Ignite Creation Date:
2024-05-05 @ 12:03 PM
Last Modification Date:
2024-10-26 @ 9:19 AM
Study NCT ID:
NCT00232882
Status:
COMPLETED
Last Update Posted:
2013-09-04
First Post:
2005-10-03
Brief Title:
Pharmacodynamic Influences of Candesartan Atenolol Hydrochlorothiazide and Drug Combinations in Hypertensive Patients
Sponsor:
Institut de Recherches Cliniques de Montreal
Organization:
Institut de Recherches Cliniques de Montreal
Study Overview
Official Title:
Neurohumoral and Oxidative Influences of Candesartan Atenolol Hydrochlorothiazide and Drug Combinations in Essential Hypertensive Patients
Status:
COMPLETED
Status Verified Date:
2013-08
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:
None
Brief Summary:
Angiotensin receptor antagonists ARA beta-blockers and diuretics do not seem to confer equivalent cardiovascular protection in hard outcomes clinical trials beta blockers inferior These results may be explained by differences in their effects on sympathetic activity oxidative stress inflammation and renin angiotensin system activation
How diuretic addition to first line therapy with ARAs and beta-blockers modulates neurohumoral and hemodynamic parameters is not well understood
The main hypothesis of this study is that an ARA candesartan combined or not with a diuretic will not increase sympathetic activity as much as a beta blocker atenolol Secondary hypothesis are of similar nature but relate to hemodynamic parameters oxidative stress markers inflammatory markers or the renin angiotensin system
The main objective of this study is to assess and compare the effects of candesartan and atenolol and their combination with low dose diuretic therapy on the autonomic nervous system hemodynamic parameterson oxidative stress on inflammatory markers and on the renin-angiotensin system
Protocol sponsored by Astra Zeneca canada
How diuretic addition to first line therapy with ARAs and beta-blockers modulates neurohumoral and hemodynamic parameters is not well understood
The main hypothesis of this study is that an ARA candesartan combined or not with a diuretic will not increase sympathetic activity as much as a beta blocker atenolol Secondary hypothesis are of similar nature but relate to hemodynamic parameters oxidative stress markers inflammatory markers or the renin angiotensin system
The main objective of this study is to assess and compare the effects of candesartan and atenolol and their combination with low dose diuretic therapy on the autonomic nervous system hemodynamic parameterson oxidative stress on inflammatory markers and on the renin-angiotensin system
Protocol sponsored by Astra Zeneca canada
Detailed Description:
INTRODUCTION
Three large clinical trials STOP-2 HOPE LIFE Hansson Lindholm et al 1999Dahlof Devereux et al 2002Yusuf Sleight et al 2000 have suggested that drugs that specifically inhibit the renin angiotensin system RAS such as ACE inhibitors and Angiotensin Receptor Antagonists ARA have blood pressure-independant cardiovascular protecting effects In the most recent of these studies the LIFE trial Losartan-based therapy was superior to atenolol-based therapy in hypertensive patients with left ventricular hypertrophy Dahlof Devereux et al 2002 Very recently the ALLHAT mega-trial suggested that diuretics were as good as ACE inhibitors for cardiovascular protection in hypertensive patients Major outcomes in moderately hypercholesterolemic hypertensive patients randomized to pravastatin vs usual care The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ALLHAT-LLT These apparently conflicting results underline that the mechanisms of cardiovascular protections are not well understood
ARAs Balt Mathy et al 2001Moreau Richer et al 1993 have sympathoinhibitory properties while beta-blockers induce a small counterregulatory activation of the sympathetic system Lijnen Amery et al 1979Sundlof Wallin et al 1983van den Meiracker Man in t Veld AJ et al 1988We have shown recently that telmisartan prevents the increase in NE normally associated with a reduction in BP while there are reports that diuretics tend to stimulate the sympathetic system Fernandez Snedden et al 1987Lake Ziegler et al 1979 It has been suggested that the superiority of ARAs could be due to their unique effects on the autonomic nervous system
Angiotensin II receptor antagonism also decrease the oxidative stress induced by angiotensin II and aldosterone de Cavanagh Ferder et al 1999Hornig Landmesser et al 2001Onozato Tojo et al 2002We have also shown that telmisartan decreases plasma aldosterone and should therefore decrease the oxidative stress associated with a reduction in aldosterone Hydrochlorothiazide and beta-blockers have not been shown to have antioxidative properties Welch Wilcox 2001Taddei Virdis et al 2001 It is possible that oxidative stress partly explains the differences between pharmacological agents
Patients included in high blood pressure clinical trials are randomized to a therapeutic strategy meaning that a stepped care approach is taken Hypertensive patients frequently need more than one drug for appropriate blood pressure control Consequently about half of study patients in these trials end up taking more than one drug during the study First step therapy is by definition prescribed to all study subjects but second or third step therapy are not as well defined In the HOPE trial ramipril was added on top of usual treatment Most of the patients included in HOPE LIFE STOP-2 and ALLHAT took at least one other antihypertensive drug most frequently a thiazide diuretic Though results were reported as being ACE inhibitor or ARA based they mostly reflect a mix of single drug and multiple drugs therapy Whether the beneficial effects of ARAs and beta-blockers are modulated by thiazide diuretics is presently unknown
We designed a parallel study that primarily assesses the differences between ARAs diuretics and beta-blockers The simultaneously measured parameters reflect renin-angiotensin system activity sympathetic activity oxidative stress and systemic inflammation Secondarily this study assesses the effects of ARA-diuretic and B-blocker-diuretic combinations on the same parameters
Results from this study will help to understand the results from the previously mentioned clinical trials The forced titration from monotherapy to a combination therapy will allow us to measure the influence of drug addition on clinically significant parameters The simultaneous assessment of renin-angiotensin system activity sympathetic activity oxidative stress and systemic inflammation will allow us to observe baseline and pharmacologically-induced associations
It is also probable that results from this study will have direct clinical influences on high blood pressure therapeutic strategies Physicians treating hypertension frequently have to choose between increasing drug doses to their maximum or adding a new drug It is presently unknown if one strategy offers more benefits than the other This study should provide physicians with clues about the expected benefits for each approach
GOALS
To assess and compare the effects of candesartan and atenolol combined with low dose diuretic therapy on the autonomic nervous system on oxidative stress on inflammatory markers and on the renin-angiotensin system
To assess and compare the effects of candesartan and atenolol and low dose diuretic therapy on the autonomic nervous system on inflammatory markers on oxidative stress on inflammatory markers and on the renin angiotensin system
PRIMARY OBJECTIVE
1 To measure and compare the effects candesartan 16 mg HCT 125 mg candesartan 16 mg HCT 250 mg and atenolol 100 125 mg on noradrenalin release 4h post-dose at trough and after a 10 minute stand
SECONDARY OBJECTIVES
1 To measure and compare the effects candesartan 16 mg HCT 125 mg candesartan 16 mg HCT 250 mg and atenolol 100 125 mg on
1 frequency power spectral analysis 4h post-dose and after a 10 minute stand
2 oxidative stress inflammatory markers and adhesion molecules 4h post-dose
3 renin aldosterone and angiotensin II releaseproduction 4h post-dose and at trough
4 Insulin and glucose plasma concentration
2 To measure and compare the influences of HCT 25 mg candesartan 16 mg and atenolol 100 mg monotherapy on
1 noradrenalin release 4h post-dose at trough and after a 10 minute stand
2 frequency power spectral analysis 4h post-dose and after a 10 minute stand
3 oxidative stress inflammatory markers and adhesion molecules 4h post-dose
4 renin aldosterone and angiotensin II releaseproduction 4h post-dose and at trough
5 Insulin and glucose plasma concentration
DESIGN
Prospective randomized open label 3 arm 2 period parallel study preceded by a placebo run in period in non-diabetic patients with essential hypertension
Titration period introduction of hydrochlorothiazide 125 mg daily atenolol 50 mg daily and candesartan 8 mg daily in the diuretic beta-blocker and angiotensin receptor blocker groups respectively First study period 4 weeks comparison of hydrochlorothiazide 25 mg atenolol 100 mg and candesartan 16mg Second study period 4 weeks comparison of hydrochlorothiazide 25 mg candesartan 16 mg atenolol 100 mg HCT 125 mg and candesartan 16mg HCT 125 mg Measurement of study parameters at trough 4h post-dose and after a 10 minutes stand after placebo and after each study period
MEASURED STUDY PARAMETERS
1 Blood pressure
2 24h blood pressure
3 Spectral analysis of heart rate LF HF LFHF
4 Plasma
1 renin
2 aldosterone
3 angiotensin II
4 catecholamines
5 8-epi-isoprostane
6 Thiobarbituric acid reactive substances TBARS
7 nitrotyrosine
8 interleukin 18
9 E selectine
10 C reactive protein
11 Insulin
12 glucose
5 Urine
1 8-epi-isoprostane
2 sodium concentration
3 creatinine concentration
Protocol Sponsored by Astra Zeneca Canada
Three large clinical trials STOP-2 HOPE LIFE Hansson Lindholm et al 1999Dahlof Devereux et al 2002Yusuf Sleight et al 2000 have suggested that drugs that specifically inhibit the renin angiotensin system RAS such as ACE inhibitors and Angiotensin Receptor Antagonists ARA have blood pressure-independant cardiovascular protecting effects In the most recent of these studies the LIFE trial Losartan-based therapy was superior to atenolol-based therapy in hypertensive patients with left ventricular hypertrophy Dahlof Devereux et al 2002 Very recently the ALLHAT mega-trial suggested that diuretics were as good as ACE inhibitors for cardiovascular protection in hypertensive patients Major outcomes in moderately hypercholesterolemic hypertensive patients randomized to pravastatin vs usual care The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ALLHAT-LLT These apparently conflicting results underline that the mechanisms of cardiovascular protections are not well understood
ARAs Balt Mathy et al 2001Moreau Richer et al 1993 have sympathoinhibitory properties while beta-blockers induce a small counterregulatory activation of the sympathetic system Lijnen Amery et al 1979Sundlof Wallin et al 1983van den Meiracker Man in t Veld AJ et al 1988We have shown recently that telmisartan prevents the increase in NE normally associated with a reduction in BP while there are reports that diuretics tend to stimulate the sympathetic system Fernandez Snedden et al 1987Lake Ziegler et al 1979 It has been suggested that the superiority of ARAs could be due to their unique effects on the autonomic nervous system
Angiotensin II receptor antagonism also decrease the oxidative stress induced by angiotensin II and aldosterone de Cavanagh Ferder et al 1999Hornig Landmesser et al 2001Onozato Tojo et al 2002We have also shown that telmisartan decreases plasma aldosterone and should therefore decrease the oxidative stress associated with a reduction in aldosterone Hydrochlorothiazide and beta-blockers have not been shown to have antioxidative properties Welch Wilcox 2001Taddei Virdis et al 2001 It is possible that oxidative stress partly explains the differences between pharmacological agents
Patients included in high blood pressure clinical trials are randomized to a therapeutic strategy meaning that a stepped care approach is taken Hypertensive patients frequently need more than one drug for appropriate blood pressure control Consequently about half of study patients in these trials end up taking more than one drug during the study First step therapy is by definition prescribed to all study subjects but second or third step therapy are not as well defined In the HOPE trial ramipril was added on top of usual treatment Most of the patients included in HOPE LIFE STOP-2 and ALLHAT took at least one other antihypertensive drug most frequently a thiazide diuretic Though results were reported as being ACE inhibitor or ARA based they mostly reflect a mix of single drug and multiple drugs therapy Whether the beneficial effects of ARAs and beta-blockers are modulated by thiazide diuretics is presently unknown
We designed a parallel study that primarily assesses the differences between ARAs diuretics and beta-blockers The simultaneously measured parameters reflect renin-angiotensin system activity sympathetic activity oxidative stress and systemic inflammation Secondarily this study assesses the effects of ARA-diuretic and B-blocker-diuretic combinations on the same parameters
Results from this study will help to understand the results from the previously mentioned clinical trials The forced titration from monotherapy to a combination therapy will allow us to measure the influence of drug addition on clinically significant parameters The simultaneous assessment of renin-angiotensin system activity sympathetic activity oxidative stress and systemic inflammation will allow us to observe baseline and pharmacologically-induced associations
It is also probable that results from this study will have direct clinical influences on high blood pressure therapeutic strategies Physicians treating hypertension frequently have to choose between increasing drug doses to their maximum or adding a new drug It is presently unknown if one strategy offers more benefits than the other This study should provide physicians with clues about the expected benefits for each approach
GOALS
To assess and compare the effects of candesartan and atenolol combined with low dose diuretic therapy on the autonomic nervous system on oxidative stress on inflammatory markers and on the renin-angiotensin system
To assess and compare the effects of candesartan and atenolol and low dose diuretic therapy on the autonomic nervous system on inflammatory markers on oxidative stress on inflammatory markers and on the renin angiotensin system
PRIMARY OBJECTIVE
1 To measure and compare the effects candesartan 16 mg HCT 125 mg candesartan 16 mg HCT 250 mg and atenolol 100 125 mg on noradrenalin release 4h post-dose at trough and after a 10 minute stand
SECONDARY OBJECTIVES
1 To measure and compare the effects candesartan 16 mg HCT 125 mg candesartan 16 mg HCT 250 mg and atenolol 100 125 mg on
1 frequency power spectral analysis 4h post-dose and after a 10 minute stand
2 oxidative stress inflammatory markers and adhesion molecules 4h post-dose
3 renin aldosterone and angiotensin II releaseproduction 4h post-dose and at trough
4 Insulin and glucose plasma concentration
2 To measure and compare the influences of HCT 25 mg candesartan 16 mg and atenolol 100 mg monotherapy on
1 noradrenalin release 4h post-dose at trough and after a 10 minute stand
2 frequency power spectral analysis 4h post-dose and after a 10 minute stand
3 oxidative stress inflammatory markers and adhesion molecules 4h post-dose
4 renin aldosterone and angiotensin II releaseproduction 4h post-dose and at trough
5 Insulin and glucose plasma concentration
DESIGN
Prospective randomized open label 3 arm 2 period parallel study preceded by a placebo run in period in non-diabetic patients with essential hypertension
Titration period introduction of hydrochlorothiazide 125 mg daily atenolol 50 mg daily and candesartan 8 mg daily in the diuretic beta-blocker and angiotensin receptor blocker groups respectively First study period 4 weeks comparison of hydrochlorothiazide 25 mg atenolol 100 mg and candesartan 16mg Second study period 4 weeks comparison of hydrochlorothiazide 25 mg candesartan 16 mg atenolol 100 mg HCT 125 mg and candesartan 16mg HCT 125 mg Measurement of study parameters at trough 4h post-dose and after a 10 minutes stand after placebo and after each study period
MEASURED STUDY PARAMETERS
1 Blood pressure
2 24h blood pressure
3 Spectral analysis of heart rate LF HF LFHF
4 Plasma
1 renin
2 aldosterone
3 angiotensin II
4 catecholamines
5 8-epi-isoprostane
6 Thiobarbituric acid reactive substances TBARS
7 nitrotyrosine
8 interleukin 18
9 E selectine
10 C reactive protein
11 Insulin
12 glucose
5 Urine
1 8-epi-isoprostane
2 sodium concentration
3 creatinine concentration
Protocol Sponsored by Astra Zeneca Canada
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