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

NCT ID: NCT01322711

Last Updated: 2015-05-28

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-03-31
• Study Completion Date: 2015-12-31

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.

Conditions

Type 2 Diabetes Mellitus; Hypercholesterolemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Atorvastatin

Intervention Type: DRUG

Atorvastatin 40 mg day

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)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Diet

Interventions

Atorvastatin

Atorvastatin 40 mg day

Intervention Type: DRUG

Placebo

Diet

Intervention Type: DRUG

Other Intervention Names

Totalip 40 mg; Torvast 40 mg

Eligibility Criteria

Inclusion Criteria

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

• 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

• 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:

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Roma La Sapienza

OTHER

Sponsor Role: lead

Responsible Party

Stefania Basili

Prof.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Stefania Basili, Prof.

Role: PRINCIPAL_INVESTIGATOR

Sapienza-Univerity of Rome

Locations

Stefania Basili

Rome, , Italy

Countries

Italy

References

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.

Reference Type: BACKGROUND

PMID: 20832062 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19965781 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 22615342 (View on PubMed)

Other Identifiers

ATORVASA

Identifier Type: -

Identifier Source: org_study_id