Clinical trial NCT01996085: Non-invasive Haemodynamic Assessment in Hypertension
Official title: The Usefulness of Non-invasive Assessment of Haemodynamic Profile in the Diagnosis and Treatment of Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Arterial Hypertension
Keywords: arterial hypertension
hemodynamics
impedance cardiography
hypotensive therapy
Lead sponsor: Military Institute od Medicine National Research Institute
Sponsor class: OTHER
First posted: 2013-11-27
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: Arterial hypertension (AH) is an important clinical social and economic problem. In the pathogenesis of AH increased BP is a result of complex mechanisms i. e. fluid retention, increased vascular resistance and hyperkinetic heart function. Impedance cardiography (ICG) is a simple and safe, non-invasive method of hemodynamic monitoring which allows simultaneous assessment of i. e. BP, cardiac index, heart rate, the fluid content in the chest and systemic vascular resistance.

The detailed effect of treatment based on ICG has not been evaluated so far in the long-term observation and for other clinically relevant parameters, such as central blood pressure, left ventricular hypertrophy, metabolic disturbances, parameters of antioxidative-oxidative balance and endothelial function. Therefore, the following main objectives of the study were defined:

* Evaluation of usefulness of impedance cardiography in optimizing treatment of patients with hypertension in the area of reduction and control of blood pressure, hemodynamic parameters, biochemical markers and quality of life.
* Evaluation of complex pathophysiological mechanisms associated with hypertension including hemodynamic, anthropometric, psychological and biochemical parameters as well as the effect of antihypertensive treatment on these phenomena.

The study will be randomized (1:1), prospective and controlled in parallel with conventional treatment. The subjects will be divided into groups according to the pre-established random order:

1. empiric group (GE), in which treatment choice will be based on clinical data and current guidelines
2. hemodynamic group (HD), in which treatment choice will be based on clinical data and current guidelines considering hemodynamic parameters established with ICG method.

All patients will undergo a detailed examination three times: before treatment, then after 3 and 12 months of treatment.

The authors expect that the study will consolidate the importance of ICG in the diagnosis of patients with AH. Simultaneous multiparametric evaluation of the subjects guarantees a unique and innovative results which can enhance our knowledge in pathophysiology of AH and reversibility of adverse mechanisms associated with this disease.

Detailed description: THE IMPORTANCE OF THE PROJECT. Arterial Hypertension (AH) is an important clinical social and economic problem and a major risk factor of coronary artery disease, heart failure, kidney failure and stroke. The risk of organ damage can be significantly reduced just by achieving proper control of blood pressure (BP). In the pathogenesis of AH increased BP is a result of complex mechanisms i. e. fluid retention, increased vascular resistance and hyperkinetic heart function. Impedance cardiography (ICG) is a simple and safe, non-invasive method of hemodynamic monitoring which allows simultaneous assessment of i. e. BP, cardiac index, heart rate, the fluid content in the chest and systemic vascular resistance. The studies conducted so far (including the applicant's own studies) have demonstrated that ICG provided a better selection of drugs and their doses in the short-term observation.

The detailed effect of such treatment strategy has not been evaluated so far in the long-term observation and for other clinically relevant parameters, such as central blood pressure, left ventricular hypertrophy, pulse wave velocity, metabolic disturbances, parameters of antioxidative-oxidative balance and endothelial function. Undoubtedly, such an evaluation may be of high importance in evaluating complex pathophysiological mechanisms associated with cardiovascular hemodynamics. It is expected that the results of this study performed in a group representing a large population of hypertensive patients will allow highly objective, multiparametric evaluation of the usefulness of ICG in hypotensive therapy. The conclusions may be clinically, socially and economically important, especially in terms of effectiveness and continuity of treatment in patients with AH and primary prevention of cardiovascular events and organ damage.

THE CONCEPT AND STUDY DESIGN.

The main aims:

1. Evaluation of usefulness of impedance cardiography in optimizing treatment of patients with hypertension in the area of reduction and control of blood pressure, hemodynamic parameters, biochemical markers and quality of life.
2. Evaluation of complex pathophysiological mechanisms associated with hypertension including hemodynamic, anthropometric, psychological and biochemical parameters as well as the effect of antihypertensive treatment on these phenomena.

The specific aims:

1. Evaluation of the added value of the algorithm of treatment based on the ICG in optimizing treatment of patients with AH in the reduction and control of BP, hemodynamic, biochemical markers and quality of life.
2. Optimization of the used algorithm of antihypertensive treatment on the basis of multiparametric clinical evaluation.
3. Determination of hemodynamic profiles of patients with AH including multiparametric clinical evaluation.
4. Evaluation of complex pathophysiological mechanisms associated with AH including hemodynamic, anthropometric, psychological and biochemical parameters.
5. Evaluation of the impact of antihypertensive treatment on the values of the studied haemodynamic and anthropometric parameters, biochemical markers and quality of life.

The study will be randomized (1:1), prospective and controlled in parallel with conventional treatment. Study group will involve 140 patients of both sexes, aged from 18 to 75 years. All patients will undergo a detailed examination three times: before treatment, then after 3 and 12 months of treatment, according to the following protocol.

Qualification visit. Clinical assessment with consideration of the criteria of inclusion and exclusion. Presentation of information on the project.

First visit (after qualification):

* physical examination with particular attention to factors of cardiovascular risk, including BP measurement in accordance with the recommendations,
* standard 12-lead electrocardiogram,
* echocardiography,
* 6-minute walk test (6-MWT),
* impedance cardiography (ICG),
* measurement of central blood pressure by applanation tonometry,
* measurement of ankle-brachial index (ABI),
* ambulatory blood pressure measurement (ABPM),
* assessment of brachial artery vasodilatation after ischemia (FMD),
* laboratory tests \[wide range\],
* psychological testing,
* anthropometry,
* assessment of hemodynamics of retrobulbar vessels with use of color Doppler imaging (CDI)
* cardiovascular risk assessment - based on the examination and the results of laboratory tests.

At the first visit antihypertensive therapy and non-pharmacological treatment (individualized diet, weight reduction, regular physical activity, ceasing smoking) will be recommended. The subjects will be divided into groups according to the pre-established random order (www.randomization.com):

1. empiric group (GE), in which treatment choice will be based on clinical data and current guidelines;
2. hemodynamic group (HD), in which treatment choice will be based on clinical data and current guidelines considering hemodynamic parameters established with ICG method.

The choice of treatment in GE group will be performed by a research team member blinded to ICG result. The subjects will not be informed about the type of intervention used. The randomization into the study groups - as on the first visit - will be maintained for all visits.

Depending on the values of SVRI, CI, HR and TFC, hemodynamic disturbances are defined as: (1) hemodynamic profile with excessive vasoconstriction (hyperconstrictive, C: in case of SVRI \> 2500 dyn•s•cm-5•m2), (2) with hyperdynamic heart function (hyperdynamic, D: CI \> 4.2 l/min/m2 and/or HR \> 80/min), (3) with characteristics of overhydration (hypervolemic, V: man - TFC \> 34 1/kOhm; women - TFC \> 24 1/kOhm), (4) balanced hemodynamic profile balanced (B, hemodynamic parameters of thresholds predefined below) - angiotensin converting enzyme inhibitors indicated.

In STEP 1, when the patient's hemodynamic profile will be hyperdynamic - beta-blocker will be recommended, when hypervolemic -diuretic, when hyperconstrictive - angiotensin converting enzyme inhibitor or angiotensin receptor blocker (if systemic vascular resistance index \> 2800 dyn•s•cm-5•m2 - angiotensin converting enzyme inhibitor/angiotensin receptor blocker with calcium blocker recommended). In cases of complex hemodynamic disturbances the combined therapy will be applied.

The STEP 2 will be reserved for the patients with relatively high blood pressure (expected reduction ≥ 20/10mmHg, 24-h mean BP ≥ 140/90 mmHg) of when impedance cardiography suggested only one hemodynamic disturbance. They were assumed to demand polytherapy for that reason the second drug will be added to the first chosen in STEP 1 in combinations:

1. beta-blocker with angiotensin converting enzyme inhibitor/angiotensin receptor blocker;
2. angiotensin converting enzyme inhibitor/angiotensin receptor blocker with diuretic;
3. diuretic with angiotensin converting enzyme inhibitor/angiotensin receptor blocker.

Second visit (after 3 months of pharmacotherapy):

* physical examination with particular attention to factors of cardiovascular risk, including BP measurement in accordance with the recommendations,
* impedance cardiography (ICG),
* measurement of central blood pressure by applanation tonometry,
* ambulatory blood pressure measurement (ABPM),
* laboratory tests \[narrow range\],
* psychological testing,
* anthropometry
* cardiovascular risk assessment - based on the examination and the results of laboratory tests.

Third visit (after 9 months from the second visit, or in cases of hospitalization for cardiovascular reasons): range of examinations and tests as at the first visit, In the course of observation, each patient will have the right to contact research team on his own initiative for questions and concerns related to participation in the study or his health condition.

CHARACTERISTICS OF THE MAIN APPLIED RESEARCH METHODS.

Laboratory tests will be performed at the Department of Laboratory Diagnostics of Military Medical Institute:

1. \[wide range\]: blood count, ionogram, creatinine, urea, uric acid, alanine aminotranserase and aspartate aminotranserase, creatine kinase (CK, CK-MB), lipid profile: total cholesterol, LDL and HDL cholesterol, triglycerides, fasting glucose, insulin, glycosylated hemoglobin (HbA1C), lipoprotein (a), leptin, adiponectin; urinalysis, microalbuminuria, homocysteine; high sensitive C-reactive protein (hsCRP), coagulogram, fibrinogen, D-dimer, superoxide dismutase, plasminogen activator inhibitor 1, resistin
2. \[narrow range\]: blood count, ionogram, creatinine, urea, lipid profile, fasting glucose Impedance cardiography (ICG). On the basis of 10-minute rest recordings of ICG the detailed analysis of mean values of hemodynamic parameters will be performed for: systolic blood pressure (SBP), mean blood pressure (MBP), diastolic blood pressure (DBP), pulse pressure (PP), heart rate (HR), stroke volume (SV) and index (SI), cardiac index (CI), systemic vascular resistance index (SVRI), total artery compliance (TAC) and characteristics of aortic flow: velocity index (VI) and acceleration index (ACI).

Final assessment will also include spectral variability of hemodynamic parameters (i. e. HR, CI, SV, SVR).

Central blood pressure measurement (applanation tonometry). Non-invasive assessment of central blood pressure and related parameters will be performed using the method of applanation tonometry (SphygmoCor Px Aortic BP Profile System). The parameters derived from aortic blood pressure waveform analysis such as i.e. aortic augmentation index (AAI), central blood pressure (CBP) and central pulse pressure (CPP) will be analyzed.

Ambulatory blood pressure monitoring (ABPM). All the patients included in the study will undergo ABPM (Spacelabs 90207; Spacelabs, Medical Inc, Redmond, Washington, USA). The average values of SBP, MBP, DBP, PP (derived from 24-h period, daytime and nightime period) and the corresponding standard deviations (SD) will be analyzed. As the minimum acceptable number of valid BP measurements a 70% is assumed.

Echocardiography. Echocardiography will be performed according to current standards with the use of Vivid 7 apparatus (GE-Healthcare, the USA). Measurements connected with size of heart chambers, contractility and left ventricle wall thickness, ejection fraction and left ventricle relaxation disorders will be evaluated and recorded. The examination will also include automated functional imaging (AFI) of left ventricle.

Flow-mediated dilatation (FMD). The measurement will be performed in the morning, in a quiet room after 10 minutes of rest in supine position. Evaluation of the brachial artery will be done in a 2-D projection, 3-5 cm above the cubital fossa, with the Doppler linear probe of frequency 8 MHz. Dilation of the brachial artery after ischemia will be expressed as a percentage change in brachial artery diameter induced by ischemia in relation to the diameter of the vessel prior to ischemia, in accordance with generally accepted methodology.

Color Doppler Imaging (CDI) of retrobulbar vessels and ophthalmic examination Evaluation of the retrobulbar vessels (ophthalmic artery OA, central retinal artery CRA and short posterior ciliary arteries (temporal and nasal) TSPCA, NSPCA) of the randomly selected eye will be done with the Doppler linear probe of frequency 6-15 MHz (LOGIQ 9 Color Doppler Imaging System; General Electric Medical Systems, Milwaukee, Wisconsin, USA) and will include assessment of peak systolic velocity (PSV), end diastolic velocity (EDV) and resistance index (RI) calculated as follows: RI = (PSV -EDV)/PSV.

All subjects underwent also the randomly selected eye examination that included: autorefractometry and air-puff tonometry (TRK-1P, TOPCON Corporation, Tokyo, Japan), slit-lamp and stereo optic disc evaluation and Spectral optical coherence tomography (OCT/SLO) (Ophthalmic Technologies, Inc. OTI, Toronto, ON, CANADA) of the optic nerve head (ONH), retinal nerve fiber layer (RNFL) and macula.

DATA ANALYSIS. All results will be archived in the form of extensive database with the possibility of multiple analysis, using advanced data analysis systems, such as Statistica, SPSS, MedCalc. To evaluate of complex pathophysiological mechanisms associated with hypertension including hemodynamic, anthropometric, psychological and biochemical parameters (well as the effect of antihypertensive treatment on these phenomena) the correlations and inter-subgroups comparisons will be performed. The results of detailed ophthalmic examination will be also referred to cardiovascular assessment.

MEASURABLE DOCUMENTED EFFECT OF THE PROBLEM. The authors expect that the study will form the basis of the substantive merits of implementing the proposed algorithm of hemodynamic assessment in broad clinical practice as a tool supporting optimization of hypotensive therapy. It is expected that the results will consolidate the importance of ICG in the diagnosis of patients with AH. Simultaneous multiparametric evaluation of the subjects guarantees a unique and innovative results which can enhance our knowledge in pathophysiology of AH and reversibility of adverse mechanisms associated with this disease. It may become an inspiration to undertake further clinical trials related to the practical application of new methods of hemodynamic monitoring.

Eligibility criteria: Inclusion Criteria:

* untreated AH (elevated BP values ≥ 3 months) and insufficiently controlled AH by one or two antihypertensive drugs.

Exclusion Criteria:

* confirmed secondary AH,
* improperly controlled AH with three or more medicines
* chronic renal failure in the third and higher stages of the disease,
* other severe concomitant diseases: systolic heart failure, cardiomyopathy, significant cardiac arrhythmia, significant valvular disease, chronic obstructive pulmonary disease (stage C/D), diabetes, previously undetected, polyneuropathy, peripheral vascular disease,
* body mass index (BMI) \> 40 kg/m2,
* mental illness, preventing cooperation with the physician,
* heart rhythm other than sinus (including, i.e. constant heart stimulation),

Primary outcomes:
measure: 24-h mean Systolic Blood Pressure (in ABPM)
timeFrame: after 3 months from recruitment
measure: 24-h mean Diastolic Blood Pressure (in ABPM)
timeFrame: after 3 months from recruitment
measure: daytime mean Systolic Blood Pressure (in ABPM)
timeFrame: after 3 months from recruitment
measure: daytime mean Diastolic Blood Pressure (in ABPM)
timeFrame: after 3 months from recruitment
measure: night-time mean Systolic Blood Pressure (in ABPM)
timeFrame: after 3 months from recruitment
measure: night-time mean Diastolic Blood Pressure (in ABPM)
timeFrame: after 3 months from recruitment
measure: Systolic Blood Pressure (in OBPM)
timeFrame: after 3 months from recruitment
measure: Diastolic Blood Pressure (in OBPM)
timeFrame: after 3 months from recruitment
measure: 24-h mean Systolic Blood Pressure (in ABPM)
timeFrame: after 12 months from recruitment
measure: 24-h mean Diastolic Blood Pressure (in ABPM)
timeFrame: after 12 months from recruitment
measure: daytime mean Systolic Blood Pressure (in ABPM)
timeFrame: after 12 months from recruitment
measure: daytime mean Diastolic Blood Pressure (in ABPM)
timeFrame: after 12 months from recruitment
measure: night-time mean Systolic Blood Pressure (in ABPM)
timeFrame: after 12 months from recruitment
measure: night-time mean Diastolic Blood Pressure (in ABPM)
timeFrame: after 12 months from recruitment
measure: Systolic Blood Pressure (in OBPM)
timeFrame: after 12 months from recruitment
measure: Diastolic Blood Pressure (in OBPM)
timeFrame: after 12 months from recruitment
Secondary outcomes:
measure: change from baseline in Systolic Blood Pressure (in OBPM) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in Diastolic Blood Pressure (in OBPM) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in 24-h Systolic Blood Pressure (in ABPM) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in 24-h Diastolic Blood Pressure (in ABPM) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in daytime Systolic Blood Pressure (in ABPM) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in daytime Diastolic Blood Pressure (in ABPM) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in night-time Systolic Blood Pressure (in ABPM) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in night-time Diastolic Blood Pressure (in ABPM) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in Systolic Blood Pressure (in OBPM) at 3 months
timeFrame: after 12 months from recruitment
measure: change from baseline in Diastolic Blood Pressure (in OBPM) at 3 months
timeFrame: after 12 months from recruitment
measure: change from baseline in 24-h Systolic Blood Pressure (in ABPM) at 3 months
timeFrame: after 12 months from recruitment
measure: change from baseline in 24-h Diastolic Blood Pressure (in ABPM) at 3 months
timeFrame: after 12 months from recruitment
measure: change from baseline in daytime Systolic Blood Pressure (in ABPM) at 3 months
timeFrame: after 12 months from recruitment
measure: change from baseline in daytime Diastolic Blood Pressure (in ABPM) at 3 months
timeFrame: after 12 months from recruitment
measure: change from baseline in night-time Systolic Blood Pressure (in ABPM) at 3 months
timeFrame: after 12 months from recruitment
measure: change from baseline in night-time Diastolic Blood Pressure (in ABPM) at 3 months
timeFrame: after 12 months from recruitment
Other outcomes:
measure: Heart Rate (HR)
timeFrame: after 3 months from recruitment
measure: Cardiac Index (CI)
timeFrame: after 3 months from recruitment
measure: Thoracic Fluid Content (TFC)
timeFrame: after 3 months from recruitment
measure: Systemic Vascular Resistance Index (SVRI)
timeFrame: after 3 months from recruitment
measure: augmentation index (AAI)
timeFrame: after 3 months from recruitment
measure: Central Systolic Blood Pressure
timeFrame: after 3 months from recruitment
measure: Central Diastolic Blood Pressure
timeFrame: after 3 months from recruitment
measure: Flow-mediated Dilatation (FMD)
timeFrame: after 3 months from recruitment
measure: Heart Rate (HR)
timeFrame: after 12 months from recruitment
measure: Cardiac Index (CI)
timeFrame: after 12 months from recruitment
measure: Thoracic Fluid Content (TFC)
timeFrame: after 12 months from recruitment
measure: Systemic Vascular Resistance Index (SVRI)
timeFrame: after 12 months from recruitment
measure: augmentation index (AAI)
timeFrame: after 12 months from recruitment
measure: Central Systolic Blood Pressure
timeFrame: after 12 months from recruitment
measure: Central Diastolic Blood Pressure
timeFrame: after 12 months from recruitment
measure: Flow-mediated Dilatation (FMD)
timeFrame: after 12 months from recruitment
measure: left ventricular mass index(LVMI)
timeFrame: after 12 months from recruitment
measure: change from baseline in Heart Rate (HR) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in Cardiac Index (CI) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in Thoracic Fluid Content (TFC) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in Systemic Vascular Resistance Index (SVRI) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in augmentation index (AAI) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in Central Systolic Blood Pressure at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in Central Diastolic Blood Pressure at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in Flow-mediated Dilatation (FMD) at 3 months
timeFrame: after 3 months from recruitment
measure: change from baseline in Heart Rate (HR) at 12 months
timeFrame: after 12 months from recruitment
measure: change from baseline in Cardiac Index (CI) at 12 months
timeFrame: after 12 months from recruitment
measure: change from baseline in Thoracic Fluid Content (TFC) at 12 months
timeFrame: after 12 months from recruitment
measure: change from baseline in Systemic Vascular Resistance Index (SVRI) at 12 months
timeFrame: after 12 months from recruitment
measure: change from baseline in augmentation index (AAI) at 12 months
timeFrame: after 12 months from recruitment
measure: change from baseline in Central Systolic Blood Pressure at 12 months
timeFrame: after 12 months from recruitment
measure: change from baseline in Central Diastolic Blood Pressure at 12 months
timeFrame: after 12 months from recruitment
measure: change from baseline in Flow-mediated Dilatation (FMD) at 12 months
timeFrame: after 12 months from recruitment
measure: change from baseline in left ventricular mass index (LVMI) at 12 months
timeFrame: after 12 months from recruitment
Locations:
city: Warsaw
country: Poland
facility: Military Institute of Medicine
state: Mazovia
Study officials:
affiliation: Department of Cardiology and Internal Diseases, Military Institute of Medicine, Poland
name: Pawel Krzesinski, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Ferrario CM, Flack JM, Strobeck JE, Smits G, Peters C. Individualizing hypertension treatment with impedance cardiography: a meta-analysis of published trials. Ther Adv Cardiovasc Dis. 2010 Feb;4(1):5-16. doi: 10.1177/1753944709348236. Epub 2009 Dec 30.
citation: Ferrario CM. New approaches to hypertension management: always reasonable but now necessary. Am J Hypertens. 2005 Feb;18(2 Pt 2):23S-25S. doi: 10.1016/j.amjhyper.2004.11.042. No abstract available.
citation: Krzesinski P, Gielerak G, Kowal J. [Impedance cardiography - a modern tool for monitoring therapy of cardiovascular diseases]. Kardiol Pol. 2009 Jan;67(1):65-71. No abstract available. Polish.
citation: Krzesinski P, Gielerak G, Stanczyk A, Piotrowicz K, Uzieblo-Zyczkowska B, Banak M, Kurpaska M, Michalczyk L, Jurek A, Wolszczak K, Galas A, Wojcik A, Skrobowski A. The effect of hemodynamically-guided hypotensive therapy in one-year observation: Randomized, prospective and controlled trial (FINEPATH study). Cardiol J. 2016;23(2):132-40. doi: 10.5603/CJ.a2016.0009. Epub 2016 Feb 15.