Hypolipemic Treatment in Acute Coronary Syndrome (ACS): Antithrombotic Effects

The recruitment status of this study is unknown because the information has not been verified recently.
Verified February 2009 by Jagiellonian University.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by:
Jagiellonian University
ClinicalTrials.gov Identifier:
NCT00725829
First received: July 7, 2008
Last updated: February 9, 2009
Last verified: February 2009
  Purpose

The aim of the current study is to evaluate whether treatment with high doses of simvastatin can reduce coagulation activation in patients with acute coronary syndromes and if ezetimibe in conjunction with simvastatin may affect blood clotting in a similar manner.

The investigators hypotheses are as follows:

  1. Intensive lipid lowering treatment with simvastatin (40 mg/day) and simvastatin (40 mg/day) combined with ezetimibe (10 mg/day) initiated after acute coronary syndrome leads to attenuation of blood coagulation including reduced thrombin generation, thrombin-mediated coagulant reactions, and improved structure of plasma clots.
  2. Anticoagulant effects of simvastatin are weaker than those observed during administration of simvastatin and ezetimibe.

Condition Intervention
Acute Coronary Syndrome
Drug: simvastatin
Drug: ezetimibe
Drug: placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Effects of Simvastatin Versus Simvastatin Combined With Ezetimibe on Blood Coagulation in Patients With Acute Coronary Events: Relationship With Cholesterol-Lowering and Anti-Inflammatory Properties

Resource links provided by NLM:


Further study details as provided by Jagiellonian University:

Primary Outcome Measures:
  • decrease in thrombin generation [ Time Frame: 2 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • increase in clot permeability [ Time Frame: 2 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 100
Study Start Date: June 2008
Estimated Study Completion Date: December 2009
Estimated Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
simvastatin 40g + ezetimibe 10g once a day
Drug: simvastatin
Simvastatin 40mg/d
Drug: ezetimibe
ezetimibe 10mg/d
Placebo Comparator: 2
simvastatin 40g + placebo once a day
Drug: simvastatin
Simvastatin 40mg/d
Drug: placebo
placebo

Detailed Description:

Clinical status will be evaluated during hospitalization, and then on the out-patient basis. All cardiovascular events (fatal or nonfatal myocardial infarction, unstable angina, sudden cardiac death, all-cause death, stroke, TIA) will be recorded and the patients who underwent acute PCI will have a follow-up coronary angiography performed according to current recommendations. However, the clinical analysis is not a major gaol of this study.

The investigators plan to evaluate following parameters:

  • Whole blood morphology, creatinine, glucose, sodium, potassium, urea, lipid profile, CK, AST, fibrinogen, using standard methods in hospital laboratory.
  • Inflammation markers - fibrinogen (nephelometry, Dade Behring) high-sensitivity C-reactive protein (nephelometry, Dade Behring); interleukin 6 (ELISA, R&D Systems).
  • Thrombin generation markers in peripheral blood - thrombin-antithrombin complexes [TAT] (ELISA, Dade Behring); prothrombin fragments 1+2 [F1+2] (ELISA, Dade Behring).
  • Fibrin clot permeation and susceptibility to lysis - measurement of Darcy's constant (dimensions of pores in the structure of the clot) by measurement of volume of buffer (0,05 mol/l Tris HCl with 0,15 mol/l NaCl) penetrating through the fibrin gel made in polystyrene pipes, 1.3 mm in diameter, with 100 ul of citrate plasma and after addition of 1U/ml human thrombin and 20 mmol/l calcium chloride in room temperature within 120 minutes according to methodology described by Mills and al.
  • Fibrin gel turbidimetry - plasma mixed with Tris buffer prepared as mentioned above in 2:3 ratio, after addition 1 U/ml thrombin and 16 mmol/l calcium chloride will be analyzed in the UV spectrometer (wave length 405 nm). Following variables will be measured: initiation time, absorption increasing time and absorption value in plateau, approximately 10 minutes after addition of thrombin to the mixture. After 2 hours, spectrophotometry assessment of the clot will be performed (400 to 800 nm) to measure the pore size and thickness of fibrin fibers using the Carr equation modified by Wolberg. Then fibrinolysis of fibrin gel will be measured by means of turbidimetry. Another lysis assay based on the measurement of D-dimer levels in the effluent flowing through fibrin gels will be performed according to the method of Collet et al.
  • Activation of the coagulation system in a "minimally modified blood" model according to Rand et al. Non-anticoagulated blood will be divided into 10 1-ml samples added to the tubes with TF and phospholipids, and then clotting will be stopped by an anticoagulant cocktail. In the supernatant samples, Western blotting and HPLC analysis of fibrinopeptides will be performed as described previously.

In 40 patients allocated at a random we will assess activation of coagulation system using the vascular injury model according to a procedure developed by us.

We will measure:

  • Activation of prothrombin
  • Conversion of fibrinogen to fibrin
  • Activation of factor V and inactivation of factor Va
  • Activation of factor XIII
  • Activation of TAFI
  • Thrombin generation

Genetic analysis The investigators will determine the PlA1 PlA2 polymorphism in the integrin β3 gene using the PCR technique in DNA samples collected from peripheral blood leukocytes.

Additionally, we are going to search for polymorphism of promoter region of IL-6 /G-174C also by means of PCR in DNA collected from peripheral blood leukocytes, using prim-ers 5'- AAT CTT TGT TGG AGG GTG AG and 5'- ACA TGC CAA GTG CTG AGT CA and restriction endonuclease Sfa NI on 2% agarose gel.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age < 75 years
  • Acute coronary syndrome (symptom onset < 12 h)

Exclusion Criteria:

  • Diabetes on insulin
  • Anticoagulant therapy
  • Renal insufficiency
  • Liver injury
  • Acute cardiovascular event within the previous 3 months
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00725829

Locations
Poland
Institute of Cardiology Recruiting
Krakow, Poland, 31202
Contact: Anetta Undas, MD, PhD    +48126143004    anettaundas@yahoo.com   
Principal Investigator: Anetta Undas, MD , PhD         
Sponsors and Collaborators
Jagiellonian University
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Anetta Undas, Professor Institute of Cardiology Jagiellonian University Krakow
Study Director: Krzysztof Zmudka, Professor Insitute of Cardiology Jagiellonian University Krakow
  More Information

No publications provided

Responsible Party: Anetta Undas, Jagiellonian University School of Medicine
ClinicalTrials.gov Identifier: NCT00725829     History of Changes
Other Study ID Numbers: Prot. 116
Study First Received: July 7, 2008
Last Updated: February 9, 2009
Health Authority: Poland: Ministry of Health

Keywords provided by Jagiellonian University:
coagulation
cholesterol
acute ischemia
fibrin clot

Additional relevant MeSH terms:
Acute Coronary Syndrome
Syndrome
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Angina Pectoris
Vascular Diseases
Chest Pain
Pain
Signs and Symptoms
Disease
Pathologic Processes
Simvastatin
Ezetimibe
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 16, 2014