Ignite Creation Date:
2024-05-06 @ 8:49 AM
Last Modification Date:
2024-10-26 @ 12:05 PM
Study NCT ID:
NCT02832973
Status:
COMPLETED
Last Update Posted:
2019-04-05
First Post:
2016-06-12
Brief Title:
Sequential Nephron Blockade vs Dual Blockade Renin-angiotensin System Bisoprolol in Resistant Arterial Hypertension
Sponsor:
Sao Jose do Rio Preto Medical School
Organization:
Sao Jose do Rio Preto Medical School
Study Overview
Official Title:
Resistant Hypertension On Treatment - Sequential Nephron Blockade Compared to Dual Blockade of the Renin-angiotensin-aldosterone System Plus Bisoprolol in the Treatment of Resistant Arterial Hypertension A Randomized Trial ResHypOT
Status:
COMPLETED
Status Verified Date:
2019-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ResHypOT
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 fibrillationatrioventricular 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
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 fibrillationatrioventricular 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
Detailed Description:
Introduction
Resistant hypertension RH is characterized when the blood pressure BP remains above the recommended goal after taking three antihypertensive drugs with synergistic actions at their maximum recommended tolerated doses for at least six months one preferably should be a diuretic True RH should be differentiated from pseudo resistance which occurs due to non-adherence to treatment inadequate BP measurements inadequate doses of medications inappropriate therapeutic regimens or the presence of the so-called white-coat effect
The exact prevalence of RH is unknown In controlled randomized studies with thousands of hypertensive patients approximately 25 to 30 of participants did not achieve the BP goal recommended by guidelines despite receiving three or more antihypertensive drugs these studies included careful assessments of adherence to therapy and even ambulatory BP monitoring ABPM which excludes patients with pseudo resistance
Observational data from the North American National Health and Nutrition Examination Survey NHANES collected in 2003-2008 showed that the prevalence of RH among adults diagnosed with hypertension HTN in this period was 89 and among adults on antihypertensive treatment it was 128 Similarly a large population study in Spain 68000 patients found that the prevalence of RH was 148 among those treated for HTN Based on these recent studies it is justifiable to say that the prevalence of RH is about 14 RH is a difficult-to-manage clinical condition due to failure of patients to adhere to treatment the physicians difficulty to adjust the medication because of genetic factors that hinder the effectiveness of treatment and medical inertia
Pathophysiology of resistant hypertension The mechanisms involved in the pathophysiology of RH are the vascular smooth muscle tone and increased blood volume intensification of the activity of the sympathetic system and hyperactivity of the renin-angiotensin-aldosterone system RAAS Increased sensitivity to sodium appears to be the main factor in understanding the pathophysiology of this syndrome not only as it incorporates the above mechanisms but also as it explains in part the variability of therapeutic response of patients with RH The RAAS is vital to the regulatory system that controls total body sodium as are atrial natriuretic peptide factors and pressure receptors in the atria and kidney Sodium and water retention can lead to resistance against antihypertensive drugs Under the physiological point of view BP is maintained by continuous regulation of cardiac output and peripheral vascular resistance exerted at three anatomic sites arterioles postcapillary venules capacitance vessels and the heart A fourth anatomical site of control the kidney contributes to the maintenance of BP by regulating intravascular volume
Rational
Thus identifying the contribution of volume and serum renin in maintaining BP levels could help tailor treatment with a more effective choice for hypertension control whether by acting on the control of volume or sodium balance or by acting on the effects of the RAAS on the kidney
Sequential nephron blockade 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 blockade of the RAAS is to increase the effect of the 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 the 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
Research question
The following research questions will be explored Do sequential nephron blockade SNB and dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol DBB constitute good therapeutic options in the reduction of peripheral blood pressure of patients with RH Which therapeutic option is able to reduce the central BP of resistant hypertensive patients Is the strategy of SNB as good as DBB Objectives This study will compare two antihypertensive treatment regimens in RH patients of the Medical School in Sao Jose do Rio Preto It aims to demonstrate the therapeutic efficacy of SNB against DBB in RH patients and to assess the side effects and adherence to therapy over 20 weeks of treatment
Methods
A randomized clinical trial with two therapeutic regimens for RH SNB and DBB will be compared in an open-label prospective study at the Medical School in Sao Jose do Rio Preto
Eighty 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 - 40 patients will receive in addition to the basal therapy spironolactone 25 mg spironolactone 25 mg plus furosemide 20 mg spironolactone 25 mg plus furosemide 40 mg and spironolactone 25 mg plus furosemide 40 mg plus amiloride 5 mg sequentially
Group 2 Dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol DBB Group - 40 patients will receive in addition to the basal therapy ramipril 5 mg ramipril 10 mg ramipril 10 mg plus bisoprolol 5 mg and ramipril 10 mg plus bisoprolol 10 mg sequentially
Forty patients fulfilling the following criteria will be enrolled in each group
The project was approved by the Research Ethics Committee of Hospital de Base of the Medical School in São José do Rio Preto FAMERP and Brazilian Research Ethics Committee 33943014600005415
The nature of the study was carefully explained to patients and all individuals after agreeing to participate in the study signed informed consent forms and filled out a standard questionnaire
Measurement of BP including 24-h ambulatory BP monitoring ABPM The BP will be measured by the indirect method following the VI Brazilian Guidelines for the Treatment of Hypertension
ABPM and home BP measurement will be carried out as additional tools to investigate hypertension according to the technical norms of the 5th Brazilian Guidelines on Ambulatory Blood Pressure Monitoring
ABPM will be performed using the Mobil-O-Graph Netherlands Anthropometric measurements Weight and height measured by anthropometric scales will be used to calculate the body mass index BMI utilizing the formula BMI weight kgheight squared m² The abdominal circumference will be measured at the midpoint between the iliac crest and the lower costal margin Values equal to or below 80 cm and 94 cm are considered appropriate for women and for men respectively
Biochemical tests and imaging Blood samples will be drawn from all patients at the first and last visits after fasting for 12 hours to measure total cholesterol high-density lipoprotein cholesterol low-density lipoprotein cholesterol very low-density lipoprotein cholesterol triglycerides glucose insulin creatinine sodium and potassium
All patients will be submitted to electrocardiography echocardiography carotid Doppler ultrasound with Doppler of the renal arteries stress testing and radial artery applanation tonometry AT
Study design
Patients will be analyzed in five visits at 28-day intervals V zero Week -4 to Week 0 All patients will remain under treatment with losartan 100 - 200 mg chlorthalidone 25 mg and amlodipine 5 mg Individuals with BP 13585 mmHg by ABPM will be randomized to one of the study groups
V1 Week 0 to Week 4 Individuals receive 25 mg of spironolactone SNB Group or 5 mg of ramipril DBB Group
V2 Week 4 to Week 8 Individuals with BP 13585 mmHg by ABPM will continue using the same regimen Subjects with BP 13585 mmHg by ABPM will receive in addition to their existing regimen furosemide 20 mg for the SNB Group and ramipril 10 mg for the DBB Group
V3 Week 8 to Week 12 Subjects with BP 13585 mmHg by ABPM will continue on the same regimen Individuals with BP 13585 mmHg by ABPM will receive an extra 40 mg of furosemide for patients in the SNB Group and 5 mg of bisoprolol for patients in the DBB Group
V4 Week 12 to Week 16 Subjects with BP 13585 mmHg by ABPM will continue using the same regimen Individuals with BP 13585 mmHg by ABPM will receive an extra 5 mg of amiloride for patients in the SNB Group and 10 mg of bisoprolol for patients in the DBB Group
V5 Week 16 to Week 20 Subjects will continue using the same regimen Blood samples will be drawn from all patients Radial artery applanation tonometry and ABPM will be performed
Statistical analysis The t-test or Wilcoxon test for quantitative variables and chi-square and Fisher test for qualitative variables were used in the comparative analysis of the clinical characteristics of RHTN patients Data were expressed as means 1 standard deviation
The sample size was estimated at 72 individuals for an expected zero difference with a SD of 12 mmHg to demonstrate the non-inferiority of the strategy of SNB compared to RASDB plus bisoprolol assuming an absolute difference of 5 mmHg for systolic BP
Non-inferiority was evaluated for a one-sided 95 confidence interval CI estimated by a linear mixed model for repeated measures P-values 005 will be considered statistically significant
Primary outcomes
Reduction of systolic BP diastolic BP mean BP and pulse pressure after 20 weeks of treatment with sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol
Secondary outcomes
Safety and tolerability biochemical changes evaluation of the renal function and recognition of hypotension ABPM Assessment of BP outcomes mean of three measurements by an automatic electronic device - Omron 711 and hemodynamic parameters Omron 9000 device will be measured in the office at all follow-up visits
Missing or dropout Participants Patients will be registered with a phone number and address for further contact in case of missing visits
Sample size
The calculation of the sample size with an alpha error of 5 statistical power of 80 standard deviation of 8 mmHg and maximum acceptable absolute difference of 6 mmHg diastolic BP indicated the necessity to study 36 patients per group SNB versus DBB However considering a potential rate of 10-15 dropout or loss to follow-up 40 will be considered for each group The difference of 5 mmHg diastolic BP has been achieved on average in clinical trials that have demonstrated the advantage of one drug over placebo or other non-pharmacological treatments in the prevention of major cardiovascular outcomes
No washout period will be used Results Baseline clinical characteristics and laboratory parameters of the 72 patients with primary resistant hypertension randomized to SNB n35 or RASDB n37 were similar across both study groups At the end of the study a significant reduction of the office pressure was observed SBP and DBP in both after intervention groups SNB group initial SBP 1745 2108 final SBP 1270 1474 Initial DBP 1053 155 final DBP 7811 928 p 00001 RASDB group initial SBP 1784 2108 final SBP 1344 2325 initial DBP 1027 1107 final DBP 7733 1375 p 00001
Central systolic pressure had a greater reduction in the SNB group p 0005 ABPM had a significant reduction of SBP and DBP in both groups SNB group p 00001 for SBP and DBP before x after intervention RASDB group p 00001 for SBP and DBP before x after intervention No discontinuation due to drug-related adverse events in both study groups
Resistant hypertension RH is characterized when the blood pressure BP remains above the recommended goal after taking three antihypertensive drugs with synergistic actions at their maximum recommended tolerated doses for at least six months one preferably should be a diuretic True RH should be differentiated from pseudo resistance which occurs due to non-adherence to treatment inadequate BP measurements inadequate doses of medications inappropriate therapeutic regimens or the presence of the so-called white-coat effect
The exact prevalence of RH is unknown In controlled randomized studies with thousands of hypertensive patients approximately 25 to 30 of participants did not achieve the BP goal recommended by guidelines despite receiving three or more antihypertensive drugs these studies included careful assessments of adherence to therapy and even ambulatory BP monitoring ABPM which excludes patients with pseudo resistance
Observational data from the North American National Health and Nutrition Examination Survey NHANES collected in 2003-2008 showed that the prevalence of RH among adults diagnosed with hypertension HTN in this period was 89 and among adults on antihypertensive treatment it was 128 Similarly a large population study in Spain 68000 patients found that the prevalence of RH was 148 among those treated for HTN Based on these recent studies it is justifiable to say that the prevalence of RH is about 14 RH is a difficult-to-manage clinical condition due to failure of patients to adhere to treatment the physicians difficulty to adjust the medication because of genetic factors that hinder the effectiveness of treatment and medical inertia
Pathophysiology of resistant hypertension The mechanisms involved in the pathophysiology of RH are the vascular smooth muscle tone and increased blood volume intensification of the activity of the sympathetic system and hyperactivity of the renin-angiotensin-aldosterone system RAAS Increased sensitivity to sodium appears to be the main factor in understanding the pathophysiology of this syndrome not only as it incorporates the above mechanisms but also as it explains in part the variability of therapeutic response of patients with RH The RAAS is vital to the regulatory system that controls total body sodium as are atrial natriuretic peptide factors and pressure receptors in the atria and kidney Sodium and water retention can lead to resistance against antihypertensive drugs Under the physiological point of view BP is maintained by continuous regulation of cardiac output and peripheral vascular resistance exerted at three anatomic sites arterioles postcapillary venules capacitance vessels and the heart A fourth anatomical site of control the kidney contributes to the maintenance of BP by regulating intravascular volume
Rational
Thus identifying the contribution of volume and serum renin in maintaining BP levels could help tailor treatment with a more effective choice for hypertension control whether by acting on the control of volume or sodium balance or by acting on the effects of the RAAS on the kidney
Sequential nephron blockade 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 blockade of the RAAS is to increase the effect of the 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 the 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
Research question
The following research questions will be explored Do sequential nephron blockade SNB and dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol DBB constitute good therapeutic options in the reduction of peripheral blood pressure of patients with RH Which therapeutic option is able to reduce the central BP of resistant hypertensive patients Is the strategy of SNB as good as DBB Objectives This study will compare two antihypertensive treatment regimens in RH patients of the Medical School in Sao Jose do Rio Preto It aims to demonstrate the therapeutic efficacy of SNB against DBB in RH patients and to assess the side effects and adherence to therapy over 20 weeks of treatment
Methods
A randomized clinical trial with two therapeutic regimens for RH SNB and DBB will be compared in an open-label prospective study at the Medical School in Sao Jose do Rio Preto
Eighty 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 - 40 patients will receive in addition to the basal therapy spironolactone 25 mg spironolactone 25 mg plus furosemide 20 mg spironolactone 25 mg plus furosemide 40 mg and spironolactone 25 mg plus furosemide 40 mg plus amiloride 5 mg sequentially
Group 2 Dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol DBB Group - 40 patients will receive in addition to the basal therapy ramipril 5 mg ramipril 10 mg ramipril 10 mg plus bisoprolol 5 mg and ramipril 10 mg plus bisoprolol 10 mg sequentially
Forty patients fulfilling the following criteria will be enrolled in each group
The project was approved by the Research Ethics Committee of Hospital de Base of the Medical School in São José do Rio Preto FAMERP and Brazilian Research Ethics Committee 33943014600005415
The nature of the study was carefully explained to patients and all individuals after agreeing to participate in the study signed informed consent forms and filled out a standard questionnaire
Measurement of BP including 24-h ambulatory BP monitoring ABPM The BP will be measured by the indirect method following the VI Brazilian Guidelines for the Treatment of Hypertension
ABPM and home BP measurement will be carried out as additional tools to investigate hypertension according to the technical norms of the 5th Brazilian Guidelines on Ambulatory Blood Pressure Monitoring
ABPM will be performed using the Mobil-O-Graph Netherlands Anthropometric measurements Weight and height measured by anthropometric scales will be used to calculate the body mass index BMI utilizing the formula BMI weight kgheight squared m² The abdominal circumference will be measured at the midpoint between the iliac crest and the lower costal margin Values equal to or below 80 cm and 94 cm are considered appropriate for women and for men respectively
Biochemical tests and imaging Blood samples will be drawn from all patients at the first and last visits after fasting for 12 hours to measure total cholesterol high-density lipoprotein cholesterol low-density lipoprotein cholesterol very low-density lipoprotein cholesterol triglycerides glucose insulin creatinine sodium and potassium
All patients will be submitted to electrocardiography echocardiography carotid Doppler ultrasound with Doppler of the renal arteries stress testing and radial artery applanation tonometry AT
Study design
Patients will be analyzed in five visits at 28-day intervals V zero Week -4 to Week 0 All patients will remain under treatment with losartan 100 - 200 mg chlorthalidone 25 mg and amlodipine 5 mg Individuals with BP 13585 mmHg by ABPM will be randomized to one of the study groups
V1 Week 0 to Week 4 Individuals receive 25 mg of spironolactone SNB Group or 5 mg of ramipril DBB Group
V2 Week 4 to Week 8 Individuals with BP 13585 mmHg by ABPM will continue using the same regimen Subjects with BP 13585 mmHg by ABPM will receive in addition to their existing regimen furosemide 20 mg for the SNB Group and ramipril 10 mg for the DBB Group
V3 Week 8 to Week 12 Subjects with BP 13585 mmHg by ABPM will continue on the same regimen Individuals with BP 13585 mmHg by ABPM will receive an extra 40 mg of furosemide for patients in the SNB Group and 5 mg of bisoprolol for patients in the DBB Group
V4 Week 12 to Week 16 Subjects with BP 13585 mmHg by ABPM will continue using the same regimen Individuals with BP 13585 mmHg by ABPM will receive an extra 5 mg of amiloride for patients in the SNB Group and 10 mg of bisoprolol for patients in the DBB Group
V5 Week 16 to Week 20 Subjects will continue using the same regimen Blood samples will be drawn from all patients Radial artery applanation tonometry and ABPM will be performed
Statistical analysis The t-test or Wilcoxon test for quantitative variables and chi-square and Fisher test for qualitative variables were used in the comparative analysis of the clinical characteristics of RHTN patients Data were expressed as means 1 standard deviation
The sample size was estimated at 72 individuals for an expected zero difference with a SD of 12 mmHg to demonstrate the non-inferiority of the strategy of SNB compared to RASDB plus bisoprolol assuming an absolute difference of 5 mmHg for systolic BP
Non-inferiority was evaluated for a one-sided 95 confidence interval CI estimated by a linear mixed model for repeated measures P-values 005 will be considered statistically significant
Primary outcomes
Reduction of systolic BP diastolic BP mean BP and pulse pressure after 20 weeks of treatment with sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol
Secondary outcomes
Safety and tolerability biochemical changes evaluation of the renal function and recognition of hypotension ABPM Assessment of BP outcomes mean of three measurements by an automatic electronic device - Omron 711 and hemodynamic parameters Omron 9000 device will be measured in the office at all follow-up visits
Missing or dropout Participants Patients will be registered with a phone number and address for further contact in case of missing visits
Sample size
The calculation of the sample size with an alpha error of 5 statistical power of 80 standard deviation of 8 mmHg and maximum acceptable absolute difference of 6 mmHg diastolic BP indicated the necessity to study 36 patients per group SNB versus DBB However considering a potential rate of 10-15 dropout or loss to follow-up 40 will be considered for each group The difference of 5 mmHg diastolic BP has been achieved on average in clinical trials that have demonstrated the advantage of one drug over placebo or other non-pharmacological treatments in the prevention of major cardiovascular outcomes
No washout period will be used Results Baseline clinical characteristics and laboratory parameters of the 72 patients with primary resistant hypertension randomized to SNB n35 or RASDB n37 were similar across both study groups At the end of the study a significant reduction of the office pressure was observed SBP and DBP in both after intervention groups SNB group initial SBP 1745 2108 final SBP 1270 1474 Initial DBP 1053 155 final DBP 7811 928 p 00001 RASDB group initial SBP 1784 2108 final SBP 1344 2325 initial DBP 1027 1107 final DBP 7733 1375 p 00001
Central systolic pressure had a greater reduction in the SNB group p 0005 ABPM had a significant reduction of SBP and DBP in both groups SNB group p 00001 for SBP and DBP before x after intervention RASDB group p 00001 for SBP and DBP before x after intervention No discontinuation due to drug-related adverse events in both study groups
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None