Ignite Creation Date:
2024-05-05 @ 5:11 PM
Last Modification Date:
2024-10-26 @ 9:29 AM
Study NCT ID:
NCT00404599
Status:
UNKNOWN
Last Update Posted:
2008-06-10
First Post:
2006-11-27
Brief Title:
Oxidative Stress Lowering Effect of Simvastatin and Atorvastatin
Sponsor:
Amsterdam UMC location VUmc
Organization:
Amsterdam UMC location VUmc
Study Overview
Official Title:
A Randomised Double Blind Parallel-Group Study of the Oxidative Stress Lowering Effect of Simvastatin and Atorvastatin
Status:
UNKNOWN
Status Verified Date:
2008-06
Last Known Status:
RECRUITING
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:
SOS
Brief Summary:
Background HMG-CoA reductase inhibitors statins are effective lipid-lowering agents and are known to reduce cardiovascular events Beneficial effects of statins seem to occur very early in the course of their therapy and subgroup analysis of large trials indicates that subjects in statin-treated arms have less cardiovascular events than subjects in placebo-controlled arm with comparable serum cholesterol levels Therefore it has been suggested that statins may have antiatherogenic effects beyond their cholesterol lowering effect Many studies have demonstrated a rapid improvement in vascular function with atorvastatine which cannot solely be accounted for by achieved lipid reduction A rapid oxidative stress lowering effect of atorvastatin has been proposed as the probable mechanism of this action Whether atorvastatine has stronger antioxidant effect and whether atorvastatin lowers oxidative stress earlier in the course of therapy than other statins has not been studied yet
Objective To compare the rapidity of onset and the extent of oxidative stress lowering of atorvastatin with that of an in terms of LDL lowering equipotent dosage of simvastatin
Methods We plan to recruit sixty statin naive patients with diabetes mellitus type 2 andor obesity BMI 25 andor hypertension RR14090 mmHg Patients with KDOQI stage 5 chronic kidney disease Cockcroft-Gault clearance of less than 15 mlmin173m2 patients who use any vitamin preparation or statins in the last three months and patients with LDL cholestrerol 25 mmoll will be excluded from the study Because of the influence of angiotensin-converting enzyme inhibitors ACE-inhibitors on oxidative stress patients will be stratified for prior ACE-inhibitor use during randomization All included patients are randomized to treatment with simvastatin 40 mg daily or atorvastatin 10 mg daily to achieve a comparable lipid reduction Established parameters of oxidative stress such as oxidized LDL malondealdehyde and isoprostane will be measured in plasma on inclusion one week six weeks and three months after inclusion We also plan to measure endothelial function parameters such as soluble Vascular Adhesion Molecule sVCAM and von Willebrand factor In addition parameters of inflammation such as high sensitive C - reactive protein TNF-alfa interleukin-6 and myeloperoxidase will be measured to investigate whether there is any correlation between oxidative stress lowering and endothelial function and inflammation The inhibitory effect of HDL to prevent oxidation of LDL will be determined by measurement of lipid peroxides formed during in vitro oxidation of LDL co-incubated with HDL The inflammatory anti-inflammatory properties of HDL will be tested by measurement of the HDL capacity to inactivate oxidized palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine ox-PAPC Collections of 24 hours of urine at the beginning and after one week six weeks and three months will be used to measure urine F2-isoprostane levels
Analyses All parameters of oxidative stress before and during treatment with both statins will be compared to determine whether atorvastatin causes a stronger and quicker reduction of oxidative stress than simvastatin Generalized estimating equations GEE will be used to compare these effects We plan to include a minimum of 30 patients in each treatment-group from the outpatient clinic of the department of internal medicine of the VU University Medical Center in Amsterdam
Expected results Atorvastatin will reduce oxidative parameters stronger and earlier than simvastatin
Objective To compare the rapidity of onset and the extent of oxidative stress lowering of atorvastatin with that of an in terms of LDL lowering equipotent dosage of simvastatin
Methods We plan to recruit sixty statin naive patients with diabetes mellitus type 2 andor obesity BMI 25 andor hypertension RR14090 mmHg Patients with KDOQI stage 5 chronic kidney disease Cockcroft-Gault clearance of less than 15 mlmin173m2 patients who use any vitamin preparation or statins in the last three months and patients with LDL cholestrerol 25 mmoll will be excluded from the study Because of the influence of angiotensin-converting enzyme inhibitors ACE-inhibitors on oxidative stress patients will be stratified for prior ACE-inhibitor use during randomization All included patients are randomized to treatment with simvastatin 40 mg daily or atorvastatin 10 mg daily to achieve a comparable lipid reduction Established parameters of oxidative stress such as oxidized LDL malondealdehyde and isoprostane will be measured in plasma on inclusion one week six weeks and three months after inclusion We also plan to measure endothelial function parameters such as soluble Vascular Adhesion Molecule sVCAM and von Willebrand factor In addition parameters of inflammation such as high sensitive C - reactive protein TNF-alfa interleukin-6 and myeloperoxidase will be measured to investigate whether there is any correlation between oxidative stress lowering and endothelial function and inflammation The inhibitory effect of HDL to prevent oxidation of LDL will be determined by measurement of lipid peroxides formed during in vitro oxidation of LDL co-incubated with HDL The inflammatory anti-inflammatory properties of HDL will be tested by measurement of the HDL capacity to inactivate oxidized palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine ox-PAPC Collections of 24 hours of urine at the beginning and after one week six weeks and three months will be used to measure urine F2-isoprostane levels
Analyses All parameters of oxidative stress before and during treatment with both statins will be compared to determine whether atorvastatin causes a stronger and quicker reduction of oxidative stress than simvastatin Generalized estimating equations GEE will be used to compare these effects We plan to include a minimum of 30 patients in each treatment-group from the outpatient clinic of the department of internal medicine of the VU University Medical Center in Amsterdam
Expected results Atorvastatin will reduce oxidative parameters stronger and earlier than simvastatin
Detailed Description:
Background HMG-CoA reductase inhibitors statins are effective lipid-lowering agents and are known to reduce cardiovascular events It was initially assumed that cholesterol reduction by statins was the only mechanism responsible for their beneficial effect However beneficial effects of statins seem to occur very early in the course of their therapy 1 and subgroup analysis of large trials indicates that subjects in statin-treated arms have less cardiovascular events than subjects in placebo-controlled arm with comparable serum cholesterol levels 2 Therefore it was suggested that statins may have antiatherogenic effects such as anti-inflammatory and antioxidative actions beyond their cholesterol lowering effect Many studies have demonstrated a rapid improvement in vascular function with atorvastatine which cannot solely be accounted for by achieved lipid reduction 3-5 In the Pravastatin or Atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 trial PROVE-IT-TIMI 22 trial with a follow-up period of 2-years and intensive statin therapy 80 mg atorvastatin showed a stronger reduction of cardiovascular events when compared with 40 mg pravastatin with an apparent benefit observed early 6 A rapid and a strong oxidative stress lowering effect of atorvastatin has been proposed as the probable mechanism of this action 7 Other statins have been shown to have anti-oxidant effects as well 89 However whether atorvastatine has stronger antioxidant effect and whether atorvastatin lowers oxidative stress early in the course of therapy than other statins has not been demonstrated up to now
Hypothesis Atorvastatin shows a more rapid and stronger antioxidative effect compared to simvastatin
Study objective The objective of this study is to compare the oxidative stress lowering capacity of atorvastatin the most widely used statin in the US with that of simvastatin in a population of patients with increased oxidative stress in patients with diabetes mellitus 10 hypertension 11 obesity 12 and chronic kidney disease 13 who are known to have increased oxidative stress
Design and methods We plan to recruit sixty statin naive patients with diabetes mellitus type-2 andor obesity BMI 25 kgm2 andor hypertension RR 14090 mmHg Patients with KDOQI stage 5 chronic kidney disease Cockcroft-Gault clearance of less than 15mlmin173m2 and patients who use any vitamin preparation or statins in the last three months will be excluded from the study Because of the documented influence of ACE-inhibitors on oxidative stress we will stratify patients for prior ACE-inhibitor use during randomization All included patients are randomized to treatment with simvastatin 40 mg daily or atorvastatin 10 mg daily in order to achieve a comparable lipid reduction Established parameters of oxidative stress such as oxidized LDL malondealdehyde will be measured 14-18 in plasma on inclusion one week six weeks and three months after the inclusion Primary end point of the study will be the absolute difference between oxidized LDL reduction between the two groups We also plan to measure endothelial function parameters such as soluble Vascular Adhesion Molecule sVCAM and von Willebrand factor In addition parameters of inflammation such as high sensitive c-reactive protein TNF-alfa and Interleuking-6 will also be measured to investigate whether there is any correlation between eventual oxidative stress lowering and endothelial function and inflammation The inhibitory effect of HDL to prevent oxidation of LDL will be determined by measurement of lipid peroxides formed during in vitro oxidation of LDL co-incubated with HDL The anti-inflammatory properties of HDL will be tested by measurement of the HDL capacity to inactivate oxidized palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine ox-PAPC For this measurement we will use a cell-free assay that has been developed by Navab and co-workers 19 Collections of 24 hours of urine at the beginning and after one week and three months will be used to measure urine F2-isoprostane levels 20-24
Power calculation
The number of patients needed to detect an absolute Oxidized LDL difference of 9 UL between the two groups over 3 months with a power of 80 α of 005 and a SD of 12 was 30 patients per group
Hypothesis Atorvastatin shows a more rapid and stronger antioxidative effect compared to simvastatin
Study objective The objective of this study is to compare the oxidative stress lowering capacity of atorvastatin the most widely used statin in the US with that of simvastatin in a population of patients with increased oxidative stress in patients with diabetes mellitus 10 hypertension 11 obesity 12 and chronic kidney disease 13 who are known to have increased oxidative stress
Design and methods We plan to recruit sixty statin naive patients with diabetes mellitus type-2 andor obesity BMI 25 kgm2 andor hypertension RR 14090 mmHg Patients with KDOQI stage 5 chronic kidney disease Cockcroft-Gault clearance of less than 15mlmin173m2 and patients who use any vitamin preparation or statins in the last three months will be excluded from the study Because of the documented influence of ACE-inhibitors on oxidative stress we will stratify patients for prior ACE-inhibitor use during randomization All included patients are randomized to treatment with simvastatin 40 mg daily or atorvastatin 10 mg daily in order to achieve a comparable lipid reduction Established parameters of oxidative stress such as oxidized LDL malondealdehyde will be measured 14-18 in plasma on inclusion one week six weeks and three months after the inclusion Primary end point of the study will be the absolute difference between oxidized LDL reduction between the two groups We also plan to measure endothelial function parameters such as soluble Vascular Adhesion Molecule sVCAM and von Willebrand factor In addition parameters of inflammation such as high sensitive c-reactive protein TNF-alfa and Interleuking-6 will also be measured to investigate whether there is any correlation between eventual oxidative stress lowering and endothelial function and inflammation The inhibitory effect of HDL to prevent oxidation of LDL will be determined by measurement of lipid peroxides formed during in vitro oxidation of LDL co-incubated with HDL The anti-inflammatory properties of HDL will be tested by measurement of the HDL capacity to inactivate oxidized palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine ox-PAPC For this measurement we will use a cell-free assay that has been developed by Navab and co-workers 19 Collections of 24 hours of urine at the beginning and after one week and three months will be used to measure urine F2-isoprostane levels 20-24
Power calculation
The number of patients needed to detect an absolute Oxidized LDL difference of 9 UL between the two groups over 3 months with a power of 80 α of 005 and a SD of 12 was 30 patients per group
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