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Aspirin Statins Or Both For The Reduction Of Thrombin Generation In Diabetic People (RATIONAL)

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ClinicalTrials.gov Identifier: NCT00793754
Recruitment Status : Completed
First Posted : November 19, 2008
Last Update Posted : October 26, 2011
Sponsor:
Information provided by:
Fundacion GESICA

Tracking Information
First Submitted Date  ICMJE November 18, 2008
First Posted Date  ICMJE November 19, 2008
Last Update Posted Date October 26, 2011
Study Start Date  ICMJE March 2009
Actual Primary Completion Date October 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 18, 2008)
Thrombin generation [ Time Frame: 8 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 18, 2008)
C-reactive protein [ Time Frame: 8 weeks ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Aspirin Statins Or Both For The Reduction Of Thrombin Generation In Diabetic People
Official Title  ICMJE Aspirin Statins Or Both For The Reduction Of Thrombin Generation In Diabetic People
Brief Summary

Despite formal recommendations, evidence of efficacy of aspirin in individuals with diabetes is scant and controversial. While the efficacy of aspirin versus placebo in patients with diabetes is currently under investigation in big randomized controlled trials, the putative additive effects of aspirin and statins in this population remain to be investigated. Moreover there are no data examining the pathophysiologic means by which aspirin with or without statins affects thrombosis in diabetic patients.

The aim of this trial is to evaluate the efficacy of low-dose aspirin (100 mg/daily), statins, both or neither for the reduction of thrombin generation. These preventive strategies will be evaluated on the top of the other strategies aimed at optimizing the care of diabetic patients in terms of metabolic control and control of the other cardiovascular risk factors.

Detailed Description

Despite the very high cardiovascular risk profile, evidence of efficacy of aspirin in individuals with diabetes is scant.

The meta-analysis on the efficacy of antiplatelet therapy involving a total of about 5,000 diabetic subjects indicates a non significant reduction in the risk of major cardiovascular events of 7%, compared with a reduction of 25% documented in secondary prevention studies.

Diabetes could represent a special case of aspirin resistance, although no specific studies have, to our knowledge, fully explored this hypothesis. The poor platelet responsiveness to aspirin has been recently proposed as a possible explanation of the failure of antiplatelet therapy to prevent cardiovascular events. The reduction in the aspirin activity in some patients is indicated by the failure in adequately suppressing thromboxane-A2 synthesis, as documented by the presence of high levels of its urinary metabolites.

The substantial lack of clear evidence is reflected by the low use of this drug in clinical practice; in fact, only 10% of diabetic patients are treated with aspirin for the prevention of cardiovascular events.

On the other hand, statins provide a similar efficacy for the prevention of major cardiovascular events in populations with and without diabetes.

It has been recently shown that platelet response to aspirin is linearly reduced with increasing cholesterol plasma levels. The presence of dyslipidemia, particularly common among diabetic patients, could thus be at least partially responsible for a lower efficacy of aspirin in this population. The concomitant use of statins could thus restore the normal platelet sensitivity to aspirin by reducing cholesterol levels

One additional reason to hypothesize a positive effect of statins in improving platelet response to aspirin is related to their anti-inflammatory properties

While the efficacy of aspirin versus placebo in patients with diabetes is currently under investigation, the additive effects of aspirin and statins in this population remain to be investigated. This aspect is of particular interest in the light of the existing debate regarding the need of multiple interventions to reduce total cardiovascular risk.

Given these premises, it is important to evaluate the effectiveness of aspirin use in primary prevention of cardiovascular events in association with statins therapy when included in a strategy of global risk control.

The RATIONAL Study will evaluate whether the combined use of aspirin (100 mg d) and statins (Atorvastatin 40 mg daily) is superior to the use of these single agents for the reduction of thrombin generation in patients with diabetes and without previous cardiovascular events.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Diabetes Mellitus
Intervention  ICMJE
  • Drug: Aspirin
    100 mg / day for 8 weeks
  • Drug: Atorvastatin
    40 mg / day for 8 weeks
  • Drug: Aspirin + Atorvastatin
    Aspirin 100 mg / day + Atorvastatin 40 mg / day for 8 weeks
Study Arms  ICMJE
  • No Intervention: 1
  • Experimental: 2
    Aspirin 100 mg / day
    Intervention: Drug: Aspirin
  • Experimental: 3
    Atorvastatin 40 mg / day
    Intervention: Drug: Atorvastatin
  • Experimental: 4
    Aspirin 100 mg / day + Atorvastatin 40 mg / day
    Intervention: Drug: Aspirin + Atorvastatin
Publications * Macchia A, Laffaye N, Comignani PD, Cornejo Pucci E, Igarzabal C, Scazziota AS, Herrera L, Mariani JA, Bragagnolo JC, Catalano H, Tognoni G, Nicolucci A. Statins but not aspirin reduce thrombotic risk assessed by thrombin generation in diabetic patients without cardiovascular events: the RATIONAL trial. PLoS One. 2012;7(3):e32894. doi: 10.1371/journal.pone.0032894. Epub 2012 Mar 28.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 21, 2011)
30
Original Estimated Enrollment  ICMJE
 (submitted: November 18, 2008)
60
Actual Study Completion Date  ICMJE October 2011
Actual Primary Completion Date October 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diabetes mellitus treated with insulin or orl agents
  • At least 50 years old

Exclusion Criteria:

  • Previous cardiovascular events
  • current or past (within last 30 days) treatment with aspirin
  • current or past (within last 180 days) treatment with statins
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00793754
Other Study ID Numbers  ICMJE 002
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Alejandro Macchia, Fundacion GESICA
Study Sponsor  ICMJE Fundacion GESICA
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Alejandro Macchia, MD Fundacion GESICA
Principal Investigator: Hernan Doval, MD Fundacion GESICA
Principal Investigator: Juan J Fuselli, MD Centro de Educación Medica e Investigaciones Clínicas Norberto Quirno
Principal Investigator: Pablo D Comignani, MD Hospital Aleman
PRS Account Fundacion GESICA
Verification Date October 2011

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