Sacubitril/Valsartan in Resistant Hypertension

Study Overview
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Brief Summary
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The present study aims to evaluate the antihypertensive effect of sacubitril/valsartan in patients with resistant hypertension compared to the use of recommended and optimized antihypertensive therapy, through a randomized clinical trial, over 12 weeks.

Detailed Description
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Worldwide, millions of people are affected by the arterial hypertension system (SAH), so that the presence of resistant hypertension (RH) significantly influences a high cardiovascular morbidity and mortality compared to those with controlled SAH, thus corroborating the need for the development of agents antihypertensive drugs with favorable efficacy and safety profiles. It is known that they are currently using the combined therapy recommended for this group of patients, among them, a significant portion of individuals with RH are unable to achieve the goal of BP control (>140/90 mmHg) even though in regular use, being subject to the greatest risk of cardiovascular outcomes and morbidity and mortality. Approved by the FDA for use in heart failure with reduced ejection fraction with beneficial effects on morbidity and mortality, identified in previous studies, the sacubitril/valsartan molecule (LCZ696) or Entresto® is a molecular complex composed of the sacubitril prodrug activated after ingestion in sacubitrilate - neprilysin inhibitor - associated with valsartan, an angiotensin II type-1 (AT1) receptor antagonist, with vasodilating action, capable of reducing BP, sympathetic tone, with antifibrotic and anti-hypertrophic effects, in addition to natriuresis and diuresis. Considering the knowledge gap to the benefits to LCZ696 in the control of blood pressure in resistant hypertension, the objective of the present study is to evaluate the efficacy (reduction of ambulatory systolic and diastolic blood pressure) and safety (adverse events, hospitalization and cardiovascular death) of the use of sacubitril/valsartan in comparison to the antihypertensive therapy recommended and optimized by the current guidelines, in patients diagnosed with RH, over12 weeks, through a randomized clinical trial.

Official Title
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Anti-Hypertensive Effect of Sacubitril/Valsartan in Resistant Hypertension: Randomized Clinical Trial - The HEVA Study

Conditions
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Resistant Hypertension, Blood Pressure

Intervention / Treatment
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* Drug: Sacubitril-Valsartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women, over 18; Diagnosed with resistant hypertension (using three or more antihypertensive agents of different classes - eg. angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, calcium channel blockers, loop and thiazide diuretics or potassium-sparing diuretics), at least 4 weeks before recruitment, with a BP that remains above the goal of 140/90 mmHg. Exclusion Criteria: Secondary and treatable hypertension; History of angioedema; significant cerebrovascular disease; Active liver disease (alanine aminotransferase or aspartate aminotransferase > 2 times the upper limit of the normal range and) Kidney dialysis or kidney transplantation or serum creatinine> 1.5 times the upper limit of the normal range or CrCl <30 mL/min; Previous or current diagnosis of heart failure; Malignancy; Any significant laboratory abnormalities such as serum potassium > 5.5 mmol/L.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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
Interventional Model Description: It was adopted an equal allocation of patients to each treatment (i.e., 1:1 randomization)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Group A: Usual recommended therapy<br>Antihypertensive regimen based on the usual recommended (optimized) therapy. | |
| Experimental: Group B: Sacubitril/Valsartan<br>Suspension of ACE inhibitors - for at least 36h of the last dose - or ARB. Initial dosage: Sacubitril/valsartan 49mg/51mg, 1 tablet twice daily. Target dose (after two weeks): 97mg/103 mg, 1 tablet twice daily. | Drug: Sacubitril-Valsartan<br>* Use of sacubitril/valsartan after suspension of ACE inhibitors or ARBs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in systolic blood pressure and diastolic blood pressure in the sitting position. | The mean reduction in systolic blood pressure and diastolic blood pressure in the sitting position | 12 weeks | 
| Mean reduction in ambulatory systolic blood pressure (maSBP) and ambulatory diastolic blood pressure | The mean reduction in ambulatory systolic blood pressure (maSBP) and ambulatory diastolic blood pressure (maDBP) | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety outcomes | Rate of hypotension, angioedema, uncontrolled blood pressure above 220x120, relevant hydroelectrolytic disorders, hospitalization, stroke and other cardiovascular events. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Resistant Hypertension, LCZ696, Blood pressure control, sacubitril/valsartan