Effect of antihypertensive treatment in isolated systolic hypertension (ISH) - systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Isolated systolic hypertension (ISH) in middle-aged and elderly is associated with high cardiovascular risk, but no randomised controlled trial has assessed the effect of antihypertensive treatment in ISH using today's definition, i.e. systolic blood pressure (SBP) ≥140 mmHg and diastolic blood pressure (DBP) <90 mmHg. METHODS: A systematic review and meta-analysis of randomised controlled trials was performed. Studies with ≥1000 patient-years of follow-up, comparing more intensive versus less intensive BP targets, or active drug versus placebo, were included if the mean baseline SBP was ≥140 mmHg and the mean baseline DBP was <90 mmHg. The primary outcome was major adverse cardiovascular events (MACE). Relative risks from each trial were pooled in random-effects meta-analyses, stratified by baseline and attained SBP level. RESULTS: Twenty-four trials, including 113,105 participants (mean age 67 years; mean blood pressure 149/83 mmHg) were included in the analysis. Overall, treatment reduced the risk of MACE by 9% (relative risk 0.91, 95% confidence interval 0.88-0.93). Treatment was more effective if baseline SBP was ≥160 mmHg (RR 0.77, 95% CIs 0.70-0.86) compared to 140-159 mmHg (RR 0.92, 95% CIs 0.89-0.95; p = 0.002 for interaction), but provided equal additional benefit across all attained SBP levels (RR 0.80, 95% CIs 0.70-0.92 for <130 mmHg, RR 0.92, 95% CIs 0.89-0.96 for 130-139 mmHg, and RR 0.87, 95% CIs 0.82-0.93 for ≥140 mmHg; p = 0.070 for interaction). CONCLUSIONS: These findings support antihypertensive treatment of isolated systolic hypertension, regardless of baseline SBP, to target SBP <140 mmHg and even <130 mmHg if well tolerated.

Aortic Root Dilatation in Hypertensive Patients with Left Ventricular Hypertrophy-Application of A New Multivariate Predictive Model. The Life Study.

BACKGROUND: Available nomograms to predict aortic root (AoR) diameter for body surface area have limitations. The purpose of this study was to evaluate the use of a new multivariate predictive model to identify AoR dilatation in hypertensive patients with left ventricular hypertrophy. METHODS: 943 of 961 patients in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiographic sub-study had the necessary baseline characteristics and echocardiographic 2D measurements of AoR size to be included. RESULTS: Predicted AoR (Sinus of Valsalva) diameter was 1.519 + (age [years] × 0.010) + (height [cm] × 0.010) - (gender [1 = M, 2 = F] × 0.247), and a measured AoR diameter exceeding the 97.5-percentile of this estimate was considered dilated. Measured AoR diameter was larger in men than in women (3.75 vs. 3.48 cm, p < 0.001) and AoR diameter predicted by the model was larger than predicted by nomogram (3.52 vs. 3.28 cm, p < 0.001). Using the multivariate model to identify patients with AoR dilatation, the prevalence was 13.7% in men and 12.3% in women (p = 0.537). There was consensus of AoR phenotype (normal/dilated) between model and nomogram in 92.8% of the patients. In multivariate logistic regression, AoR dilatation by model definition was predicted by presence of aortic regurgitation (OR 2.67, p < 0.001) and SD increase in age (OR 0.75, p = 0.023), pulse pressure (OR 0.64, p < 0.001), left ventricular mass index (OR 1.36, p = 0.08) and stroke volume (OR 1.45, p = 0.002), but not by body weight. CONCLUSIONS: Using the proposed model the prevalence of AoR dilatation was equal in men and women and the model seems to address the effects of gender, age and body size on AoR size. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00338260.

Diverse pharmacological properties, trial results, comorbidity prescribing and neural pathophysiology suggest European hypertension guideline downgrading of beta-blockers is not justified.

Beta-blockers have solid documentation in preventing cardiovascular complications in the treatment of hypertension; atenolol, metoprolol, oxprenolol and propranolol demonstrate proven cardiovascular prevention in hypertension mega-trials. Hypertension is characterised by activation of the sympathetic nervous system from early to late phases, which makes beta-blockers an appropriate treatment seen from a pathophysiological viewpoint, especially in patients with an elevated heart rate. Beta-blockers represent a heterogenous class of drugs with regard to both pharmacodynamic and pharmacokinetic properties. This position is manifest by reference to another clinical context, beta-blocker treatment of heart failure, where unequivocally there is no class effect (no similar benefit from all beta-blockers); there are good and less good beta-blockers for heart failure. Analogous differences in beta-blocker efficacy is also likely in hypertension. Beta-blockers are widely used for the treatment of diseases comorbid with hypertension, in approximately 50 different concomitant medical conditions that are frequent in patients with hypertension, leading to many de facto beta-blocker first choices in clinical practice. Thus, beta-blockers should be regarded as relevant first choices for hypertension in clinical practice, particularly if characterised by a long half-life, highly selective beta-1 blocking activity and no intrinsic agonist properties.SUMMARYBeta-blockers have solid documentation in preventing cardiovascular complications in the treatment of hypertension; atenolol, metoprolol, oxprenolol and propranolol demonstrate proven cardiovascular prevention in hypertension mega-trialsHypertension is characterised by activation of the sympathetic nervous system from early to late phases, which makes beta-blockers an appropriate treatment seen from a pathophysiological viewpoint, especially in patients with an elevated heart rateBeta-blockers represent a heterogenous class of drugs with regard to both pharmacodynamic and pharmacokinetic propertiesThis position is manifest by reference to another clinical context, beta-blocker treatment of heart failure, where unequivocally there is no class effect (no similar benefit from all beta-blockers); there are good and less good beta-blockers for heart failureAnalogous differences in beta-blocker efficacy is also likely in hypertensionBeta-blockers are widely used for the treatment of diseases comorbid with hypertension, in approximately 50 different concomitant medical conditions that are frequent in patients with hypertension, leading to many de facto beta-blockers first choices in clinical practiceThese observations, in totality, inform our opinion that beta-blockers are relevant first choices for hypertension in clinical practice and this fact needs highlightingFurther, these arguments suggest European hypertension guideline downgrading of beta-blockers is not justified.

Smoking and overweight associated with masked uncontrolled hypertension: a Hypertension Optimal Treatment (HOT) Sub-Study.

PURPOSE: The Hypertension Optimal Treatment (HOT) Study investigated the relationship between target office diastolic blood pressure (BP) ≤80, ≤85 or ≤90 mmHg and cardiovascular morbidity and mortality in 18,790 patients aged 50-80 years. The home BP sub-study enrolled 926 patients and the aim was to clarify whether the separation into the BP target groups in the office prevailed in the out-of-office setting. The present study aimed to identify variables that characterised masked uncontrolled hypertension (MUCH) and white coat uncontrolled hypertension (WUCH). MATERIAL AND METHODS: The sub-study participants took their home BP when office BP had been up titrated. The cut-off for normal or high BP was set to ≥135/85 mmHg at home and ≥140/90 mmHg in the office. We analysed data by using multivariate and stepwise multivariate logistic regression with home and office BP combinations as the dependent variables. RESULTS: WUCH was associated with lower body mass index (BMI) (odds ratio (OR) 0.92, 95% confident intervals (CIs) 0.88-0.96, p < 0.001). MUCH was associated with smoking (OR 1.89, 95% CIs 1.25-2.86, p = 0.0025) and with lower baseline heart rate (OR 0.98, 95% CIs 0.97-0.99, p = 0.03) and higher BMI (OR 1.03, CIs 1.00-1.06, p = 0.04). MUCH remained associated with smoking (OR 2.76, 95% CIs 1.76-4.35, p < 0.0001) also when using ≥140/90 mmHg as the cut-off for both home and office BP. MUCH was also associated with higher BMI (OR 1.05, 95% CIs 1.01-1.09, p = 0.009) while WUCH was associated with lower BMI (OR 0.93, 95% CIs 0.90-0.97, p = 0.0005) when using ≥140/90 mmHg as a cut-off. CONCLUSION: Our data support that 'reversed or masked' treated but uncontrolled hypertension (MUCH) is common and constitutes about 25% of treated hypertensive patients. This entity (MUCH) is rather strongly associated with current smoking and overweight while uncontrolled white coat (office) hypertension (WUCH) is associated with lower BMI.

Cardiovascular outcomes at recommended blood pressure targets in middle-aged and elderly patients with type 2 diabetes mellitus and hypertension.

PURPOSE: Available data of event-based clinical outcomes trials show that little evidence supports the guidelines recommendations to lower blood pressure (BP) to <130/80 mmHg in middle-aged and elderly people with type 2 diabetes mellitus and hypertension. We addressed this issue by post-hoc analysing the risk of cardiovascular (CV) events in mostly elderly high-risk hypertensive patients with type 2 diabetes mellitus participating in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial. MATERIAL AND METHODS: Patients (n = 5250) were divided into 4 groups according to the proportion of on-treatment visits before the occurrence of an event (<25% to ≥ 75%) in which BP was reduced to <140/90 or <130/80 mmHg. RESULTS: After adjustment for baseline demographic differences between groups, a reduction in the proportion of visits in which BP achieved <140/90 mmHg accompanied a progressive increase in the risk of CV mortality and morbidity as well as of cause-specific events such as stroke, myocardial infarction and heart failure. A progressive reduction in the proportion of visits in which BP was reduced <130/80 mmHg did not have any effect on CV risks. CONCLUSION: In mostly elderly high-risk hypertensive patients with type 2 diabetes mellitus participating in the VALUE trial, achieving more frequently BP <140/90 mmHg showed a marked protective effect on overall and all cause-specific cardiovascular outcomes. This was not the case for a more frequent achievement of the more intensive BP target, i.e. <130/80 mmHg.

Cardiovascular outcomes at recommended blood pressure targets in middle-aged and elderly patients with type 2 diabetes mellitus compared to all middle-aged and elderly hypertensive study patients with high cardiovascular risk.

PURPOSE: Event-based clinical outcome trials have shown limited evidence to support guidelines recommendations to lower blood pressure (BP) to <130/80 mmHg in middle-aged and elderly hypertensive patients with diabetes mellitus or with general high cardiovascular (CV) risk. We addressed this issue by post-hoc analysing the risk of CV events in patients who participated in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial and compared the hypertensive patients with type 2 diabetes mellitus with all high-risk hypertensive patients. MATERIALS AND METHODS: Patients were divided into 4 groups according to the proportion of on-treatment visits before the occurrence of an event (<25% to ≥75%) in which BP was reduced to <140/90 or <130/80 mmHg. Patients with diabetes mellitus (n = 5250) were compared with the entire VALUE population with high CV risk (n = 15,245). RESULTS: After adjustments for baseline differences between groups, a reduction in the proportion of visits in which BP was reduced to <140/90 mmHg, but not to <130/80 mmHg, was accompanied by a progressive increase in the risk of CV morbidity and mortality as well as stroke, myocardial infarction and heart failure in both diabetes mellitus and in all high-risk patients. Target BP <130/80 mmHg reduced stroke risk in the main population but not in the diabetes mellitus patients. Patients with diabetes mellitus had higher event rates for the primary cardiac endpoint and all-cause mortality driven by a higher rate of heart failure. CONCLUSION: In the high-risk hypertensive patients of the VALUE trial achieving more frequently BP <140/90 mmHg, but not <130/80 mmHg, showed principally the same protective effect on overall and cause-specific cardiovascular outcomes in patients with diabetes mellitus and in the general high-risk hypertensive population.

On-treatment HDL cholesterol predicts incident atrial fibrillation in hypertensive patients with left ventricular hypertrophy.

Purpose: Hypertensive patients are at increased risk of atrial fibrillation (AF). Although low baseline high density lipoprotein (HDL) cholesterol has been associated with a higher risk of AF, this has not been verified in recent population-based studies. Whether changing levels of HDL over time are more strongly related to the risk of new AF in hypertensive patients has not been examined.Material and methods: Incident AF was examined in relation to baseline and on-treatment HDL levels in 8267 hypertensive patients with no history of AF, in sinus rhythm on their baseline electrocardiogram, randomly assigned to losartan- or atenolol-based treatment. HDL levels at baseline and each year of testing were categorised into quartiles according to baseline HDL levels.Results: During 4.7 ± 1.10 years of follow-up, 645 patients (7.8%) developed new AF. In univariate Cox analyses, compared with the highest quartile of HDL levels (>1.78 mmol/l), patients with on-treatment HDL in the lowest quartile (≤ 1.21 mmol/l) had a 53% greater risk of new AF. Patients with on-treatment HDL in the second and third quartiles had intermediate increased risks of AF. Baseline HDL in the lowest quartile was not a significant predictor of new AF (hazard ratio (HR): 1.14, 95% confidence interval (CI): 0.90-1.43). In multivariable Cox analyses adjusting for multiple baseline and time-varying covariates, the lowest quartile of on-treatment HDL remained associated with a nearly 54% increased risk of new AF (HR: 1.54, 95% CI: 1.16-2.05) whereas a baseline HDL≤ ⩽1.21 mmol/l was not predictive of new AF (HR: 1.01, 95% CI: 0.78-1.31).Conclusion: Lower on-treatment HDL is strongly associated with risk of new AF. These findings suggest that serial assessment of HDL can estimate AF risk better than baseline HDL in hypertensive patients with left ventricular hypertrophy. Future studies may investigate whether therapies that increase HDL can lower risk of developing AF.Clinical Trials Registration: http://clinicaltrials.gov/ct/show/NCT00338260?order=1.

Ten-year prediction of cardiovascular disease in healthy Norwegian men, based on NORRISK-2. / Tiårsprediksjon av hjerte- og karsykdom hos friske norske menn basert på NORRISK-2.

BACKGROUND: Norwegian guidelines for primary prevention of cardiovascular disease recommend the use of the NORRISK-2 risk model, with some additions. We wished to investigate whether NORRISK-2 could predict cardiovascular disease in healthy Norwegian men who took part in the Oslo Ischaemia Study. MATERIAL: NORRISK-2 scores were calculated for 2 014 men in the age group 40-60 years who were included in the Oslo Ischaemia Study in 1972-75. Cox regression analyses were used to calculate the hazard ratio for death and cardiovascular disease within ten years of the participants' initial assessment. RESULTS: No participant was lost to follow-up of the 2 014 men, 125 died in the first ten years after inclusion, 61 of whom died from cardiovascular disease. Those who died were older than those who survived, with a larger proportion of daily smokers, and they had higher systolic blood pressure and resting pulse, increased total cholesterol and lower physical fitness. The majority of those who died from acute myocardial infarction and ischaemic stroke within ten years were classified in the high-risk group in NORRISK-2. INTERPRETATION: NORRISK-2 satisfactorily identified the high-risk persons in this cohort of healthy, middle-aged Norwegian men. This supports use of the Norwegian guidelines in the decision on possible primary protection against cardiovascular disease.

Association of left bundle branch block with new onset abnormal wall motion in treated hypertensive patients with left ventricle hypertrophy: the LIFE Echo Sub-study.

AIMS: We aimed to investigate whether left bundle branch block (LBBB) is related to new-onset left ventricle (LV) wall motion abnormalities during treatment in hypertensive patients with electrocardiographic (ECG) defined left ventricular hypertrophy (LVH). METHODS AND RESULTS: 960 patients with essential hypertension and ECG-LVH participating in the LIFE Echo Sub-study were investigated at baseline and annually with echocardiography, during randomized antihypertensive therapy. After excluding patients with LV wall motion abnormalities at baseline and patients developing new-onset LBBB during study time, we investigated 784 patients. The participants with (n = 32) and without (n = 752) LBBB were similar regarding most baseline variables. Logistic regression models controlling for LV mass index, Framingham risk score, and randomized treatment assignment were used to assess the odds ratio of developing new-onset abnormal LV wall motion on annual follow-up echocardiograms. The likelihood of developing new global LV wall motion abnormalities in patients with LBBB was not higher compared to those without LBBB except at year 5 (p = .002). The likelihood of developing new segmental LV wall motion abnormalities in patients with LBBB was however higher compared to patients without LBBB after 1 year (OR = 3.1, 95% CI = 0.7-14.2, p = .173); 2 years (OR = 6.9, 2.1-22.4, p = .003); 3 years (OR = 5.3, 2.0-14.3, p < .001), 4 years (OR = 4.0, 1.6-10.3, p = .003 and 5 years (OR = 4.1, 1.0-16.2, p = .394) of treatment. CONCLUSION: Among patients with ECG-LVH, undergoing antihypertensive treatment, the presence of LBBB independently identifies individuals with ∼3- to 7-fold greater odds of developing new segmental abnormal LV wall motion. These findings suggest that LBBB may be a marker for progressive myocardial disease.

Antihypertensive therapy prevents new-onset atrial fibrillation in patients with isolated systolic hypertension: the LIFE study.

Aims: Atrial fibrillation (AF) is associated with increased cardiovascular risk and the incidence increases with age, hypertension and left ventricular hypertrophy (LVH). Reducing in-treatment systolic blood pressure (SBP) prevents new-onset AF but has previously not been studied in patients with isolated systolic hypertension (ISH). We aimed to investigate the effect on preventing new-onset AF by decreased in-treatment SBP in patients with ISH compared to patients with non-ISH. Methods and results: Double-blind, randomized, parallel-group study of 1320 patients with ISH and electrocardiographic (ECG) LVH, included among the 9193 patients in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Annual ECGs were Minnesota coded centrally, and new-onset AF was evaluated in 1248 ISH patients and compared with 7583 non-ISH patients during mean 4.8 ± 0.9 years follow-up. Cox regression analyses were used to assess the effect of reduced in-treatment SBP. New-onset AF occurred in 61 (4.9%) ISH patients and 292 (3.9%) non-ISH patients. In multivariate analysis lower in-treatment SBP was associated with 17% risk reduction (p = 0.008) for new-onset AF in ISH patients and 9% risk reduction (p = 0.006) in non-ISH patients per 10 mmHg decrease in in-treatment SBP, independent of treatment modality, baseline risk factors, baseline SBP and in-treatment heart rate and ECG-LVH. There was a significant interaction (p = 0.041) in favor of SBP reduction and AF prevention in ISH vs. non-ISH patients. Conclusion: Our data suggest that the effect of in-treatment SBP reduction in preventing new-onset AF is stronger in ISH compared to non-ISH patients with hypertension and ECG-LVH. However, the principal findings were the same in ISH and non-ISH patients.

Blood pressure variability and risk of cardiovascular events and death in patients with hypertension and different baseline risks.

Aims: Blood pressure variability is associated with increased risk of cardiovascular events, particularly in high-risk patients. We assessed if variability was associated with increased risk of cardiovascular events and death in hypertensive patients at different risk levels. Methods and results: The Valsartan Antihypertensive Long-term Use Evaluation trial was a randomized controlled trial of valsartan vs. amlodipine in patients with hypertension and different risks of cardiovascular events, followed for a mean of 4.2 years. We calculated standard deviation (SD) of mean systolic blood pressure from visits from 6 months onward in patients with ≥3 visits and no events during the first 6 months. We compared the risk of cardiovascular events in the highest and lowest quintile of visit-to-visit blood pressure variability, using Cox regression. For analysis of death, variability was analysed as a continuous variable. Of 13 803 patients included, 1557 (11.3%) had a cardiovascular event and 1089 (7.9%) died. Patients in the highest quintile of SD had an increased risk of cardiovascular events [hazard ratio (HR) 2.1, 95% confidence interval (95% CI) 1.7-2.4; P < 0.0001], and a 5 mmHg increase in SD of systolic blood pressure was associated with a 10% increase in the risk of death (HR 1.10, 95% CI 1.04-1.17; P = 0.002). Associations were stronger among younger patients and patients with lower systolic blood pressure, and similar between patients with different baseline risks, except for higher risk of death among patients with established cardiovascular disease. Conclusion: Higher visit-to-visit systolic blood pressure variability is associated with increased risk of cardiovascular events in patients with hypertension, irrespective of baseline risk of cardiovascular events. Associations were stronger in younger patients and in those with lower mean systolic blood pressure.

Heart failure with preserved ejection fraction. / Hjertesvikt med normal ejeksjonsfraksjon.

BACKGROUND: Approximately one half of all patients with heart failure have normal ejection fraction in the left ventricle, and heart failure is attributed to stiffness of the cardiac muscle. The most common cause is hypertension with ventricular hypertrophy. MATERIAL AND METHOD: Literature searches were conducted in PubMed. After we made our selection, a total of 15 articles on heart failure with normal ejection fraction were included. In addition, we included nine articles from our own literature archive. RESULTS: The diagnosis of heart failure with normal ejection fraction presupposes clinical findings consistent with heart failure and objective signs of diastolic dysfunction. The main objective sign is increased left ventricular filling pressure estimated by echocardiography. Ventricular hypertrophy and increased natriuretic peptides support the diagnosis. INTERPRETATION: Underlying conditions and symptoms are treated, and in general the same drugs are used as for heart failure with reduced ejection fraction.

Hypertension and cardiovascular risk: General aspects.

Hypertension is the strongest or one of the strongest risk factors for almost all different cardiovascular diseases acquired during life, including coronary disease, left ventricular hypertrophy and valvular heart diseases, cardiac arrhythmias including atrial fibrillation, cerebral stroke and renal failure. The continuous relationship between blood pressure and cardiovascular and renal events makes the distinction between high normal blood pressure and hypertension based on arbitrary cut-off values for blood pressures. Overall the prevalence of hypertension in different European countries appears to be around 30-45% of the general population, with a steep increase with ageing. The prevention of cardiovascular disease and treatment recommendations should be related to quantification of total cardiovascular risk which could be estimated from several different models. However the impact of age on risk is so strong that young adults (particularly women) are unlikely to reach high-risk levels even when they have more than one major risk factor and a clear increase in relative risk. Therefore age-adjusted models, models assessing relative risks compared to others of same age and models including thorough assessments of target organ damage and ambulatory 24h blood pressure are needed together with national models because of the large variations between countries.

The Un-Observed Automated Office Blood Pressure Measurement Technique Used in the SPRINT Study Points to a Standard Target Office Systolic Blood Pressure <140 mmHg.

The SPRINT study investigators used the un-observed automated office blood pressure measurement technique. When their achieved systolic blood pressure is corrected, target systolic blood pressure for most people remains unchanged: <140mmHg for prevention of cardiovascular diseases and death.