Effect of Renal Sympathetic Denervation on Resistant Hypertension and Cardiovascular Hemodynamic in Comparison to Intensive Medical Therapy Utilizing Impedance Cardiography

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate that Renal Sympathetic Denervation (RDN) improves the control of blood pressure (BP) in patients with treatment-resistant hypertension, as compared to intensive medical therapy (IMT) using hemodynamic parameters and then applying a predefined algorithm of drug selection (i.e. integrated hemodynamic management - IHM) during 6 months intensive treatment program (receiving antihypertensive care according to the 2007 ESH Guidelines). Working hypothesis: When it is possible to disrupt the sympatho-renal axis by RDN - BP reduction occurs to a greater extent and more rapidly than applying intensive medical therapy using IHM.

Detailed Description
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Hypertension is the most common cardiovascular disease, affecting approximately 1 billion1 people worldwide. Hypertension is a major public health concern, because of its complications (coronary artery disease, heart failure, renal disease, stroke). Early blood pressure control in hypertensive patients guarantees the best prevention of cardiovascular events on the long term (2007 ESH-ESC Guidelines on the Management of Hypertension; VALUE study). However, in spite of education efforts and antihypertensive drugs, blood pressure control rates remain low. The most common cause of uncontrolled BP is inadequate pharmacological treatment, because the selection of antihypertensive agents is often done independently of the hemodynamic status of the patient (volemic status, peripheral resistance, cardiac inotropy). The sympatho-renal axis describes the dual role of the kidney as originator of some central nervous system afferent signals and recipient of efferent sympathetic signals. Both the contribution of the kidney to central sympathetic drive and the consequences of sympathetic efferent drive to the kidney contribute to the development and sustenance of hypertension. Poly-pharmacy strategies for the treatment of elevated blood pressure have identified populations of patients with treatment resistant hypertension. Treatment Resistant Hypertension(TRH) is a blood pressure that remains above goal in spite of the concomitant use of antihypertensive medications from more than 3 drug classes. Patients who require more than 4 drug classes to have their blood pressure controlled are also considered to have resistant hypertension. Preferably, the regimen should include a diuretic and all doses should be optimal2 .The true prevalence of treatment resistant hypertension is unknown. In clinical trials from 20 to 40% of randomized patients did not reach blood pressure targets3. In the National Health and Nutrition Examination Survey in USA (2003-2008), non-pregnant adults with hypertension were classified as resistant if their blood pressure was 140/90 mmHg or higher and if they reported using antihypertensive medications from 3 different drug classes or drugs from 4 antihypertensive drug classes regardless of blood pressure. The prevalence was 12.8% of the drug-treated hypertensive population. Risk factors for treatment-resistant hypertension include older age and obesity . Treatment-resistant patients are more likely to have albuminuria, reduced renal function, and a history of diabetes mellitus, coronary heart disease, stroke or heart failure. They are at increased risk of cardiovascular complications although the true incidence of death and morbidity remains currently unknown. In the Spanish Ambulatory Blood Pressure Monitoring Registry5, 8295 of 68045 treated patients (12.2%) had treatment resistant hypertension, defined as an office blood pressure equal to or exceeding 140 mm Hg systolic and/or 90 mm Hg diastolic. RDN is a novel procedure which has been approved safe and gives a remarkable reduction of BP in treatment-resistant hypertensive patients. The HOTMAN® System is a novel impedance cardiographic device, measuring and calculating hemodynamic parameters. The HOTMAN® System may help the physician to control blood pressure in patients with resistance hypertension. * Our pilot study(Renal sympathetic denervation in patients with treatment-resistant hypertension after witnessed intake of medication before qualifying ambulatory blood pressure.Fadl Elmula FE, Hoffmann P, Fossum E, Brekke M, Gjønnæss E, Hjørnholm U, Kjær VN, Rostrup M, Kjeldsen SE, Os I, Stenehjem AE, Høieggen A.Hypertension. 2013 Sep;62(3):526-32)has showed that The mean office and ambulatory BPs remained unchanged at 1, 3, and 6 months in the 6 patients, whereas there was no known change in antihypertensive medication. Two patients, however, had a fall in both office and ambulatory BPs. Our findings question whether BP falls in response to RDN in patients with true treatment-resistant hypertension.That is why we intended to do an intrim analysis after inclusion of around 30% of the total number planned to be included in the study.

Official Title
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Effect of Renal Sympathetic Denervation on Resistant Hypertension and Cardiovascular Hemodynamic in Comparison to Intensive Medical Therapy Utilizing Impedance Cardiography

Conditions
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Hypertension, Resistant to Conventional Therapy

Intervention / Treatment
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* Procedure: The SymplicityTM Renal Denervation System
* Device: The HOTMAN® System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Average SBP >140mmHg, measured per guidelines 24 hour average ABPM daytime SBP >135mm/Hg On stable medication regimen of full tolerated doses of 3 or more antihypertensive meds, with one being a diuretic No changes for a minimum of 2 weeks prior to screening No planned medication changes for 6 months Age 18-80 years At minimum, 3 antihypertensive medications must meet one or more of the following full dose criteria: Highest labeled dose according to medication's labeling Highest usual dose per clinical guidelines-JNC-7 Highest tolerated dose Highest appropriate dose for the patient per the PI's clinical judgment Exclusion Criteria: Hemodynamically or anatomically significant renal artery abnormalities or stenosis >50% or prior renal artery intervention eGFR < 45 mL/min/1.73m2 (MDRD formula) Albumin/creatinine ratio > 50 mg/mmol Type 1 diabetes mellitus Known alcohol or drug abuse Symptomatic orthostatic hypotension in past year Stenotic valvular heart disease for which BP reduction would be hazardous MI, unstable angina, or CVA in the prior 6 months Known primary pulmonary HTN Known pheochromocytoma, Cushing's disease, coarctation of the aorta, hyperthyroidism or hyperparathyroidism Known primary hyperaldosteronism not adequately treated.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: group Co<br>group Co receives intensive medical therapy utilizing integrated hemodynamic management calculated by impedance cardiography of The HOTMAN® System | Device: The HOTMAN® System<br>* Impedance Cardiography by HOTMAN system will evaluates non-invasively hemodynamic parameters in patients randomized to group Co<br>|
| Active Comparator: group RDN<br>For patients who will be randomly assigned to undergo renal denervation by The SymplicityTM Renal Denervation System, the femoral artery will be accessed with the standard endovascular technique and the catheter will be advanced into the renal artery and connected to a radiofrequency generator. As in Symplicity HTN 1 and 2 trials, four-to-six discrete, low-power radiofrequency ablations lasting up to 2 min each and of 8 watts or less to obtain up to four-six ablations separated both longitudinally and rotationally within each renal artery. During ablation, the catheter system monitored tip temperature and impedance, altering radiofrequency energy delivery in response to a predetermined algorithm. | Procedure: The SymplicityTM Renal Denervation System<br>* For patients who will be randomly assigned to undergo renal denervation (group RDN), the femoral artery will be accessed with the standard endovascular technique and the catheter will be advanced into the renal artery and connected to a radiofrequency generator. As in Simplicity HTN 1 and 2 trials, four-to-six discrete, low-power radiofrequency ablations lasting up to 2 min each and of 8 watts or less to obtain up to four-six ablations separated both longitudinally and rotationally within each renal artery. During ablation, the catheter system monitored tip temperature and impedance, altering radiofrequency energy delivery in response to a predetermined algorithm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change in office systolic blood pressure(SBP) | is the absolute change in office SBP, after a 6 months follow-up. | at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Short and long term safety of RDN as an interventional procedure | Safety of RDN will be assessed at 1, 3, 5 and 10 years by clinical, laboratory and radiology examinations. | up to10 years | 
| Percentage of normalization of blood pressure(BP) at office, home and ABPM | This will include the percentage of normalization of daytime SBP at office, home and ABPM. | at 6 months and later | 
| The normalization of hemodynamics. | The normalization of hemodynamics: Cardiac Index (CI), Heart rate, Stroke systemic vascular resistance index (SSVRI), pulse wave velocity(PWV) and central BP. | at 6 month and later | 
| Cost effectiveness | It will be assessed the Cost effectiveness of Renal denervation as treatment of resistant hypertension compared to control group. | At 6 month and later | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal sympathetic denervation, Impedance cardiography