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Effects of Aspirin Treatment on Fibrin Network Formation in Patients With Type 1 Diabetes

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ClinicalTrials.gov Identifier: NCT01397513
Recruitment Status : Completed
First Posted : July 19, 2011
Last Update Posted : July 19, 2011
Sponsor:
Information provided by:
Karolinska Institutet

Tracking Information
First Submitted Date  ICMJE July 14, 2011
First Posted Date  ICMJE July 19, 2011
Last Update Posted Date July 19, 2011
Study Start Date  ICMJE March 2006
Actual Primary Completion Date July 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 18, 2011)
Fibrin network permeability [ Time Frame: At the start and end of each 4-week treatment period ]
Changes in fibrin network permeability after 4 weeks of treatment with either aspirin 75 or 320mg.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: July 18, 2011)
  • Fibrin network permeability [ Time Frame: At the start and end of each 4-week treatment period ]
    Subgroup analyses comparing the treatment effects of aspirin 75 or 320mg on fibrin network permeability in patients with good and poor glycemic control, respectively.
  • Platelet microparticles [ Time Frame: At the start and end of each 4-week treatment period ]
    Changes in plasma concentrations of platelet microparticles after 4 weeks of treatment with either aspirin 75 or 320mg.
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 Effects of Aspirin Treatment on Fibrin Network Formation in Patients With Type 1 Diabetes
Official Title  ICMJE Effects of Low and High Doses of Aspirin Treatment on Fibrin Network Formation in Patients With Type 1 Diabetes and Possible Influence of the Glycemic Control.
Brief Summary

The fibrin network is an important component of an arterial thrombus and its structure influences the degradation of the formed clot. A tighter and less permeable fibrin network, which is less susceptible to fibrinolysis, is formed in patients with manifest cardiovascular disease (CVD) or conditions associated with increased risk of atherothrombotic complications. In a previous study we have shown reduced fibrin network permeability in patients with type 1 diabetes, which may contribute to their increased risk of CVD. Low dose aspirin treatment is standard in management of CVD; however, the effect seems reduced in patients with diabetes. Our previous studies have shown that aspirin treatment alters the fibrin network in non-diabetic individuals and increases the fibrin network permeability. The effect of aspirin on fibrin network formation in patients with diabetes is unclear.

We hypothesized that patients with type 1 diabetes might need higher doses of aspirin than the recommended low dose (75mg) treatment to gain effects on fibrin network permeability, and that the effects of aspirin treatment on fibrin network in these patients are influenced by the glycemic control.

Detailed Description

Diabetes is associated with increased platelet activation, elevated plasma fibrinogen levels and impaired fibrinolysis, factors which may contribute to the elevated risk of cardiovascular disease (CVD) in these patients. Increased platelet activation in patients with diabetes is reflected by elevated levels of platelet microparticles, which are small circulating procoagulant vesicles shed from the platelet membrane upon activation. CVD in these patients may start as early as in the age of 25-30 years and the course is often aggressive and with poor prognosis. Treatment with a daily low dose of acetylsalicylic acid (aspirin 75 mg) is one of the cornerstones in management of CVD in non-diabetic patients; however, the effect seems reduced in patients with diabetes. The mechanisms behind this treatment failure with aspirin in diabetes patients are unclear. Aspirin is a complex drug with multiple effects. The most well known is acetylation and inhibition of platelet cyclooxygenase (COX), but COX-independent mechanisms may also of importance in protection of cardiovascular complications. One such mechanism is alteration of the fibrin/fibrinogen properties and the fibrin network structure, possibly through acetylation of the lysine residues in the fibrinogen molecule involved in crosslinking of fibrin. The fibrin network structure seems important in development of atherothrombotic events, as individuals at high risk of CVD, including patients with type 1 diabetes, as well as patients with manifest CVD have a tighter and less permeable fibrin network structure. The altered fibrin network in patients with type 1 diabetes may in part be due to increased fibrinogen glycation, which may occur on lysine residues. Treatment with aspirin increases fibrin network permeability in non-diabetic subjects. However, the effect of aspirin on fibrin network permeability in patients with diabetes is unclear. Possible competition between acetylation and glycation on lysine residues in the fibrinogen molecule might contribute to the reduced preventive effect of aspirin in management of CVD in patients with diabetes and higher doses of aspirin might therefore be required in these patients.

Our hypothesis was that glycation and acetylation occur at the same binding sites in the fibrinogen molecule. Thus, poor glycemic control and increased glycation may lead to lower acetylation of the fibrinogen molecule than during good glycemic control in turn leading to an altered fibrin network.

The aims of the present study were to analyse the effects of low (75 mg) and high dose (320 mg) aspirin treatment on fibrin network formation in patients with type 1 diabetes (primary aim), and to investigate the possible influence of the glycemic control (secondary aim). As platelet microparticles may influence the fibrin formation [17, 18] and since aspirin has well-known effects on platelet function, we also measured plasma concentrations of platelet microparticles.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Diabetes Mellitus, Type 1
Intervention  ICMJE Drug: Aspirin
Tablets, 75 or 320mg once daily for 4 weeks. A 4-week wash-out period separated the two treatment periods.
Other Name: Trombyl
Study Arms  ICMJE
  • Active Comparator: Aspirin 75mg
    Intervention: Drug: Aspirin
  • Active Comparator: Aspirin 320mg
    Intervention: Drug: Aspirin
Publications *

*   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: July 18, 2011)
48
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE February 2011
Actual Primary Completion Date July 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diabetes mellitus, type 1
  • Levels of HbA1C (glycated hemoglobin) <7.4% (NGSP standard)
  • Levels of HbA1C >8.4% (NGSP standard)

Exclusion Criteria:

  • Prior aspirin treatment
  • Treatment with anticoagulant drugs
  • Ongoing treatment with NSAIDs or other antiplatelet drugs
  • A history of macrovascular disease
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years to 70 Years   (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 Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01397513
Other Study ID Numbers  ICMJE 151:2005/76316
2005/1403-31/2 ( Other Identifier: Ethics Committe in Stockholm )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gun Jörneskog, Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital
Study Sponsor  ICMJE Karolinska Institutet
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Gun Jörneskog, MD PhD Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital
PRS Account Karolinska Institutet
Verification Date March 2006

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