The Effect of Beta-Blockers and Aspirin on Hemostasis and Endothelial Function After Acute Mental Stress
Information source: Swiss Federal Institute of Technology
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Arteriosclerosis; Stress, Psychological
Intervention: inderal (drug), acetylsalicylic acid (drug) (Drug)
Phase: Phase 1/Phase 2
Status: Active, not recruiting
Sponsored by: Swiss Federal Institute of Technology
Official(s) and/or principal investigator(s):
Joachim E Fischer, MD, MSc, Principal Investigator, Affiliation: Swiss Federal Institute of Technology, Institute of Behavioral Sciences
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.
Official title: 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 design: Prevention, Randomized, Double-Blind, Placebo Control, Factorial Assignment, Efficacy Study
Primary outcome: 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.
Change scores of a) monocyte and T-lymphocyte expression of L-selectin, lymphocyte-function associated antigen (LFA-1), and CD40L
monocyte tissue-factor antigen (CD 142) expression
plasma levels of TAT, t-PA, and PAI-1
plasma levels of soluble intercellular adhesion molecule (sICAM-1), soluble vascular adhesion molecule (sVCAM-1), endothelin-1, and vWF
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
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
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
Minimum age: 40 Years.
Maximum age: 55 Years.
- 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.
- Individuals reporting cardiovascular disease, renal disorders, endocrine disorders,
hepatopathy, psychiatric disorders or who take regular medication for any of these
- 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
- All subjects on regular beta-blocking or aspirin medication are excluded from the
- 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
Locations and Contacts
Institute of Behavioral Sciences, Swiss Federal Institute of Technology, Zurich CH-8092, Switzerland
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.
Starting date: October 2003
Ending date: August 2004
Last updated: October 24, 2006