Non-invasive Haemodynamic Assessment in Hypertension
Condition: Arterial Hypertension
MeSH terms: Hypertension
Study type: Interventional

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.
    

Intervention name(s): lisinopril; Telmisartan; Nebivolol; Indapamide/hydrochlorothiazide; Amlodipine; lisinopril; Telmisartan; Nebivolol; Indapamide/hydrochlorothiazide; Amlodipine
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Angiotensin converting enzyme inhibitor recommended in case of:
"hyperconstrictive" profile (SVRI > 2500-2800 dyn•s•cm-5•m2)
"hyperdynamic" profile (CI > 4.2 l/min/m2 and/or HR > 80/min) and office SBP ≥ 160 mm Hg and/or DBP ≥ 100 mmHg and/or 24-h mean SBP ≥ 140 mm Hg and/or 24-h mean DBP ≥ 90 mm Hg (in combination with nebivolol)
"hypervolemic" profile (man - TFC > 34 1/kOhm; women - TFC > 24 1/kOhm) and office SBP ≥ 160 mm Hg and/or DBP ≥ 100 mmHg and/or 24-h mean SBP ≥ 140 mm Hg and/or 24-h mean DBP ≥ 90 mm Hg (in combination with diuretic)
"balanced" profile; Angiotensin receptor blocker recommended in terms as for lisinopril in case of its intolerance (e.i. cough); Beta-blocker recommended in case of:
1."hyperdynamic" profile (CI > 4.2 l/min/m2 and/or HR > 80/min); "hypervolemic" profile (man - TFC > 34 1/kOhm; women - TFC > 24 1/kOhm)
"hyperconstrictive" profile (SVRI > 2500-2800 dyn•s•cm-5•m2) and office SBP ≥ 160 mm Hg and/or DBP ≥ 100 mmHg and or 24-h mean SBP ≥ 140 mm Hg and/or 24-h mean DBP ≥ 90 mm Hg (in combination with lisinopril/telmisartan); 1/ SVRI > 2800 dyn•s•cm-5•m2 (in combination with lisinopril/telmisartan); Drug choice at the discretion of physician (blinded to ICG); Angiotensin receptor blocker recommended as for lisinopril in case of its intolerance (e.i. cough); Drug choice at the discretion of physician (blinded to ICG); Drug choice at the discretion of physician (blinded to ICG); Drug choice at the discretion of physician (blinded to ICG)
Intervention MeSH terms: Amlodipine; Hydrochlorothiazide; Telmisartan; Lisinopril; Nebivolol; Indapamide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Diagnostic
Keywords: arterial hypertension; hemodynamics; impedance cardiography; hypotensive therapy