Platelet reactivity in diabetic patients and the effects of different antithrombotic agents on the results of multiple platelet function tests

Cardiovascular disease is the leading cause of morbidity and mortality in
patients with type 2 diabetes mellitus (T2DM) mellitus. Specifically, recent
studies have demonstrated that T2DM is associated with a twofold to fourfold
risk of developing coronary artery disease (CAD), peripheral arterial disease
(PAD), and stroke. Several mechanisms account for the increased
atherothrombotic risk in diabetes mellitus patients, including a high intrinsic
(or baseline) platelet reactivity status.
As a consequence, two recent primary prevention trials in T2DM patients
attempted to provide proof of the principle that primary prevention by means of
aspirin therapy reduces the incidence of atherothrombotic events on the
long-term. Although both trials did not show a superiority of aspirin therapy
when compared to placebo, a trend favoring aspirin therapy was clearly visible.
Abovementioned results have fueled the discussion why low-dose aspirin failed
to show superiority and currently, the body of evidence is growing that the
efficacy of low-dose aspirin in patients with diabetes on the platelet level is
substantially lower than in individuals without diabetes.
Another interesting subgroup of patients in whom aspirin therapy has failed to
show superiority in primary prevention includes women. Are there any apparent
reasons for these sex-related differences? The answer is yes. First of all,
women tend to develop heart disease between 10 and 15 years later than men.
This may explain why consistent benefits of aspirin on all major cardiovascular
endpoints, including myocardial infarction and stroke, were observed only among
women aged 65 years or older. Second and probably more important, sex
differences in salicylate metabolism, platelet responses, vascular reactivity,
and the nature of atherosclerotic disease also cause different biological
responses between men and women
In the present study, we sought to explore the differences in baseline
(intrinsic) platelet reactivity status between T2DM and healthy volunteers with
multiple platelet function assays. Moreover, we will investigate the response
to different forms and intensities of antiplatelet therapies and lastly, we
will explore any sex-related differences within the group of T2 diabetics and
healthy volunteers.

Primary Objectives:
1. To compare the magnitude of baseline (or intrinsic) platelet reactivity
between T2DM patients and healthy volunteers using multiple platelet function
assays

2. To compare the magnitude of baseline (or intrinsic) platelet reactivity
between male and female healthy volunteers using multiple platelet function
assays

3. To compare the magnitude of baseline (or intrinsic) platelet reactivity
between male and female T2DM using multiple platelet function assays

4. To investigate the effects of different antiplatelet agents (low-dose
aspirin alone once daily, followed by low-dose aspirin twice daily),
(clopidogrel alone followed by prasugrel alone) or (low dose aspirin once daily
followed by dual antiplatelet therapy with aspirin and clopidogrel) on the
change in absolute magnitude of baseline (or intrinsic) platelet reactivity
between T2DM patients and healthy volunteers

5. To investigate the effects of different antiplatelet agents (low-dose
aspirin alone once daily, followed by low-dose aspirin twice daily),
(clopidogrel alone followed by prasugrel alone) or (low dose aspirin once daily
followed by dual antiplatelet therapy with aspirin and clopidogrel) on the
change in absolute magnitude of baseline (or intrinsic) platelet reactivity
among male and female healthy volunteers

6. To investigate the effects of different antiplatelet agents (low-dose
aspirin alone once daily, followed by low-dose aspirin twice daily),
(clopidogrel alone followed by prasugrel alone) or (low dose aspirin once daily
followed by dual antiplatelet therapy with aspirin and clopidogrel) on the
change in absolute magnitude of baseline (or intrinsic) platelet reactivity
among male and female T2DM patients

Secondary Objectives:
1. To investigate the magnitude of baseline (or intrinsic) platelet reactivity
among T2DM patients and to compare the results of multiple platelet function
assays with one and another

2. To investigate the magnitude of baseline (or intrinsic) platelet reactivity
among healthy volunteers and to compare the results of multiple platelet
function assays with one and another

3. To investigate the effects of different antiplatelet agents (low-dose
aspirin alone once daily, followed by low-dose aspirin twice daily),
(clopidogrel alone followed by prasugrel alone) or (low dose aspirin once daily
followed by dual antiplatelet therapy with aspirin and clopidogrel) among
healthy volunteers and to compare results of multiple platelet function assays
with one and another

4. To investigate the effects of different antiplatelet agents (low-dose
aspirin alone once daily, followed by low-dose aspirin twice daily),
(clopidogrel alone followed by prasugrel alone) or (low dose aspirin once daily
followed by dual antiplatelet therapy with aspirin and clopidogrel) among T2DM
patients and to compare results of multiple platelet function assays with one
and another

Tertiairy (exploratory) Objectives:
1. To explore the relationship between the magnitude of Baseline platelet
reactivity (as measured with various platelet function tests) among T2DM
patients and healthy volunteers and the occurrence of atherothrombotic events
at 5 years follow-up

2. To explore possible relationships between the magnitude of platelet
reactivity (as measured with various platelet functions tests) and genetic
variations in selected candidate genes

3. To explore possible relationships between antiplatelet therapy
responsiveness and genetic variations in selected candidate genes

This is an open label, randomized trial

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Suitable candidates (male and female T2DM patients and male and female healthy
volunteers) will be invited to the outpatient clinical of our department of
Research and Development for intrinsic (baseline) platelet function evaluation,
physical examination and a standardized interview. After checking all the in-
and exclusion criteria, written informed consent will be obtained before
initiating any study procedure.
Study site personnel will question each patient and will record on the CRF the
occurrence and nature of pre-existing conditions. These include: demographics,
medical history and vital signs. After drawing of the baseline blood samples,
subjects will be randomly assigned in an open-label fashion to one of the three
treatment arms of the study. Randomization will be performed with sealed
envelopes.
At baseline, 1 week and after 4 weeks, platelet function evaluation will be
performed with different platelet function assays to measure the effects of the
different antiplatelet regimens on the magnitude of platelet reactivity.