Sequential Nephron Blockade vs. Dual Blockade Renin-angiotensin System + Bisoprolol in Resistant Arterial Hypertension

NCT02832973 | Completed Phase 4

• 1 other identifier: SaoJoseRPU
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

Brief Summary

A randomized clinical trial comparing sequential nephron blockage (SNB) with dual blockade of the renin-angiotensin system (RAAS) plus bisoprolol (DBB) in the treatment of resistant arterial hypertension (RH) was designed to investigate the importance of the SNB and the contribution of its volume component versus DBB and the importance of the serum renin in maintaining BP levels. This randomized trial with two treatment arms could help tailor therapy by identifying a more effective choice to control hypertension whether by acting on the control of volume or sodium balance, or by acting on the effects of the RAAS on the kidney. Methods - Participants: 80 patients undergoing treatment for RH with losartan (100-200 mg), chlorthalidone (25 mg), and amlodipine (5 mg) will be randomly divided into two groups after applying inclusion and exclusion criteria. Group 1: Sequential nephron blockade (SNB Group) n = 40 Group 2: Dual blockade of the RAAS plus bisoprolol (DBB Group) n = 40 Intervention: SNB consists in a progressive increase in sodium depletion. After the administration of a thiazide diuretic (chlorthalidone) and aldosterone receptor blocker, low doses of furosemide are administered and subsequently amiloride is prescribed to enhance the natriuretic effect. The dual blockade of the RAAS plus bisoprolol is used to increase the effect of angiotensin receptor 1 blockers (ARBs). Therapy then requires sequentially adding an angiotensin converting enzyme (ACE) inhibitor to reduce the levels of angiotensin (Ang) II resulting from blockage of the Ang II receptor and then to administer a beta-blocker to decrease the elevated renin secretion due to both the ACE inhibitors and ARBs Objective: This study, which compares two antihypertensive treatment regimens in patients with RH, has the following objectives: to demonstrate the therapeutic efficacy of SNB against DBB in RH patients, and to assess the side effects and adherence to treatment over 20 weeks of treatment. Enrollment: The eligibility criteria will follow those shown in the flowchart for the diagnosis of RH of the First Brazilian Position on RH. Patients will be excluded if they have: chronic renal failure, atrial fibrillation/atrioventricular block, contraindication to the drugs that will be used, refusal or failure to follow the regimen and secondary hypertension. Follow-up: Patients will be analyzed in five visits at intervals of 28 days for 20 weeks

Conditions

Hypertension Resistant to Conventional Therapy

Keywords

Hypertension Resistant to Conventional Therapy; Natriuretic Agents; Renin-Angiotensin System; Bisoprolol

Outcome Measures

Primary Outcomes (1)

• Reduction of Systolic BP, diastolic BP, mean BP and pulse pressure levels will be used to compare sequential nephron blockade versus dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol

  Systolic BP (mmHg), Diastolic BP (mmHg), Mean BP (mmHg) and Pulse Pressure (mmHg)

  Twenty weeks

Secondary Outcomes (3)

• Electrolytes changes: Sodium, Potassium Chlorine after 20 weeks of treatment with sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol

  Twenty weeks

• Reduction of creatinine clearance after 20 weeks of treatment with sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol

  Twenty weeks

• Hypotension

  Twenty weeks

Study Arms (2)

Spironolactone, Furosemide Amiloride

EXPERIMENTAL

Spironolactone 25 mg qd, Furosemide 20 mg qd, Furosemide 40 mg qd, Amiloride 5 mg qd

Drug: Spironolactone; Drug: Furosemide,; Drug: Amiloride

Ramipril, Bisoprolol

ACTIVE COMPARATOR

Ramipril 5 mg qd, Ramipril 10 mg qd, Bisoprolol 5 mg qd, Bisoprolol 10 mg qd

Drug: Ramipril; Drug: Bisoprolol

Interventions

Spironolactone DRUG

Spironolactone 25 mg

Also known as: Natriuretic diuretics

Spironolactone, Furosemide Amiloride

Furosemide, DRUG

Furosemide 20-40 mg

Also known as: Furosemide 20-40 mg

Spironolactone, Furosemide Amiloride

Amiloride DRUG

Amiloride 5 mg

Also known as: Amiloride 5 mg

Spironolactone, Furosemide Amiloride

Ramipril DRUG

Ramipril 5-10 mg

Also known as: ACE inhibitor

Ramipril, Bisoprolol

Bisoprolol DRUG

Bisoprolol 5-10 mg

Also known as: Betablocker

Ramipril, Bisoprolol

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Clinical diagnosis of Resistant Hypertension Must to able swallow antihypertensive drug classes at maximum tolerated doses.

You may not qualify if:

• Secondary Hypertension Chronic renal failure Coronary artery disease Atrial fibrillation Atrioventricular block Refuse or fail to follow regimen

Sponsors & Collaborators

• Sao Jose do Rio Preto Medical School: lead

Study Sites (1)

Juan Carlos Yugar-Toledo

São José do Rio Preto, São Paulo, 15090000, Brazil

Location

Related Publications (15)

• Knauf H, Mutschler E. Sequential nephron blockade breaks resistance to diuretics in edematous states. J Cardiovasc Pharmacol. 1997 Mar;29(3):367-72. doi: 10.1097/00005344-199703000-00010.

  PMID: 9125675 BACKGROUND

• Blumenfeld JD, Sealey JE, Mann SJ, Bragat A, Marion R, Pecker MS, Sotelo J, August P, Pickering TG, Laragh JH. Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects. Am J Hypertens. 1999 May;12(5):451-9. doi: 10.1016/s0895-7061(99)00005-9.

  PMID: 10342782 BACKGROUND

• Azizi M, Menard J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation. 2004 Jun 1;109(21):2492-9. doi: 10.1161/01.CIR.0000131449.94713.AD. No abstract available.

  PMID: 15173039 BACKGROUND

• Sociedade Brasileira de Cardiologia; Sociedade Brasileira de Hipertensao; Sociedade Brasileira de Nefrologia. [VI Brazilian Guidelines on Hypertension]. Arq Bras Cardiol. 2010 Jul;95(1 Suppl):1-51. No abstract available. Portuguese.

  PMID: 21085756 BACKGROUND

• Sociedade Brasileira de Cardiologia (SBC); Sociedade Brasileira de Hipertensao (SBH); Sociedade Brasileira de Nefrologia (SBN). [V Guidelines for ambulatory blood pressure monitoring (ABPM) and III Guidelines for home blood pressure monitoring (HBPM)]. Arq Bras Cardiol. 2011 Sep;97(3 Suppl 3):1-24. No abstract available. Portuguese.

  PMID: 22262107 BACKGROUND

• Kearney PM, Whelton M, Reynolds K, Whelton PK, He J. Worldwide prevalence of hypertension: a systematic review. J Hypertens. 2004 Jan;22(1):11-9. doi: 10.1097/00004872-200401000-00003.

  PMID: 15106785 RESULT

• ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97. doi: 10.1001/jama.288.23.2981.

  PMID: 12479763 RESULT

• Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008 Jun;51(6):1403-19. doi: 10.1161/HYPERTENSIONAHA.108.189141. Epub 2008 Apr 7.

  PMID: 18391085 RESULT

• Alessi A, Brandao AA, Coca A, Cordeiro AC, Nogueira AR, Diogenes de Magalhaes F, Amodeo C, Saad Rodrigues CI, Calhoun DA, Barbosa Coelho E, Pimenta E, Muxfeldt E, Consolin-Colombo FM, Salles G, Rosito G, Moreno H Jr, Martin JF, Yugar JC, Aparecido Bortolotto L, Nazario Scala LC, Goncalves de Sousa M, Gomes MA, Malachias MB, Gus M, Passarelli O Jr, Jardim PC, Toscano PR, Sanchez RA, Dischinger Miranda R, Povoa R, Barroso WK. First Brazilian position on resistant hypertension. Arq Bras Cardiol. 2012 Jul;99(1):576-85. doi: 10.1590/s0066-782x2012000700002. No abstract available. English, Portuguese.

  PMID: 22948302 RESULT

• Persell SD. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension. 2011 Jun;57(6):1076-80. doi: 10.1161/HYPERTENSIONAHA.111.170308. Epub 2011 Apr 18.

  PMID: 21502568 RESULT

• de la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P, Oliveras A, Ruilope LM. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension. 2011 May;57(5):898-902. doi: 10.1161/HYPERTENSIONAHA.110.168948. Epub 2011 Mar 28.

  PMID: 21444835 RESULT

• Faselis C, Doumas M, Papademetriou V. Common secondary causes of resistant hypertension and rational for treatment. Int J Hypertens. 2011 Mar 2;2011:236239. doi: 10.4061/2011/236239.

  PMID: 21423678 RESULT

• Alvarez-Alvarez B, Abad-Cardiel M, Fernandez-Cruz A, Martell-Claros N. Management of resistant arterial hypertension: role of spironolactone versus double blockade of the renin-angiotensin-aldosterone system. J Hypertens. 2010 Nov;28(11):2329-35. doi: 10.1097/HJH.0b013e32833d4c99.

  PMID: 20651602 RESULT

• Yugar-Toledo JC, Minari TP, de Mello PG, do Espirito Santo Cestario E, de Azevedo Rubio T, da Costa LMC, Yugar LBT, Sedenho-Prado LG, Tacito LHB, Cosenso-Martin LN, Fattori A, Pisani LP, Vilela-Martin JF, Moreno H. Effects of different antihypertensive drug classes on central and ambulatory blood pressure in resistant hypertension: A randomized clinical trial. Br J Clin Pharmacol. 2026 Jan;92(1):186-197. doi: 10.1002/bcp.70249. Epub 2025 Aug 26.

  PMID: 40859651 DERIVED

• Cestario EDES, Fernandes LAB, Giollo-Junior LT, Uyemura JRR, Matarucco CSS, Landim MIP, Cosenso-Martin LN, Tacito LHB, Moreno H Jr, Vilela-Martin JF, Yugar-Toledo JC. Resistant Hypertension On Treatment (ResHypOT): sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol in the treatment of resistant arterial hypertension - study protocol for a randomized controlled trial. Trials. 2018 Feb 12;19(1):101. doi: 10.1186/s13063-017-2343-3.

  PMID: 29433578 DERIVED

MeSH Terms

Conditions

Hypertension Resistant to Conventional Therapy

Interventions

Spironolactone; Furosemide; Amiloride; Ramipril; Angiotensin-Converting Enzyme Inhibitors; Bisoprolol

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sulfanilamides; Sulfonamides; Amides; Aniline Compounds; Amines; Sulfones; Sulfur Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols

Study Officials

• Juan C Yugar-Toledo, MD, PhD

  Sao Jose do Rio Preto Medical School

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: June 12, 2016
• First Posted: July 14, 2016
• Study Start: September 1, 2015
• Primary Completion: December 1, 2017
• Study Completion: March 1, 2018
• Last Updated: April 5, 2019

Record last verified: 2019-04

Locations

BR (1)