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Hypertension guidelines recommend ambulatory blood pressure (ABP), central aortic pressure (CAP), and pulse wave velocity (PWV) as parameters for estimating blood pressure (BP) control and vascular impairment. Recent advances in technology have enabled devices to combine non-invasive estimation of these parameters over the 24-hour ABP monitoring. However, currently there is limited evidence on the usefulness of such an approach for routine hypertension management.
We recently launched an investigator-initiated, international, multicenter, observational, prospective study, the Vascular health Assessment Of The Hypertensive patients (VASOTENS) Registry, aimed at (1) evaluating non-invasive 24-hour ABP and arterial stiffness estimates (through 24-hour pulse wave analysis, PWA) in hypertensive subjects undergoing ambulatory blood pressure monitoring (ABPM) for clinical reasons; (2) assessing the changes in estimates following treatment; (3) weighing the impact of 24-hour PWA on target organ damage and cardiovascular prognosis; (4) assessing the relationship between arterial stiffness, BP absolute mean level and variability, and prognosis; and (5) validating the use of a 24-hour PWA electronic health (e-health) solution for hypertension screening.
Approximately 2000 subjects, referred to 20 hypertension clinics for routine diagnostic evaluation and follow-up of hypertension of any severity or stage, will be recruited. Data collection will include ABPM, performed with a device allowing simultaneous non-invasive assessment of 24-hour CAP and arterial stiffness (BPLab), and clinical data (including cardiovascular outcomes). As recommended by current guidelines, each patient will be followed-up with visits occurring at regular intervals (ideally every 6 months, and not less than once a year depending on disease severity). A Web-based telemedicine platform (THOLOMEUS) will be used for data collection. The use of the telemedicine system will allow standardized and centralized data collection, data validation by experts and counseling to remote centers, setup and maintenance of the Registry, and prompt data analysis.
First follow-up results are expected to be available in the next 2 years.
The results of the VASOTENS Registry will help define the normalcy thresholds for current and future indices derived from 24-hour PWA, according to outcome data, and will also provide supporting evidence for the inclusion of this type of evaluation in hypertension management.
Clinicaltrials.gov NCT02577835; https://clinicaltrials.gov/ct2/show/NCT02577835 (Archived by WebCite at http://www.Webcitation.org/6hzZBKY2Q)
Central aortic pressure (CAP) and pulse wave velocity (PWV) are independent predictors for the development of cardiovascular (CV) diseases [
The most widely adopted methods for evaluating pulse waveforms are those based on applanation tonometry and transfer functions [
There is previous evidence that non-invasive assessment of 24-hour arterial stiffness and central hemodynamics in daily life conditions measured by the device used in this study (BPLab device, BPLab GmbH, Schwalbach am Taunus, Hessen, Germany) may help in assessing the arterial function impairment in hypertensive patients. We recently showed larger 24-hour CAP and peripheral AIx values in 661 patients with hypertension compared to 142 normotensive controls [
Recent advances in technology enabled devices to combine non-invasive estimation of CAP and arterial stiffness in ambulatory conditions over the 24-hours, based on the oscillometric method [
To provide further insight on the matter, we created a large database (or registry) of ABPM recordings obtained with the BPLab monitor, which is able to determine CAP, PWV, and AIx, over the 24-hours, based on a clinically validated technology of PWA of oscillometric BP measurements [
This paper summarizes the study protocol (final version, dated 20/02/2015, available as an online supplement to this paper) (
The VASOTENS (Vascular health Assessment Of The Hypertensive patients) Registry aims at evaluating the clinical value and the prognostic impact of 24-hour ambulatory non-invasive estimation of arterial stiffness and central hemodynamics by PWA in patients with hypertension undergoing an ABPM for clinical reasons in hypertension clinics. Specific study objectives include (1) the evaluation of 24-hour PWV, AIx and CAP in hypertensive patients over consecutive ABPMs performed at regular intervals, as recommended by current guidelines, for a minimum of 2 years (main study objective); (2) the evaluation of the changes in BP and arterial stiffness estimates following treatment initiation or modification, according to current guidelines; (3) the assessment of the impact of non-invasive arterial stiffness estimation on cardiac, vascular and renal damage and patient’s CV prognosis (fatal and non-fatal events); (4) the definition of the normal thresholds for PWV, AIx and CAP, in hypertensive patients, according to outcome data; and (5) the definition of the relationship between arterial stiffness, BP absolute level and BP variability, and outcomes.
The outcome-based results provided by the VASOTENS Registry will help establish a worldwide network of certified centers performing ambulatory PWA and will help validate and foster the use of the 24-hour PWA electronic health (e-health) solution for hypertension screening and follow-up. Ultimately, the study-based evidence of the clinical relevance of 24-hour non-invasive central arterial stiffness and hemodynamics assessment may help favor the inclusion of such evaluations among the standard procedures made available in hypertension centers, as well as practical recommendations for improving hypertension management and control.
The VASOTENS Registry is an international, multicenter, observational, non-randomized, prospective study.
A minimum of 20 hypertension centers will be involved worldwide, each providing at least 100 participants, in order to allow recruitment of a sufficiently consistent sample size able to demonstrate the study objectives. A list of participating centers grouped by countries is shown in
Participants referred to the study centers for routine diagnostic evaluation of hypertension or established hypertensive patients will be eligible for inclusion in the study. Individuals fulfilling eligibility criteria (
Criteria
Inclusion criteria
Male and female
Age ≥18 years
Participants referred to routine diagnostic evaluation for hypertension of any severity or stage, or established hypertensive patients
Good quality ABPM performed for clinical reasons with a BPLab device
Availability of individual measurements for ABPM on a bpw file (BPLab format)
Data directly uploaded on the telemedicine platform of the study
Availability of basic clinical information (see
Availability of a signed informed consent form
Exclusion criteria
Age <18 years
Atrial fibrillation, frequent ectopic beats, second or third degree atrioventricular blocks, or other conditions which might make difficult or unreliable the automatic BP measurement with the oscillometric technique
Upper arm circumference <22 cm
Pregnancy
However, naïve hypertensive participants will also be enrolled, provided that an ABPM is required for evaluating their potential hypertension status, according to current recommendations [
The project will not involve any type of diagnostic evaluation or pharmacological intervention and the investigators will be free to manage the patients included in the Registry according to the requirements of clinical practice and current guidelines [
Demographic and clinical information
Age
Gender
Height (cm)
Weight (kg)
Ethnicity
Superficial distance between jugulum and symphysis (surrogate of aortic length; cm)
Waist circumference (cm)
Smoking status
Alcohol drinking
Coffee or tea drinking
Dyslipidemia (yes/no and indication on treatment)
Diabetes (yes/no and indication on treatment)
Diagnosis of hypertension (yes/no and indication on treatment)
Family history of premature CV disease
Medical history with particular regard to previous and/or concurrent CV diseases
Office BP (mmHg) and heart rate (bpm) obtained in the same treatment condition as ABPM
Electrocardiogram (ECG) indication on left ventricular hypertrophy, Sokolow–Lyon and Cornell index)
Left ventricular mass index (LVMI, as g/m2) at echocardiogram
When available, diameter of the aorta (aortic annulus, root and sinotubular junction, in cm) and/or cardiac output (as L/min), assessed by the echocardiogram
Intima-media thickness (IMT, mm) at carotid ultrasonography
When available, ankle-brachial index
Microalbuminuria (as mg/24h) or albumin-creatinine ratio (mg/g), and serum creatinine (g/dL), with subsequent calculation of estimated glomerular filtration rate (eGFR) by the Cockroft-Gault equation
When available, PWV (m/s), Aix (%), and CAP (mmHg) taken during the office visit with a validated device different from the BPLab device (eg, Sphygmocor or Complior)
Twenty-four hour ABPM will be performed with the BPLab device, which has been found to be accurate for estimation of both BP and vascular indices in properly conducted validation studies [
Current guidelines will be followed for proper recording performance [
The oscillometric BPLab device will also allow measurements of ambulatory arterial stiffness and central hemodynamics by recording pulsatile pressure changes at the brachial artery level. Briefly, during BP measurement, the pressure waveforms in the cuff are recorded during a step-by-step deflation and then digitalized and stored in the device memory. When data are uploaded on the Web-based telemedicine platform, the software processes the signal using proprietary mathematical algorithms. These are based on a specially developed hemodynamic model to get the PWV and transfer function that utilizes a modification in a certain frequency range within the acquired pulse signal to derive the aortic pressure wave, and thus to assess CAP and AIx. A detailed description of the methodology may be found elsewhere [
Data contained in existing electronic databases or data of newly enrolled subjects fulfilling the inclusion criteria will be uploaded and entered on the study website. These data will include ABPM measures (peripheral or brachial BP, CAP, and arterial stiffness) obtained with a BPLab device and clinical data. Data collection will be ensured by a certified Web-based telemedicine platform (THOLOMEUS, Biotechmed Ltd., Somma Lombardo, Varese Italy) available on the Tholomeus website [
Workflow of the THOLOMEUS Web-based telemedicine system used in the VASOTENS Registry.
The study will be conducted according to Good Clinical Practice guidelines and the Declaration of Helsinki [
Given its observational nature, no formal monitoring of the study is foreseen for this study. However, electronic data verification will be done remotely by a data manager who will get in touch with the investigators and, when needed, will ask the investigator to correct the erroneous data or complete missing data on the e-CRF. The investigator will be required to verify and check that the information provided on the e-CRF is as precise and accurate as possible. The procedures for data monitoring and verification will be ensured by the presence of logical checks and range (defined a priori) for the different variables and by automatic identification of inconsistencies by the e-CRF used to manage the database. The controls and related corrections will be made on the e-CRF directly by the investigator on the website. Since no standardized or centralized analysis of laboratory tests will be done, except for ABPM, particular attention will be dedicated to check the congruency of data collected through ultrasonography, ECG, and biochemistry.
An important part of the study-related activities will be aimed at disseminating the knowledge on the correct use of ambulatory CAP and arterial stiffness estimation in clinical practice and in research, and thus at achieving a possibly standardized and widespread use of this integrated technology. Manuscripts reporting main study results and documents embedding specific recommendations on the use of the technique will be developed. All publications related to the study results will be prepared by the study coordinators with the support of the scientific committee and will include any investigator significantly contributing to the success of the study. A complete list of investigators will be provided at the end of each manuscript. The original study protocol (with appendices) can be downloaded from, and any future study results will be published on the VASOTENS study website.
The primary study endpoint will consist of the calculations of the average 24-hour values of PWV, CAP, and AIx during the study. The main time points will be the baseline versus the end of the study, corresponding to 2 years following enrolment, but averages will be computed for each study visit occurring during the follow-up.
The endpoints considered secondary study variables and evaluated according to the same timeline applied to the primary outcome measures are shown in
Outcome measures
Average 24-hour brachial (or peripheral) SBP and DBP
24-hour brachial SBP and DBP variability estimated by:
Unweighted standard deviation: the standard deviation of 24-hour mean value of brachial SBP and DBP [
Weighted standard deviation: the standard deviation of the average of all brachial SBP and DBP values during day-time and night-time, with weights corresponding to the duration of day-time and night-time [
Average real variability (ARV): the mean of the successive absolute differences between adjacent brachial SBP and DBP values over the 24-hours [
Cardiac damage, defined by the presence of cardiac hypertrophy, as determined by echocardiography (LVMI >115 g/m2 in men and >95 g/m2 in women according to the recommendations of the American Society of Echocardiography) [
Vascular damage, defined by the presence of carotid wall thickening or plaque (intima media thickness, IMT >0.9 mm) at ultrasonography and, if available, by an ankle-brachial index (ABI) <0.9 [
Renal damage, defined by microalbuminuria (30-300 mg/24 h) or albumin–creatinine ratio (30–300 mg/g) (preferentially on morning spot urine) or reduced estimated glomerular filtration rate (eGFR <60 ml/min/1.73 m2) [
Cardiovascular fatal or non-fatal events: death or hospitalization for congestive heart failure, myocardial infarction, angina, stroke or cerebrovascular accident, renal failure, or other cardiovascular diseases
Given the observational nature of the study and the lack of precedent studies with a similar design and objectives, it is difficult to define a proper sample size. According to the number of subjects enrolled and followed-up in previous cross-sectional or prospective trials [
Analysis will be performed on all participants with valid ABPM recordings at study entry and during the follow-up. Principal derived ABPM variables and arterial stiffness measures will be immediately calculated once the data will be uploaded on the website and their quality verified. Analysis of 24-hour recordings will be preceded by removal of artifacts according to previously described editing criteria [
Basic descriptive statistics will be provided for all variables with calculations of absolute and relative frequencies for categorical variables and calculation of average value, standard deviation, and minimum and maximum for continuous variables. The relationship between BP and arterial stiffness estimates, and organ damage and prognosis will be evaluated by appropriate parametric or non parametric tests, depending on the type of data distribution (normal or non-normal). The occurrence of any cardiovascular event during the study will be evaluated by the Kaplan-Meier method. Time-to-event curves will be drawn and the survival analysis will be performed according to the Cox proportional hazard model to analyze predictors of outcomes. Data management and analysis will be carried out by SPSS for Windows version 20. A
Enrolment of patients in the first study centers started in October 2015. The first data analysis is expected to be performed by the end of 2017 or early 2018.
The VASOTENS Registry is an international, multicenter, observational, non-randomized, prospective study devised to evaluate the clinical impact and usefulness of 24-hour PWA for hypertension management.
With respect to all of the studies briefly reviewed in this paper, our Registry may offer, for the first time, the possibility to shed light on the role of 24-hour ambulatory central hemodynamics and stiffness as predictors of cardiovascular outcomes. The study results may help determine whether the clinical value of ABPM might be further increased by incorporating information on ambulatory CAP and stiffness. The results of the VASOTENS Registry will help define the normalcy thresholds for current and future indices derived from 24-hour PWA, according to outcome data. They will also provide supporting evidence for the inclusion of such evaluations in recommendations on hypertension management and its possible impact on the general population health state. Thanks to this study, an important lack of knowledge will be worked-out and the foundation for future studies with a more robust design could be hopefully laid.
The non-randomized uncontrolled nature of the study and the rather wide selection criteria may increase the risk of obtaining heterogeneous and poorly powered results. In addition, the fact that patients will be recruited in hypertension centers may result in a potential selection bias: the sample being unrepresentative or not fully representative of the general population of patients with hypertension. Despite these important limitations, we think that since the study is carried out in a real-life setting and that it is a longitudinal long-term outcome-driven study, it represents an important added value.
An important component of this study is disseminating the knowledge on correct use of ambulatory CAP and arterial stiffness estimation and to help create an e-health network for a standardized and widespread use of this hypertension screening tool. In order to achieve this, apart from data collection, several disseminating activities are required. An exchange of knowledge between participating centers will be achieved by the cooperation of investigators in preparing a possibly unified methodology of ABPM data collection and analysis and by jointly addressing methodological issues that may arise during the project. Data collected in the Registry will foster the performance of studies aimed at optimizing a possible clinical application of non-invasive ambulatory arterial stiffness estimation. The study will help provide instructions on appropriate ambulatory arterial stiffness monitoring methodology to other physicians, particularly to intermediate level centers, not necessarily experts in ABPM use and arterial stiffness determination. A major task of the consortium will be to provide these participants with accurate information on correct methodology and interpretation of such data, in order to support them in case of difficulties and to monitor the correctness of the use of the methodology in these centers during the project. The study findings will favor preparation of specific recommendations on the use and clinical application of ABPM integrated with arterial stiffness evaluation. The study will also ensure cooperation between international and national scientific societies in the area related to ABPM and arterial stiffness monitoring. This will facilitate the dissemination of information on the project and its findings and will also allow an interaction with writing committees involved in the preparation of guidelines pertinent to this area
The results of the data collected at baseline and during regular follow-up of hypertensive patients in the VASOTENS Registry will help define the normalcy thresholds for current and future indices derived from 24-hour PWA, according to outcome data. They will also provide supporting evidence on the clinical usefulness of such a technological approach, based on telemedicine, for the screening and follow-up of the vascular function status of the patients with hypertension.
VASOTENS Registry Study Protocol.
Updated SPIRIT checklist.
List of centers.
ambulatory blood pressure
ambulatory blood pressure monitoring
Augmentation Index
blood pressure
central aortic pressure
cardiovascular
electrocardiogram
electronic case report form
left ventricular motility injury
pulse-wave analysis
pulse wave velocity
systolic blood pressure
Vascular health ASsessment Of The HypertENSive Patients
This is an investigator-initiated study, endorsed by the Russian and Italian Societies of Hypertension. The study coordinator, Italian Institute of Telemedicine, is the promoter and main sponsor of the study, and makes available its resources and facilities for conducting the trial. BPLab GmbH provides the ambulatory blood pressure devices, and Biotechmed Ltd provides the Web-based telemedicine platform used for data collection, at no cost. These funding sources had no role in the design of the study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. For this study, no additional funding source is available.
SO conceived the study and defined the study design with INP. SO and INP wrote the protocol. SO, INP, GP, and ANR contributed to refinement of the study protocol. All authors approved the final manuscript.
SO is scientific consultant of Biotechmed Ltd. The other authors do not declare any conflicts of interest.