beneficial effect on preventing hemorrhagic stroke.

Background: The extent to which moderate overweight (body mass index [BMI], 25.0-29.9 [calculated as weight in kilograms divided by height in meters squared]) and obesity (BMI, >/= 30.0) are associated with increased risk of coronary heart disease (CHD) through adverse effects on blood pressure and cholesterol levels is unclear, as is the risk of CHD that remains after these mediating effects are considered., Methods: Relative risks (RRs) of CHD associated with moderate overweight and obesity with and without adjustment for blood pressure and cholesterol concentrations were calculated by the members of a collaboration of prospective cohort studies of healthy, mainly white persons and pooled by means of random-effects models (RRs for categories of BMI in 14 cohorts and for continuous BMI in 21 cohorts; total N = 302 296)., Results: A total of 18 000 CHD events occurred during follow-up. The age-, sex-, physical activity-, and smoking-adjusted RRs (95% confidence intervals) for moderate overweight and obesity compared with normal weight were 1.32 (1.24-1.40) and 1.81 (1.56-2.10), respectively. Additional adjustment for blood pressure and cholesterol levels reduced the RR to 1.17 (1.11-1.23) for moderate overweight and to 1.49 (1.32-1.67) for obesity. The RR associated with a 5-unit BMI increment was 1.29 (1.22-1.35) before and 1.16 (1.11-1.21) after adjustment for blood pressure and cholesterol levels., Conclusions: Adverse effects of overweight on blood pressure and cholesterol levels could account for about 45% of the increased risk of CHD. Even for moderate overweight, there is a significant increased risk of CHD independent of these traditional risk factors, although confounding (eg, by dietary factors) cannot be completely ruled out.

Background: Only limited data are available for risk factors for intracerebral haemorrhage (ICH) in subjects with established cerebrovascular disease., Design: We performed a nested case-control study of participants of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). This was a randomized, placebo-controlled trial that established the beneficial effects of blood pressure lowering in 6105 patients with cerebrovascular disease., Methods: Each of 41 subjects who experienced ICH during a mean follow-up of 3.9 years was matched to 1-3 control subjects. Lipoprotein particles and other plasma markers were measured in baseline blood samples from PROGRESS participants., Results: In comparison with control subjects, ICH cases had increased mean low-density lipoprotein (LDL) diameter (P=0.04) and increased large LDL particle concentration (P=0.03). The odds ratio (adjusted for regression dilution bias) for ICH risk with 10 mmHg increase in systolic blood pressure (SBP) was 1.45 (95% confidence interval: 1.01-2.09, P=0.05), with a 1 nm increase in mean LDL diameter it was 2.15 (95% confidence interval: 0.97-4.77, P=0.06), and with 100 nmol/l increase in large LDL particle concentration it was 1.18 (95% confidence interval: 0.98-1.43, P=0.08). Plasma levels of C-reactive protein (CRP), soluble vascular cell adhesion molecule 1 (sVCAM-1), homocysteine, amino-terminal-pro-B-type natriuretic peptide (NT-proBNP), and renin were not associated with ICH risk., Conclusion: SBP predicted ICH risk in subjects with cerebrovascular disease, whereas CRP, sVCAM-1, homocysteine, NT-proBNP, and renin did not predict ICH risk. The trends for prediction of ICH risk by mean LDL particle diameter and large LDL particle concentration are hypothesis generating and require confirmation in larger studies.

Objective: The plasma amino-terminal-pro-B-type natriuretic peptide (NT-proBNP) level predicted congestive heart failure, myocardial infarction, and ischaemic stroke in participants of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a placebo-controlled study of the effects of blood pressure lowering on cardiovascular events among individuals with cerebrovascular disease. Active treatment comprised a flexible regimen based on perindopril, with the addition of indapamide at the discretion of treating physicians. Active treatment reduced cardiovascular events, and we therefore investigated whether active treatment modified NT-proBNP and other cardiovascular risk factors., Methods: We measured NT-proBNP and other cardiovascular risk factors at randomization and after 13 months of therapy in a subset of 357 PROGRESS participants., Results: Baseline systolic and pulse pressures were higher in individuals with elevated baseline NT-proBNP levels. In comparison with placebo, active treatment reduced the blood pressure and NT-proBNP levels, and increased renin levels. Reduction of NT-proBNP levels by active treatment was most evident in individuals with baseline NT-proBNP levels in the highest quarter (> 26 pmol/l), with a median reduction of 16 pmol/l (interquartile range 0-51 pmol/l, P = 0.004), corresponding to a median decrease of 39% (interquartile range 0-69%). Active treatment reduced blood pressure similarly for individuals in each of the four quarters of baseline NT-proBNP. Active therapy had no effect on plasma lipid, C-reactive protein, homocysteine, or soluble vascular cell adhesion molecule 1 levels., Conclusion: We conclude that plasma NT-proBNP level, in addition to predicting cardiovascular risk, may provide a measure of risk reduction by blood pressure-lowering therapy.

Objective: To explore the likely optimum blood pressure (BP) level for patients with a history of cerebrovascular disease., Methods: The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a randomized, placebo-controlled trial that established the beneficial effects of BP lowering in 6105 patients with cerebrovascular disease. The present study comprises two series of post hoc analyses. The first was designed to investigate the effects of randomized treatment on recurrent stroke by baseline BP levels, and the second was a corresponding observational analysis investigating the association between achieved follow-up BP levels and recurrent stroke risk., Results: Analyses of the randomized treatment comparisons showed that BP lowering with combination therapy produced similar risk reductions in each of four subgroups defined by baseline BP of less than 120, 120-139, 140-159, and 160 mmHg or greater (P homogeneity = 0.5). The effects of single-drug therapy were also comparable across these subgroups (P homogeneity = 0.2), but consistently greater benefits were observed with combination compared to single-drug therapy. The analyses of achieved follow-up BP showed that the lowest risk of recurrence was among the one-quarter of participants with the lowest follow-up BP levels (median 112/72 mmHg), and that risks rose progressively with higher follow-up BP levels. Minor side-effects were progressively more common at lower BP levels (P homogeneity = 0.04), but there was no excess of serious complications (all P homogeneity > 0.2)., Conclusion: These analyses provide no evidence of a J-curve relationship between BP level and stroke risk among patients with cerebrovascular disease, and identify no patient group among whom more intensive BP lowering would not be expected to produce greater risk reductions.

Objective: Declining mean systolic and diastolic blood pressures were observed in most populations of the World Health Organization MONICA (monitoring trends and determinants in cardiovascular disease) project from the mid-1980s to mid-1990s. We tested whether pooled results would show mean change associated with decline in high readings only, resulting from better antihypertensive medication, or with similar falls in low, middle, and high readings, implying other causes., Design: Independent, random sample, cross sectional population surveys, each end of the MONICA decade., Setting: 38 populations in 21 countries across four continents., Participants: Design target in each survey of 200 participants in each 10 year age and sex group from age 35 to 64, Main Outcome Measures: Changes in the population in mean systolic and diastolic blood pressure, and in low, middle, and high readings-the 20th, 50th, and 80th centiles-and the differences between these changes., Results: Individual populations differed considerably, but pooling the 38 population results gave mean changes in systolic blood pressure of -2.2 mm Hg in men, -3.3 mm Hg in women, and in diastolic blood pressure of -1.4 mm Hg in men and -2.2 mm Hg in women (overall average -2.26 mm Hg, population median -1.55 mm Hg). Antihypertensive medication, associated with high readings, rose by 0.5% to 11.4%. However, average falls in low and middle blood pressure readings were so similar to those in high readings and in the mean that no effect from improving treatment of hypertension was detected. Results in contrasted subgroups were consistent., Conclusions: Blood pressure fell across 38 MONICA populations at all levels of readings, with no differential fall in high readings attributable to better control of hypertension. Despite the importance of medication to individuals, in that decade other determinants of blood pressure lowering must have been more pervasive and powerful in whole populations.

Background and Purpose: Patients with atrial fibrillation have a high risk of stroke and other vascular events even if anticoagulated. The primary objective here is to determine whether routine blood pressure-lowering provides additional protection for this high-risk patient group., Methods: This study was a subsidiary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS)--a randomized, placebo-controlled trial that established the beneficial effects of blood pressure--lowering in a heterogeneous group of patients with cerebrovascular disease. A total of 6105 patients were randomly assigned to either active treatment (2 to 4 mg perindopril for all participants plus 2.0 to 2.5 mg indapamide for those without an indication for or a contraindication to a diuretic) or matching placebo(s). Outcomes are total major vascular events, cause-specific vascular outcomes, and death from any cause., Results: There were 476 patients with atrial fibrillation at baseline, of whom 51% were taking anticoagulants. In these patients, active treatment lowered mean blood pressure by 7.3/3.4 mm Hg and was associated with a 38% (95% confidence interval [CI], 6 to 59) reduction in major vascular events and 34% (95% CI, -13 to 61) reduction in stroke. The benefits of blood pressure-lowering in patients with atrial fibrillation were achieved irrespective of the use of anticoagulant therapy (P homogeneity=0.8) or the presence of hypertension (P homogeneity=0.4)., Conclusions: For most patients with atrial fibrillation, routine blood pressure-lowering is likely to provide protection against major vascular events additional to that conferred by anticoagulation.

Background: The prevalence of white matter hyperintensities (WMHs) detected on cerebral MRI is associated with hypertension, but it is not known whether blood pressure lowering can arrest their progression. We report here the results of an MRI substudy of PROGRESS (Perindopril Protection Against Recurrent Stroke Study), a randomized trial of blood pressure lowering in subjects with cerebrovascular disease., Methods and Results: The substudy comprised 192 participants who had a cerebral MRI both at baseline and after a mean follow-up time of 36 months (SD=6.0 months). At the first MRI, WMHs were graded with a visual rating scale from A (no WMH) to D (severe WMH). Participants were assigned to a combination of perindopril plus indapamide (or their placebos; 58%) or to single therapy with perindopril (or placebo). At the time of the second MRI, the blood pressure reduction in the active arm compared with the placebo arm was 11.2 mm Hg for systolic blood pressure and 4.3 mm Hg for diastolic blood pressure. Twenty-four subjects (12.5%) developed new WMHs at follow-up. The risk of new WMH was reduced by 43% (95% CI -7% to 89%) in the active treatment group compared with the placebo group (P=0.17). The mean total volume of new WMHs was significantly reduced in the active treatment group (0.4 mm3 [SE=0.8]) compared with the placebo group (2.0 mm3 [SE=0.7]; P=0.012). This difference was greatest for patients with severe WMH at entry, 0.0 mm3 (SE=0) in the active treatment group versus 7.6 mm3 (SE=1.0) in the placebo group (P<0.0001)., Conclusions: These results indicate that an active blood pressure-lowering regimen stopped or delayed the progression of WMHs in patients with cerebrovascular disease.

Controversy persists as to whether reducing the blood pressure of patients with a history of stroke leads to an increased risk of silent brain infarct (SBI) and dementia. A total of 667 patients were randomized to receive the angiotensin-converting enzyme (ACE) inhibitor perindopril (4 mg daily), with or without the diuretic indapamide (2 mg daily) or matching placebo(s). Brain CT scanning was performed annually over the mean follow-up period of 3.9 years. Active treatment reduced the blood pressure (systolic/diastolic) by 5.2/2.6 mmHg over the follow-up period. A total of 119 new SBI were detected and 92% of them were lacunar type small infarcts. The frequency of reaching the primary end-point (recurrent symptomatic stroke or new SBI) was similar in the placebo group (26.5%) and in the active treatment group (25.9%). There was no significant difference in brain atrophy indices between two groups. In the subgroup with a history of large artery infarction, 7 out of 55 patients from the placebo group developed new SBI, while none of the 40 patients from the active treatment group did so (p = 0.020). The baseline diastolic blood pressure was significantly associated with the risk of new SBI (p = 0.004), but the stroke subtype was not. In conclusion, blood pressure-lowering with a perindopril-based regimen did not increase the risk of SBI and brain atrophy in patients with a history of stroke. The baseline diastolic blood pressure was an independent predictor of new SBI, but the index stroke subtype did not influence the risk of SBI.

The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene might have consequences for the risks of vascular diseases. We examined the ACE genotype and the effects of a perindopril-based blood pressure-lowering regimen on macrovascular events, dementia, and cognitive decline among hypertensive and nonhypertensive patients with a history of cerebrovascular disease. ACE I/D genotypes were measured in 5688 of 6105 individuals with previous stroke or transient ischemic attack who participated in the PROGRESS trial. The DD genotype was significantly (P<0.0001) less frequent in Asian subjects (Chinese and Japanese, 14.7%) than in non-Asian subjects (32.0%). Controlling for racial background, there were no associations between ACE genotypes and cerebrovascular disease history or cardiovascular risk factors, including baseline blood pressure. The ACE genotype was not associated with the long-term risks of stroke, cardiac events, mortality, dementia, or cognitive decline; neither did the ACE genotype predict the blood pressure reduction associated with the use of the ACE inhibitor perindopril. Similarly, there was no evidence that the ACE genotype modified the relative benefits of ACE inhibitor-based therapy over placebo. This study provides no evidence that in patients with cerebrovascular disease, knowledge of ACE genotype is useful for predicting either the risk of disease or the benefits of perindopril-based blood pressure-lowering treatment.