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Atorvastatin, Aspirin, Oxidative Stress, Coagulation and Platelet Activation Indexes

Primary Purpose

Type 2 Diabetes Mellitus, Hypercholesterolemia

Status
Unknown status
Phase
Phase 4
Locations
Italy
Study Type
Interventional
Intervention
Atorvastatin
Placebo
Sponsored by
University of Roma La Sapienza
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type 2 Diabetes Mellitus focused on measuring Thromboxane, Aspirin, Atorvastatin, Platelet activation, Thrombin Activation, Oxidative stress

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

For Hypercholesterolemic patients:

Inclusion Criteria:

  • Patients with polygenic hypercholesterolemia (LDL-C > 160 mg/dl)
  • Males and Females
  • White race
  • Sign of the informed consent

Exclusion Criteria:

  • Liver insufficiency
  • Serious renal disorders
  • Diabetes mellitus
  • Arterial hypertension
  • History or evidence of previous myocardial infarction or other atherothrombotic diseases
  • Any autoimmune diseases
  • Cancer
  • Present or recent infections
  • Patients were taking nonsteroidal antiinflammatory drugs, drugs interfering with cholesterol metabolism, or vitamin supplements

For T2 Diabetic patients:

Inclusion Criteria:

  • Patients with T2DM diagnosed according to the American Diabetes Association definition
  • Treatment with 100 mg/day aspirin from at least 30 days
  • Males and Females
  • White race
  • Sign of the informed consent

Exclusion Criteria:

  • recent history (< 3 months) of acute vascular events
  • clinical diagnosis of type 1 DM
  • serum creatinine level greater than 2.5 mg/dl
  • active infection or malignancy
  • cardiac arrhythmia or congestive heart failure
  • use of non-steroidal anti-inflammatory drugs, vitamin supplements, or other antiplatelet drugs such as clopidogrel in the previous 30 days

Sites / Locations

  • Stefania Basili

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Atorvastatin

Diet

Arm Description

Each day accordingly to randomization patients allocated to Atorvastatin received a pill of 40 mg of atorvastatin. In diabetic patients the concomitant aspirin treatment include a previous 30 days treatment with 100 mg daily of aspirin. All patients followed the diet used in the placebo group.

Low-fat diet with mean macronutrient profiles that were close to the present Adult Treatment Panel III guidelines (7% energy from saturated fat and, 200 mg dietary cholesterol per day)

Outcomes

Primary Outcome Measures

Evaluation of effect of Atorvastatin Therapy in Hypercholesterolemic Patients (n=30) and Diabetic Patients (n=30)
In Hypercholesterolemic patients (n=30) and in Diabetic patients (n=30) under chronic treatment with low dose aspirin (100 mg daily for at least 30 days), blood and urine samples were taken at each above reported time to evaluate the effect of atorvastatin or no treatment (Diet) on platelet recruitment, platelet and serum isoprostanes, platelet and serum thromboxane A2, platelet and serum NOX2 activation indexes, thrombin activation indexes, urinary excretion of thromboxane and isoprostanes.

Secondary Outcome Measures

Full Information

First Posted
March 24, 2011
Last Updated
May 27, 2015
Sponsor
University of Roma La Sapienza
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1. Study Identification

Unique Protocol Identification Number
NCT01322711
Brief Title
Atorvastatin, Aspirin, Oxidative Stress, Coagulation and Platelet Activation Indexes
Official Title
Effects on Oxidative Stress, Coagulation, Platelet Activation and Inflammatory Indexes of Atorvastatin and/or Aspirin Treatment in Patients at High Risk of Vascular Events
Study Type
Interventional

2. Study Status

Record Verification Date
May 2015
Overall Recruitment Status
Unknown status
Study Start Date
March 2011 (undefined)
Primary Completion Date
October 2015 (Anticipated)
Study Completion Date
December 2015 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Roma La Sapienza

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Primary and secondary prevention trials with statins, as well as with antiplatelet, clearly demonstrated that these drugs are able to reduce cardiovascular events. Even if the principal mechanism of action of statins is to lower cholesterol, other effects, the so-called pleiotropic effects, have been considered as adjunctive properties potentially accounting for the anti-atherosclerotic effect of statins. Inhibition of oxidative stress may be considered an intriguing pleiotropic effect in view of the fact that oxidative stress is thought to be a key event in the initiation and progression of atherosclerotic disease. Reduction of several markers of oxidative stress including isoprostanes, 8-hydroxydeoxyguanosine (8-OHdG), and nitrotyrosine have been observed after statin treatment. NADPH oxidase is among the most important sources of reactive oxygen species involved in atherosclerotic disease. The investigators developed an ELISA to evaluate serum levels of soluble-gp91phox, the catalytic core of phagocyte NADPH oxidase. Recently the investigators showed that statins (30 days treatment) exert an antioxidant effect via inhibition of soluble gp91phox expression. The exact mechanism by which atorvastatin reduces NADPH oxidase, however, is unclear. Recent study showed that statin treatment inhibits leukocyte ROCK activity, a protein kinase implicated in the activation of NADPH oxidase, with a mechanism that seems to be independent from lowering cholesterol. To further study the mechanism(s) implicate in gp91phox downregulation by statin the investigators planned the present study in patients with high risk of vascular events such as hypercholesterolemic and Type 2 Diabetes mellitus patients. In addition the investigators want to evaluate the synergistic role of atorvastatin with aspirin treatment.
Detailed Description
Primary and secondary prevention trials with statins, as well as with antiplatelet, clearly demonstrated that these drugs are able to reduce cardiovascular events. Even if the principal mechanism of action of statins is to lower cholesterol, other effects, the so-called pleiotropic effects, have been considered as adjunctive properties potentially accounting for the antiatherosclerotic effect of statins. Inhibition of oxidative stress may be considered an intriguing pleiotropic effect in view of the fact that oxidative stress is thought to be a key event in the initiation and progression of atherosclerotic disease. Reduction of several markers of oxidative stress including isoprostanes, 8-hydroxydeoxyguanosine (8-OHdG), and nitrotyrosine have been observed after statin treatment. NADPH oxidase is among the most important sources of reactive oxygen species involved in atherosclerotic disease. The investigators developed an ELISA to evaluate serum levels of soluble-gp91phox, the catalytic core of phagocyte NADPH oxidase. Recently the investigators showed that statins (30 days treatment) exert an antioxidant effect via inhibition of soluble gp91phox expression. The exact mechanism by which atorvastatin reduces NADPH oxidase, however, is unclear. Recent study showed that statin treatment inhibits leukocyte ROCK activity, a protein kinase implicated in the activation of NADPH oxidase, with a mechanism that seems to be independent from lowering cholesterol. Accelerated atherosclerosis is a typical feature of type 2 diabetes mellitus (T2DM). Thus, patients with T2DM have a 2- to 4-fold increased risk of cardiovascular diseases (CAD) and 2- to 6-fold increased risk of stroke. Platelets play a major role in the etiology of atherosclerotic disease, as shown by the significant decrease of cardiovascular events in patients treated with aspirin, an inhibitor of COX1 that prevents platelet thromboxane (Tx) A2 formation. Despite this, interventional trials with aspirin in diabetic patients failed to show a beneficial effect. It has been previously demonstrated that COX1 inhibition determines a shift in arachidonic acid metabolism towards other pathways, such as the lipooxygenase system. The investigators speculate that COX1 inhibition could also be associated with increased conversion of arachidonic acid to platelet isoprostane formation; the increase of platelet isoprostanes would balance the inhibition of TxA2, thus hampering the antiplatelet effect of aspirin. As reported above, statins have been reported to down-regulate systemic isoprostanes with a mechanism that may involve inhibition of NADPH oxidase,therefore it could be interesting to examine if statins improve the antiplatelet effect of aspirin via inhibition of platelet isoprostanes. To further study the mechanism(s) implicate in gp91phox downregulation by statin the investigators planned the present study in patients with hypercholesterolemia. Furthermore, the second part of the study will be addressed to evaluate the synergistic role of atorvastatin with aspirin treatment in Type 2 Diabetes mellitus patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes Mellitus, Hypercholesterolemia
Keywords
Thromboxane, Aspirin, Atorvastatin, Platelet activation, Thrombin Activation, Oxidative stress

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Atorvastatin
Arm Type
Active Comparator
Arm Description
Each day accordingly to randomization patients allocated to Atorvastatin received a pill of 40 mg of atorvastatin. In diabetic patients the concomitant aspirin treatment include a previous 30 days treatment with 100 mg daily of aspirin. All patients followed the diet used in the placebo group.
Arm Title
Diet
Arm Type
Placebo Comparator
Arm Description
Low-fat diet with mean macronutrient profiles that were close to the present Adult Treatment Panel III guidelines (7% energy from saturated fat and, 200 mg dietary cholesterol per day)
Intervention Type
Drug
Intervention Name(s)
Atorvastatin
Other Intervention Name(s)
Totalip 40 mg, Torvast 40 mg
Intervention Description
Atorvastatin 40 mg day
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Diet
Primary Outcome Measure Information:
Title
Evaluation of effect of Atorvastatin Therapy in Hypercholesterolemic Patients (n=30) and Diabetic Patients (n=30)
Description
In Hypercholesterolemic patients (n=30) and in Diabetic patients (n=30) under chronic treatment with low dose aspirin (100 mg daily for at least 30 days), blood and urine samples were taken at each above reported time to evaluate the effect of atorvastatin or no treatment (Diet) on platelet recruitment, platelet and serum isoprostanes, platelet and serum thromboxane A2, platelet and serum NOX2 activation indexes, thrombin activation indexes, urinary excretion of thromboxane and isoprostanes.
Time Frame
Baseline, 2 hours, 24 hours, 3 days, 7 days, 30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
For Hypercholesterolemic patients: Inclusion Criteria: Patients with polygenic hypercholesterolemia (LDL-C > 160 mg/dl) Males and Females White race Sign of the informed consent Exclusion Criteria: Liver insufficiency Serious renal disorders Diabetes mellitus Arterial hypertension History or evidence of previous myocardial infarction or other atherothrombotic diseases Any autoimmune diseases Cancer Present or recent infections Patients were taking nonsteroidal antiinflammatory drugs, drugs interfering with cholesterol metabolism, or vitamin supplements For T2 Diabetic patients: Inclusion Criteria: Patients with T2DM diagnosed according to the American Diabetes Association definition Treatment with 100 mg/day aspirin from at least 30 days Males and Females White race Sign of the informed consent Exclusion Criteria: recent history (< 3 months) of acute vascular events clinical diagnosis of type 1 DM serum creatinine level greater than 2.5 mg/dl active infection or malignancy cardiac arrhythmia or congestive heart failure use of non-steroidal anti-inflammatory drugs, vitamin supplements, or other antiplatelet drugs such as clopidogrel in the previous 30 days
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stefania Basili, Prof.
Organizational Affiliation
Sapienza-Univerity of Rome
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stefania Basili
City
Rome
ZIP/Postal Code
00161
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
20832062
Citation
Carnevale R, Pignatelli P, Di Santo S, Bartimoccia S, Sanguigni V, Napoleone L, Tanzilli G, Basili S, Violi F. Atorvastatin inhibits oxidative stress via adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients. Atherosclerosis. 2010 Nov;213(1):225-34. doi: 10.1016/j.atherosclerosis.2010.08.056. Epub 2010 Aug 19.
Results Reference
background
PubMed Identifier
19965781
Citation
Pignatelli P, Carnevale R, Cangemi R, Loffredo L, Sanguigni V, Stefanutti C, Basili S, Violi F. Atorvastatin inhibits gp91phox circulating levels in patients with hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):360-7. doi: 10.1161/ATVBAHA.109.198622. Epub 2009 Dec 3. Erratum In: Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):e20.
Results Reference
background
PubMed Identifier
22615342
Citation
Pignatelli P, Carnevale R, Pastori D, Cangemi R, Napoleone L, Bartimoccia S, Nocella C, Basili S, Violi F. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012 Jul 3;126(1):92-103. doi: 10.1161/CIRCULATIONAHA.112.095554. Epub 2012 May 21.
Results Reference
derived

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Atorvastatin, Aspirin, Oxidative Stress, Coagulation and Platelet Activation Indexes

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