Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified June 2012 by University of Roma La Sapienza.
Recruitment status was  Recruiting
Sponsor:
Information provided by (Responsible Party):
Stefania Basili, University of Roma La Sapienza
ClinicalTrials.gov Identifier:
NCT01322711
First received: March 24, 2011
Last updated: June 12, 2012
Last verified: June 2012
  Purpose

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.


Condition Intervention Phase
Type 2 Diabetes Mellitus
Hypercholesterolemia
Drug: Atorvastatin
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by University of Roma La Sapienza:

Primary Outcome Measures:
  • Evaluation of effect of Atorvastatin Therapy in Hypercholesterolemic Patients (n=30) and Diabetic Patients (n=30) [ Time Frame: Baseline, 2 hours, 24 hours, 3 days, 7 days, 30 days ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 60
Study Start Date: March 2011
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Atorvastatin

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.

Drug: Atorvastatin
Atorvastatin 40 mg day
Other Names:
  • Totalip 40 mg
  • Torvast 40 mg
Placebo Comparator: Diet
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)
Drug: Placebo
Diet

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01322711

Contacts
Contact: Stefania Basili, Prof. +39-06-49974678 stefania.basili@uniroma1.it
Contact: Francesco Violi, Prof. +39-06-4461933 francesco.violi@uniroma1.it

Locations
Italy
Stefania Basili Recruiting
Rome, Italy, 00161
Contact: Stefania Basili, MD    +39-06-49974678    stefania.basili@uniroma1.it   
Contact: Francesco Violi, MD    +39-06-4461933    francesco.violi@uniroma1.it   
Principal Investigator: Stefania Basili, MD         
Sponsors and Collaborators
University of Roma La Sapienza
Investigators
Principal Investigator: Stefania Basili, Prof. Sapienza-Univerity of Rome
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Stefania Basili, Prof., University of Roma La Sapienza
ClinicalTrials.gov Identifier: NCT01322711     History of Changes
Other Study ID Numbers: ATORVASA
Study First Received: March 24, 2011
Last Updated: June 12, 2012
Health Authority: Italy: Ethics Committee

Keywords provided by University of Roma La Sapienza:
Thromboxane
Aspirin
Atorvastatin
Platelet activation
Thrombin Activation
Oxidative stress

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Hypercholesterolemia
Dyslipidemias
Endocrine System Diseases
Glucose Metabolism Disorders
Hyperlipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Aspirin
Atorvastatin
Analgesics
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Anticholesteremic Agents
Antimetabolites
Antipyretics
Antirheumatic Agents
Cardiovascular Agents
Central Nervous System Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Fibrin Modulating Agents
Fibrinolytic Agents
Hematologic Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on November 20, 2014