The Effect of Beta-Blockers and Aspirin on Hemostasis and Endothelial Function After Acute Mental Stress
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|ClinicalTrials.gov Identifier: NCT00174902|
Recruitment Status : Unknown
Verified October 2003 by Swiss Federal Institute of Technology.
Recruitment status was: Active, not recruiting
First Posted : September 15, 2005
Last Update Posted : October 25, 2006
|First Submitted Date ICMJE||September 9, 2005|
|First Posted Date ICMJE||September 15, 2005|
|Last Update Posted Date||October 25, 2006|
|Study Start Date ICMJE||October 2003|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
||Change scores in plasma levels of D-dimer determined by subtracting levels immediately after the stressor as compared to baseline levels prior to the stressor.|
|Original Primary Outcome Measures ICMJE||Same as current|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||The Effect of Beta-Blockers and Aspirin on Hemostasis and Endothelial Function After Acute Mental Stress|
|Official Title ICMJE||The Effect of Beta-Blockers, Aspirin, and Natural Habituation on Procoagulant Activity, Expression of Cellular Adhesion Molecules, and Endothelial Activation in Response to Acute Mental Stress: a Randomized Controlled Trial.|
|Brief Summary||This randomized double-blinded controlled trial uses a factorial design to investigate whether application of beta-blockers (inderal 80 mg) or aspirin (100 mg) or a combination thereof has an effect on the activation of the hemostatic system, the platelets and the endothelium in response to acute mental stress. Specifically we test the hypothesis that inderal attenuates the activation of the hemostatic system as compared to placebo. The second hypothesis is that aspirin attenuates the activation of platelets as compared to placebo. Subjects will be randomly allocated to either of the four following study arms: placebo - inderal - aspirin - inderal plus aspirin. Subjects will receive the study medication for five days prior to the mental stress. The acute mental stress consists of a public speaking session of 10 min duration immediately followed by a mental arithmetic test of 5 min duration. Blood will be collected prior to the stress, immediately thereafter, at 45 min at at 1 hour and 45 min.|
Background: Population based studies have established hemostatic abnormalities as independent risk factors for atherosclerosis and related adverse outcomes. These abnormalities are characterized as prothrombotic by elevated plasma levels of e.g. fibrinogen or D-dimer. Prothrombotic states appear to aggravate the impact of other risk factors, e.g. hypertension. Other epidemiologic studies have shown a sizable association between chronic mental stress (e. g. marital discord in women) or acute mental stress (anger) and coronary heart disease. A large case-crossover study attributed a 2.3-fold increased relative risk of acute myocardial infarction during the 2 hours following outbursts of anger. This risk was modified by aspirin (risk ratio of 2.9 in non-users, risk-ratio of 1.4 with prior to aspirin intake). We have recently shown that acute mental stress is followed by profound rises of D-dimer and induction of a prothrombotic state. In real life, individuals are frequently and repetitively exposed to similar stressors (e.g. work or marital discord). Those who fail to habituate and to mitigate their adrenergic responses and hemostatic changes, may be at increased risk of rapid progression of atherosclerosis. These individuals might particularly benefit from preventive medication with beta-blockers or aspirin.
Objectives: To elucidate whether administration of non-specific beta-blockers, aspirin or both may abrogate the prothrombotic shift in the hemostatic balance in response to acute mental stress.
To elucidate the pathway leading from central nervous system arousal after acute mental stress to increases in plasma D-dimer levels by investigating intermediate steps in the process, including activation of mononuclear and endothelial cells, of platelets, and of hemostatic factors.
To show that some individuals do not habituate when repetitively being exposed to the same stressor or/and that habituation blunts the stress response as do beta-blocking medication, aspirin or both.
Subjects: 80 healthy male and nonpregnant female non-smokers aged 40 - 55 years.
Methods: Randomized, double-blind, two-by-two factorial design. A public speaking stress will be applied in two different experiments. 1) The first experiment consists of a habituation study wherein 20 subjects will be stressed three times with intervals of 1 week apart. 2) The second experiment consists of a medication study wherein 60 individuals (other than those taking part in the habituation study) will be randomly assigned to one of the following four arms: 1) placebo/placebo, 2) placebo/beta-blocker, 3) placebo/aspirin, 4) beta-blocker/aspirin. Beta-blocker medication consists of 80 mg/day of propranolol (Inderal LA 80), aspirin will be given in a dose of 100 mg/day. Blood will be collected before, immediately after, and at 45 min, and at 1 hour and 45 min after the stress task in both experiments. In both experiments, subjects will be fully debriefed after the first stressor. The primary dependent variable is the change score of plasma levels of D-dimer after the stressor. Data will be analyzed by two-way ANOVA with the experimental condition being the first factor and with the experiment repetition being the second factor. Intermediate variables measured for elucidating the biological pathway leading to changes in D-dimer are: a) arousal of neuro-endocrine circuits: plasma levels of epinephrine and nor-epinephrine, salivary cortisol levels; b) activation / alteration of circulating mononuclear cells: quantitative determination of subpopulations by flow-cytometry, expression of L-selectin (CD62L), lymphocyte function associated antigen 1 (LFA-1), CD154 (expressed on activated T-lymphocytes), and tissue-factor on monocytes; c) activation of endothelial cells: plasma levels of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cellular adhesion molecule 1 (sVCAM-1), endothelin-1, and von Willebrand factor (vWF); d) balance between prothrombotic and fibrinolytic activity: plasma levels of D-dimer, fibrinogen, thrombin/antithrombin III complexes, tissue plasminogen activator, and plasminogen activator inhibitor-1.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 1
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Factorial Assignment
Primary Purpose: Prevention
|Intervention ICMJE||Drug: inderal (drug), acetylsalicylic acid (drug)|
|Study Arms ICMJE||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Unknown status|
|Original Enrollment ICMJE||Same as current|
|Study Completion Date ICMJE||August 2004|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
|Ages ICMJE||40 Years to 55 Years (Adult)|
|Accepts Healthy Volunteers ICMJE||Yes|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Switzerland|
|Removed Location Countries|
|NCT Number ICMJE||NCT00174902|
|Other Study ID Numbers ICMJE||SNF 32-68277|
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||Swiss Federal Institute of Technology|
|Collaborators ICMJE||Swiss National Science Foundation|
|PRS Account||Swiss Federal Institute of Technology|
|Verification Date||October 2003|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP