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

This study has been completed.
Sponsor:
Information provided by:
Karolinska Institutet
ClinicalTrials.gov Identifier:
NCT01397513
First received: July 14, 2011
Last updated: July 18, 2011
Last verified: March 2006
  Purpose

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.


Condition Intervention Phase
Diabetes Mellitus, Type 1
Drug: Aspirin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by Karolinska Institutet:

Primary Outcome Measures:
  • Fibrin network permeability [ Time Frame: At the start and end of each 4-week treatment period ] [ Designated as safety issue: No ]
    Changes in fibrin network permeability after 4 weeks of treatment with either aspirin 75 or 320mg.


Secondary Outcome Measures:
  • Fibrin network permeability [ Time Frame: At the start and end of each 4-week treatment period ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Changes in plasma concentrations of platelet microparticles after 4 weeks of treatment with either aspirin 75 or 320mg.


Enrollment: 48
Study Start Date: March 2006
Study Completion Date: February 2011
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Aspirin 75mg 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
Active Comparator: Aspirin 320mg 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

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.

  Eligibility

Ages Eligible for Study:   30 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01397513

Locations
Sweden
Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital
Stockholm, Sweden, 18288
Sponsors and Collaborators
Karolinska Institutet
Investigators
Principal Investigator: Gun Jörneskog, MD PhD Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital
  More Information

Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Gun Jörneskog, Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital
ClinicalTrials.gov Identifier: NCT01397513     History of Changes
Other Study ID Numbers: 151:2005/76316, 2005/1403-31/2
Study First Received: July 14, 2011
Last Updated: July 18, 2011
Health Authority: Sweden: Karolinska Institutet

Keywords provided by Karolinska Institutet:
Fibrin network structure
Aspirin treatment
Platelet microparticles

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Aspirin
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents
Hematologic Agents
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Central Nervous System Agents

ClinicalTrials.gov processed this record on July 31, 2014