Assessment and management of exaggerated blood pressure response to standing and orthostatic hypertension: consensus statement by the European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability.

Recent evidence suggests that an exaggerated blood pressure (BP) response to standing (ERTS) is associated with an increased risk of adverse outcomes, both in young and old individuals. In addition, ERTS has been shown to be an independent predictor of masked hypertension. In the vast majority of studies reporting on the prognostic value of orthostatic hypertension (OHT), the definition was based only on systolic office BP measurements. This consensus statement provides recommendations on the assessment and management of individuals with ERTS and/or OHT. ERTS is defined as an orthostatic increase in SBP at least 20 mmHg and OHT as an ERTS with standing SBP at least 140 mmHg. This statement recommends a standardized methodology to assess ERTS, by considering body and arm position, and the number and timing of BP measurements. ERTS/OHT should be confirmed in a second visit, to account for its limited reproducibility. The second assessment should evaluate BP changes from the supine to the standing posture. Ambulatory BP monitoring is recommended in most individuals with ERTS/OHT, especially if they have high-normal seated office BP. Implementation of lifestyle changes and close follow-up are recommended in individuals with ERTS/OHT and normotensive seated office BP. Whether antihypertensive treatment should be administered in the latter is unknown. Hypertensive patients with ERTS/OHT should be managed as any other hypertensive patient. Standardized standing BP measurement should be implemented in future epidemiological and interventional studies.

Research strategies in treatment of hypertension: value of retrospective real-life data.

This review will discuss the limitations of data collected by RCTs in relation to their applicability to daily life clinical management. It will then argue that these limitations are only partially overcome by modifications of RCT design and conduction (e.g. 'pragmatic trials') while being substantially attenuated by real-life-derived research, which can fill many gaps left by trial-collected evidence and have thus an important complementary value. The focus will be on the real-life research approach based on the retrospective analysis of the now widely available healthcare utilization databases (formerly known as administrative databases), which will be discussed in detail for their multiple advantages as well as challenges. Emphasis will be given to the potential of these databases to provide low-cost information over long periods on many different healthcare issues, drug therapies in particular, from the general population to clinically important subgroups, including (i) prognostic aspects of treatments implemented at the medical practice level via hospitalization and fatality data and (ii) medical practice-related phenomena such as low treatment adherence and therapeutic inertia (unsatisfactorily evaluated by RCTs). It will also be mentioned that thanks to the current availability of these data in electronic format, results can be obtained quickly, helping timely decisions under emergencies. The potential shortcomings of this approach (confounding by indication, misclassification, and selection bias) will also be discussed along with their possible minimization by suitable analytic means. Finally, examples of the contributions of studies on hypertension and other cardiovascular risk factors will be offered based on retrospective healthcare utilization databases that have provided information on real-life cardiovascular treatments unavailable via RCTs.

An Unexpected Cause of Severe Hypertension and Bradycardia: The Role of Hemodynamic Assessment by Echocardiography.

Severe hypertension has numerous etiologies. When accompanied by bradycardia, the spectrum of differential diagnoses is greatly narrowed and is commonly seen in patients with increased intracranial pressure. However, other etiologies such as bradycardia-induced hypertension are rarely mentioned. Here we report the case of a 73-year-old woman presenting with symptoms of heart failure, severe hypertension, and bradycardia with a 2:1 atrioventricular block. Echocardiography demonstrated increased left ventricular filling secondary to bradycardia and prolonged diastole, leading to greater ventricular stretch, increased contractile force and greater stroke volume (Frank-Starling mechanism), which subsequently caused elevated systolic blood pressure (BP), low diastolic BP and a wide pulse pressure. Treating the bradycardia by pacing led to an immediate and substantial BP reduction, although complete BP normalization had a slower time course and was probably due to the concomitant effect of the antihypertensive treatment initiation. This pathophysiological mechanism has received little attention in the literature. Further, stimulation of sympathetic afferents located in the heart by distension of the cardiac walls as well as the role of vagally innervated cardiopulmonary receptors due to the increased pressure in the heart and the pulmonary artery should also be kept in mind as alternative hypotheses.

Cost-effectiveness of the adherence with recommendations for clinical monitoring of patients with diabetes.

BACKGROUND AND AIMS: To validate a set of indicators for monitoring the quality of care of patients with diabetes in 'real-life' practice through its relationship with measurable clinical outcomes and healthcare costs. METHODS AND RESULTS: A population-based cohort study was carried out by including the 20,635 patients, residents in the Lombardy Region (Italy), who in the year 2012 were newly taken-in-care for diabetes. Adherence with clinical recommendations (i.e., controls for glycated haemoglobin, lipid profile, urine albumin excretion and serum creatinine) was recorded during the first year after the patient was taken-in-care, and categorized according whether he/she complied with none or almost none (0 or 1), just some (2) or all or almost all (3 or 4) the recommendations, respectively denoted as poor, intermediate and high adherence. Short- and long-term complications of diabetes, and healthcare cost incurred by the National Health Service, were assessed during follow-up. Compared with patients with poor adherence, those with intermediate and high adherence respectively showed (i) a delay in outcome occurrence of 13 days (95% CI, -2 to 27) and 23 days (9-38), and (ii) a lower healthcare cost of 54 € and 77 €. In average, a gain of 18 Euros and 15 Euros for each day free from diabetic complication by increasing adherence respectively from poor to intermediate and from poor to high were observed. CONCLUSION: Close control of patients with diabetes through regular clinical examinations must be considered the cornerstone of national guidance, national audits, and quality improvement incentive schemes.

Comprehensive assessment of hypertensive heart disease: cardiac magnetic resonance in focus.

Arterial hypertension represents the most frequent cardiovascular risk factor that is associated with cardiac remodeling. Hypertensive heart disease was defined by the presence of left ventricular hypertrophy (LVH) and diastolic dysfunction, and it has been diagnosed by echocardiography in everyday clinical practice. Interstitial myocardial fibrosis is the underlying cause of hypertension-induced cardiac remodeling, and it could not be visualized with different echocardiographic methods. Cardiac magnetic resonance (CMR) and its methods such as late gadolinium enhancement, and T1 mapping provides qualitative and quantitative assessment of interstitial myocardial fibrosis in hypertensive patients. Furthermore, CMR can provide differentiation of LVH between hypertensive patients and cardiomyopathies (hypertrophic or Fabry disease). Timely diagnosis of cardiac impairment and early treatment is essential because regression of LVH could be achieved with adequate treatment. Diffuse cardiac fibrosis in hypertensive patients might be an underlying mechanism that explains the increased cardiovascular morbidity and mortality in this population. Future longitudinal investigations are necessary to determine causal relationship between diffuse fibrosis and cardiovascular outcome in these patients. The aim of this review is to summarize the current knowledge regarding CMR techniques and their potential usage in patients with hypertensive heart disease.

Left ventricular hypertrophy in isolated and dual masked hypertension.

Masked hypertension (MH) is defined as normal office blood pressure (BP) and elevated ambulatory BP (ABP) or home BP or both. This study assessed the association of MH (ie, isolated home, isolated ABP and dual MH) with echocardiographic left ventricular hypertrophy (LVH). The present analysis of the PAMELA study included 1087 untreated and treated participants with normal office BP and a measurable LV mass (LVM). A total of 193 individuals (17.7%) had any MH (ie, normal office BP, elevated ABP or home BP or both), 48 had dual MH (25%), 62 isolated ambulatory MH (32%), and 83 isolated home MH (43%). Average LVM indexed to body surface area was superimposable in the three MH phenotypes (being the largest difference between groups <3 g/m2 ) and significantly higher than in true normotensives. This was also for the LVH prevalence that varied across the MH subgroups in a narrow range (from 8.3% to 10.8%). In conclusion, individuals from the general population with isolated MH, in which either home or ABP was elevated, exhibited an increased risk of LVH similar to that entailed by dual MH. Our findings add the notion both home and ABP measurements are useful to more accurately assess the risk of LVH associated with MH in the community.

Incident Left Ventricular Hypertrophy in Masked Hypertension.

In the PAMELA study (Pressioni Arteriose Monitorate e Loro Associazioni), clinical variables, an echocardiogram, as well as office and ambulatory blood pressure (ABP) were simultaneously measured at baseline and after a 10-year follow-up. The study design allowed us to assess the value of masked hypertension (MH) as a predictor of new-onset left ventricular hypertrophy (LVH). The present analysis included 803 participants without LVH at baseline (left ventricular mass index <115 g/m2 in men and <100 g/m2 in women). Based on office and 24-hour mean ABP values, subjects were divided into 3 groups: normal subjects (normotensive, office blood pressure [BP] <140/90 mm Hg and 24-hour mean ABP <130/80 mm Hg), MH (office BP, normal, and 24-hour mean ABP, elevated), and sustained hypertension (office and 24-hour BP, both elevated). At entry, 57 of 803 subjects fulfilled diagnostic criteria for MH (7.1%); 182 participants developed LVH (22.6%). Compared with subjects with normal in-office and out-of-office BP, the risk of new-onset LVH was greater in MH (odds ratio, 2.22; CI, 1.11-4.46, P=0.0250) after adjustment for potential confounders. This was also the case for the absolute increase of left ventricular mass index. Our study provides a new piece of evidence that MH, identified by office and ABP values, is associated with an increased risk of new-onset LVH. Moreover, our findings convey the notion that office BP may inaccurately estimate the risk of incident LVH in the general population.

Acute Increases in Serum Creatinine After Starting Angiotensin-Converting Enzyme Inhibitor-Based Therapy and Effects of its Continuation on Major Clinical Outcomes in Type 2 Diabetes Mellitus.

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.

Initial Antihypertensive Treatment Strategies and Therapeutic Inertia.

In many hypertensive patients, treatment is not upgraded despite lack of blood pressure control because of therapeutic inertia. Information is limited, however, on the extent of this phenomenon in real-life medicine. We studied 125 635 patients (age 40-85 years) from the Lombardy region (Italy) who started antihypertensive treatment with 1 drug (n=100 982) or a 2-drug fixed-dose or free combination (n=24 653). A log-binomial regression model was used to estimate the prevalence ratio of combination therapy in relation to the initial treatment strategy. In the initial monotherapy group, patients under drug combinations were 22%, 27%, 32%, and 36% at 6 months, 1, 2, and 3 years later. In the initial combination treatment group, the corresponding percentages were 85%, 82%, 79%, and 78%. This translated into a markedly greater covariate-adjusted propensity of being under a multidrug prescription throughout the follow-up: 3.92 (95% CI, 3.84-4.00) after 6 months and 3.18 (3.12-3.25), 2.56 (2.51-2.60), and 2.23 (2.19-2.27) after 1, 2 and 3 years of treatment. In a propensity score analysis, initial 2-drug combination treatment was also associated with significant reductions in the risk of death (-20%, 11% to 28%) and hospitalization for cardiovascular events (-16%, 10% to 21%) compared with initial monotherapy. Thus, in real life, a large number of patients prescribed initial monotherapy fails to move to combination treatment, as recommended by guidelines. This implies that therapeutic inertia frequently prevents proper treatment uptitration, thereby playing a major role in the low rate of hypertension control that exists worldwide.

Developing and validating a novel multisource comorbidity score from administrative data: a large population-based cohort study from Italy.

OBJECTIVE: To develop and validate a novel comorbidity score (multisource comorbidity score (MCS)) predictive of mortality, hospital admissions and healthcare costs using multiple source information from the administrative Italian National Health System (NHS) databases. METHODS: An index of 34 variables (measured from inpatient diagnoses and outpatient drug prescriptions within 2 years before baseline) independently predicting 1-year mortality in a sample of 500 000 individuals aged 50 years or older randomly selected from the NHS beneficiaries of the Italian region of Lombardy (training set) was developed. The corresponding weights were assigned from the regression coefficients of a Weibull survival model. MCS performance was evaluated by using an internal (ie, another sample of 500 000 NHS beneficiaries from Lombardy) and three external (each consisting of 500 000 NHS beneficiaries from Emilia-Romagna, Lazio and Sicily) validation sets. Discriminant power and net reclassification improvement were used to compare MCS performance with that of other comorbidity scores. MCS ability to predict secondary health outcomes (ie, hospital admissions and costs) was also investigated. RESULTS: Primary and secondary outcomes progressively increased with increasing MCS value. MCS improved the net 1-year mortality reclassification from 27% (with respect to the Chronic Disease Score) to 69% (with respect to the Elixhauser Index). MCS discrimination performance was similar in the four regions of Italy we tested, the area under the receiver operating characteristic curves (95% CI) being 0.78 (0.77 to 0.79) in Lombardy, 0.78 (0.77 to 0.79) in Emilia-Romagna, 0.77 (0.76 to 0.78) in Lazio and 0.78 (0.77 to 0.79) in Sicily. CONCLUSION: MCS seems better than conventional scores for predicting health outcomes, at least in the general population from Italy. This may offer an improved tool for risk adjustment, policy planning and identifying patients in need of a focused treatment approach in the everyday medical practice.

Strategies to meet the need for long-term data.

Chronic diseases afflict patients for many years, often to the end of life, and there is increasing need for estimating lifelong risk and for evaluating the effects of treatment in the long term. Yet recommendations for lifelong treatment are most frequently based on findings from randomized clinical trials lasting only a few years. There is therefore a clear need for much longer term data, and here we present the advantages and disadvantages of many strategies, including the use of long-term posttrial follow-up, of long-term prospective cohort studies, registry databases, and of administrative databases. We also emphasize the need for long-term cost-effectiveness studies. One of the most promising strategies comes from linkage of data gathered through the ever-expanding pool of administrative databases worldwide with data from other sources, including randomized trials and the many forms of observational study.

Untreated masked hypertension and carotid atherosclerosis: a meta-analysis.

AIM: Masked hypertension (MH) is recognized as a clinical entity with an unfavorable cardiovascular prognosis; a limited number of reports, however, investigated the impact of this condition on subclinical vascular damage. We performed a meta-analysis aimed at evaluating the association of MH with subclinical carotid atherosclerosis in initially untreated subjects. DESIGN: Studies were identified by the following search terms: "masked hypertension", "isolated clinic normotension", "white coat normotension", "carotid artery", "carotid atherosclerosis", "carotid intima-media thickness", "carotid damage" and "carotid thickening". Full articles published in English language reporting data from studies performed in untreated adult individuals were considered. RESULTS: Overall, 2752 untreated subjects (1039 normotensive, 497 MH and 766 hypertensive individuals) of both genders were included in five studies (sample size range 18-222 for MH participants). Common carotid intima-media thickness (IMT) showed a progressive increase from normotensive (681 ± 24 µm) to MH (763 ± 57 µm) (standardized mean difference, SMD: 0.51 ± 0.19, 95% CI 0.13-0.89, p < 0.01) and to sustained hypertensive subjects (787 ± 58 µm) (SMD: 0.33 ± 0.07, 95% CI 0.20-0.46, p < 0.01). The statistical difference between MH and NT became borderline after correction for publication bias. A sensitivity analysis showed that the final result was not substantially affected by a single study effect. CONCLUSIONS: Our findings support the view that MH subjects tend to have a higher risk of developing early carotid atherosclerosis than their true normotensive counterparts. From a practical perspective, the ultrasound search of preclinical carotid disease may improve cardiovascular risk stratification and decision making strategies in these subjects.

Untreated Masked Hypertension and Subclinical Cardiac Damage: A Systematic Review and Meta-analysis.

AIM: Data on the association of masked hypertension (MH) (i.e., normal office and elevated out-of-office blood pressure (BP)) with cardiac damage are scanty. We performed a meta-analysis in order to provide a comprehensive information on subclinical cardiac alterations in subjects with MH. DESIGN: Studies were identified by the following search terms: "masked hypertension," "white coat normotension," "isolated ambulatory hypertension," "left ventricular mass," "left ventricular hypertrophy," "cardiac damage," and "echocardiography." Full articles published in English language providing data on left ventricular (LV) mass and/or prevalence of LV hypertrophy in MH, as assessed by ambulatory BP monitoring, were considered. RESULTS: Overall, 4,884 untreated subjects (2,467 normotensive, 776 MH, and 1,641 sustained hypertensive individuals) of both genders included in 12 studies were analyzed. LV mass index showed a progressive increase from normotensive (79.2 ± 0.35 g/m(2)) to MH (91.6 ± 4.0 g/m(2)) (standard difference in means (SDM): 0.50 ± 0.11, confidence interval (CI): 0.28-0.73, P < 0.01) and to hypertensive subjects (102.9 ± 3.3g/m(2)) (SDM: 0.22 ± 0.07, CI: 0.09-0.35, P < 0.01). After assessing data for publication bias, the difference between groups was still significant. CONCLUSIONS: Our findings support an association between MH and increased risk of LV structural alterations compared to true normotensive individuals. Due to the worse cardiovascular prognosis associated with subclinical cardiac damage, subjects with MH should be carefully screened in order to detect hypertensive organ damage and provide appropriate therapeutic interventions.

European Society of Hypertension practice guidelines for ambulatory blood pressure monitoring.

Given the increasing use of ambulatory blood pressure monitoring (ABPM) in both clinical practice and hypertension research, a group of scientists, participating in the European Society of Hypertension Working Group on blood pressure monitoring and cardiovascular variability, in year 2013 published a comprehensive position paper dealing with all aspects of the technique, based on the available scientific evidence for ABPM. The present work represents an updated schematic summary of the most important aspects related to the use of ABPM in daily practice, and is aimed at providing recommendations for proper use of this technique in a clinical setting by both specialists and practicing physicians. The present article details the requirements and the methodological issues to be addressed for using ABPM in clinical practice, The clinical indications for ABPM suggested by the available studies, among which white-coat phenomena, masked hypertension, and nocturnal hypertension, are outlined in detail, and the place of home measurement of blood pressure in relation to ABPM is discussed. The role of ABPM in pharmacological, epidemiological, and clinical research is also briefly mentioned. Finally, the implementation of ABPM in practice is considered in relation to the situation of different countries with regard to the reimbursement and the availability of ABPM in primary care practices, hospital clinics, and pharmacies.

Similarities and differences between renal sympathetic denervation and carotid baroreceptor stimulation.

The two novel approaches recently introduced for the treatment of resistant hypertension, i.e. carotid baroreceptor stimulation and renal denervation, share a number of similarities but are also characterized by important differences. The similarities include the evidence that both interventions have as common pathophysiological background the state of sympathetic overdrive characterizing essential hypertension. In addition both procedures 1) are invasive, 2) exert in the short-term period clearcut blood pressure lowering effects and 3) still face a number of open questions, particularly related to the long-term blood pressure lowering effects, impact on end-organ damage and on cardiovascular events. The differences include the fact that two procedures act on distinct targets that trigger sympathetic activation and consequently blood pressure increase. In addition, only in the case of carotid baroreceptor stimulation the blood pressure effects can be easily assessed immediately following the implantation. Finally, the economic costs, metabolic effects and impact on vagal modulation of heart rate are different between the two interventions. This paper will provide a comparison of the background, effects and outcome of renal denervation and carotid baroreceptor stimulation, stressing whenever possible the clinical implications of the main features of the two interventions.

Assessment of target organ damage in the evaluation and follow-up of hypertensive patients: where do we stand?

Hypertension is associated with damage to the heart, kidneys, and vascular tree. Assessment of target organ damage (TOD) allows better prediction of cardiovascular risk than conventional risk assessment. Regression of TOD during antihypertensive treatment, which depends on the blood pressure (BP) reduction and the specific ancillary properties of each drug, may indirectly indicate that BP is well controlled. It is unclear whether regression of TOD during treatment is associated with favorable outcome and should be used as a surrogate endpoint. There is evidence that regression of left ventricular hypertrophy and albuminuria are associated with a favorable outcome. However, recent studies cast doubts on this evidence. Thus, assessment of TOD is important to define cardiovascular risk, but, so far, regression of TOD cannot be regarded as a major surrogate therapeutic target. The present paper will provide a critical overview of the data available in the literature.

European Society of Hypertension position paper on ambulatory blood pressure monitoring.

Ambulatory blood pressure monitoring (ABPM) is being used increasingly in both clinical practice and hypertension research. Although there are many guidelines that emphasize the indications for ABPM, there is no comprehensive guideline dealing with all aspects of the technique. It was agreed at a consensus meeting on ABPM in Milan in 2011 that the 34 attendees should prepare a comprehensive position paper on the scientific evidence for ABPM.This position paper considers the historical background, the advantages and limitations of ABPM, the threshold levels for practice, and the cost-effectiveness of the technique. It examines the need for selecting an appropriate device, the accuracy of devices, the additional information and indices that ABPM devices may provide, and the software requirements.At a practical level, the paper details the requirements for using ABPM in clinical practice, editing considerations, the number of measurements required, and the circumstances, such as obesity and arrhythmias, when particular care needs to be taken when using ABPM.The clinical indications for ABPM, among which white-coat phenomena, masked hypertension, and nocturnal hypertension appear to be prominent, are outlined in detail along with special considerations that apply in certain clinical circumstances, such as childhood, the elderly and pregnancy, and in cardiovascular illness, examples being stroke and chronic renal disease, and the place of home measurement of blood pressure in relation to ABPM is appraised.The role of ABPM in research circumstances, such as pharmacological trials and in the prediction of outcome in epidemiological studies is examined and finally the implementation of ABPM in practice is considered in relation to the issue of reimbursement in different countries, the provision of the technique by primary care practices, hospital clinics and pharmacies, and the growing role of registries of ABPM in many countries.