- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00174902
The Effect of Beta-Blockers and Aspirin on Hemostasis and Endothelial Function After Acute Mental Stress
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.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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
Enrollment
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Zurich, Switzerland, CH-8092
- Institute of Behavioral Sciences, Swiss Federal Institute of Technology
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Life-time non-smoker or non-smoker for more than a year,
- native language Swiss-German,
- systolic blood pressure <160 mm Hg, diastolic blood pressure <100 mm Hg.
- Subjects must have a body mass index that is not considered to be a cardiovascular risk factor, i.e. ≤ 26.5 kg/m2.
Exclusion Criteria:
- Individuals reporting cardiovascular disease, renal disorders, endocrine disorders, hepatopathy, psychiatric disorders or who take regular medication for any of these conditions.
- Persons are excluded, who report to drink >5 cups (0.15 l each) of brewed coffee (> 500 mg caffeine) a day, or who report drink more than 1.0 l beer and 0.45 l wine per day, respectively.
- All subjects on regular beta-blocking or aspirin medication are excluded from the study.
- Participants will be required not to take aspirin or any other non-steroidal anti-inflammatory drug during the study period, beginning 10 days prior to the first study medication.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: PREVENTION
- Allocation: RANDOMIZED
- Interventional Model: FACTORIAL
- Masking: DOUBLE
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
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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.
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Secondary Outcome Measures
Outcome Measure |
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Change scores of a) monocyte and T-lymphocyte expression of L-selectin, lymphocyte-function associated antigen (LFA-1), and CD40L
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monocyte tissue-factor antigen (CD 142) expression
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plasma levels of TAT, t-PA, and PAI-1
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plasma levels of soluble intercellular adhesion molecule (sICAM-1), soluble vascular adhesion molecule (sVCAM-1), endothelin-1, and vWF
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Joachim E Fischer, MD, MSc, Swiss Federal Institute of Technology, Institute of Behavioral Sciences
Publications and helpful links
General Publications
- von Kanel R, Mills PJ, Ziegler MG, Dimsdale JE. Effect of beta2-adrenergic receptor functioning and increased norepinephrine on the hypercoagulable state with mental stress. Am Heart J. 2002 Jul;144(1):68-72. doi: 10.1067/mhj.2002.123146.
- Mischler K, Fischer JE, Zgraggen L, Kudielka BM, Preckel D, von Kanel R. The effect of repeated acute mental stress on habituation and recovery responses in hemoconcentration and blood cells in healthy men. Life Sci. 2005 Jul 22;77(10):1166-79. doi: 10.1016/j.lfs.2005.03.006. Epub 2005 Apr 26.
- von Kanel R, Kudielka BM, Preckel D, Hanebuth D, Fischer JE. Delayed response and lack of habituation in plasma interleukin-6 to acute mental stress in men. Brain Behav Immun. 2006 Jan;20(1):40-8. doi: 10.1016/j.bbi.2005.03.013.
- von Kanel R, Preckel D, Zgraggen L, Mischler K, Kudielka BM, Haeberli A, Fischer JE. The effect of natural habituation on coagulation responses to acute mental stress and recovery in men. Thromb Haemost. 2004 Dec;92(6):1327-35. doi: 10.1160/TH04-04-0223.
Study record dates
Study Major Dates
Study Start
Study Completion
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Behavioral Symptoms
- Cardiovascular Diseases
- Vascular Diseases
- Arterial Occlusive Diseases
- Stress, Psychological
- Arteriosclerosis
- Physiological Effects of Drugs
- Adrenergic beta-Antagonists
- Adrenergic Antagonists
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Antihypertensive Agents
- Vasodilator Agents
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Analgesics
- Sensory System Agents
- Anti-Inflammatory Agents, Non-Steroidal
- Analgesics, Non-Narcotic
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Fibrinolytic Agents
- Fibrin Modulating Agents
- Platelet Aggregation Inhibitors
- Cyclooxygenase Inhibitors
- Antipyretics
- Propranolol
- Aspirin
Other Study ID Numbers
- SNF 32-68277
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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