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

March 24, 2011
June 12, 2012
March 2011
October 2012   (final data collection date for primary outcome measure)
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.
Same as current
Complete list of historical versions of study NCT01322711 on ClinicalTrials.gov Archive Site
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Atorvastatin, Aspirin, Oxidative Stress, Coagulation and Platelet Activation Indexes
Effects on Oxidative Stress, Coagulation, Platelet Activation and Inflammatory Indexes of Atorvastatin and/or Aspirin Treatment in Patients at High Risk of Vascular Events

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.

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.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Type 2 Diabetes Mellitus
  • Hypercholesterolemia
  • Drug: Atorvastatin
    Atorvastatin 40 mg day
    Other Names:
    • Totalip 40 mg
    • Torvast 40 mg
  • Drug: Placebo
    Diet
  • 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.

    Intervention: Drug: Atorvastatin
  • 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)
    Intervention: Drug: Placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
60
December 2012
October 2012   (final data collection date for primary outcome measure)

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
Both
18 Years to 75 Years
No
Contact: Stefania Basili, Prof. +39-06-49974678 stefania.basili@uniroma1.it
Contact: Francesco Violi, Prof. +39-06-4461933 francesco.violi@uniroma1.it
Italy
 
NCT01322711
ATORVASA
No
Stefania Basili, University of Roma La Sapienza
University of Roma La Sapienza
Not Provided
Principal Investigator: Stefania Basili, Prof. Sapienza-Univerity of Rome
University of Roma La Sapienza
June 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP