Introduction:
Silent brain infarcts (SBIs) are a recently recognized, commonly noted and yet poorly
understood finding of cerebral infarction on imaging studies without a clinically
apparent neurological deficit. The availability of high resolution brain imaging such as
MRI has made the recognition and characterization of these covert markers of
cerebrovascular disease possible. SBIs, also referred to as silent strokes, are
subcortical cavities or cortical areas of gliosis presumed to be caused by previous
infarction.
The prevalence of SBIs in the general population ranges between 8 and 28% in large
cardiovascular and aging studies performed in Europe and North America. A key finding has
been that prevalence rates are relatively low before age 65 with a gradual increase seen
with aging. Among vascular risk factors, hypertension has the strongest association with
SBIs, however other vascular risk factors, such as stroke, have been associated with
increased prevalence of these lesions. The overall prevalence of SBI far exceeds that of
symptomatic stroke and is estimated that for every symptomatic stroke there are
approximately 10 SBIs.
Incidence data for SBIs are sparse, likely a reflection of the need for repeat imaging
studies. Incidence in the general population is estimated at 3% and 6.5% per year from
large population studies. A high incidence of SBIs has been reported following procedures
such as aortic valve replacement or carotid endarterectomy, likely directly related to
these procedures. Research data in a cohort of TIA patients who underwent initial MRI at
the time of the diagnosis and then repeat brain MRI one year after the index event showed
a 37% incidence of new SBIs.
There has been considerable evidence linking SBIs with an increased risk for subsequent
occurrence of stroke, development of cognitive decline and mortality, suggesting that
SBIs are precursors of more severe ischemic brain disease.
Coated-platelets are a class of activated platelets, detected only after simultaneous
stimulation with two agonists, thrombin and collagen, or thrombin and convulxin, a
collagen receptor agonist from tropical rattlesnake venom. In stroke-free controls,
coated-platelets represent approx. 30% of all platelets. Coated-platelet levels are
increased in stroke patients as compared to those with lacunar stroke or controls; higher
coated-platelet levels measured at the time of the clinical infarct correlate with an
increased risk for recurrence at 12 months while lower coated-platelet levels are related
to the occurrence of very early inpatient major hemorrhagic complications. These data
support a role for platelet procoagulant potential in the balance between thrombosis and
hemorrhage.
Several investigations highlight the possibility that coated-platelets play a role in the
events preceding stroke. In asymptomatic carotid stenosis, patients with coated-platelet
levels 45.2% are at highest risk for incident stroke as compared to those with levels <
45.2 %. In SAH patients, delayed cerebral ischemia (ischemic strokes occurring days after
the initial hemorrhage) was linked to a steep increase in coated-platelet levels
immediately predating the infarct. Recent work in stroke patients found higher
coated-platelet levels significantly associated with the presence and number of SBIs.
Longitudinal data in stroke patients exploring the impact of medications used for
secondary stroke prevention identified clopidogrel as the only pharmacological agent
leading to a sustained decrease in coated-platelet levels after initiation of therapy.
Aspirin, anticoagulation therapy or statins did not lead to a similar effect.
Methods:
The goal of the investigators study is to evaluate the efficacy of clopidogrel on the
incidence of silent brain infarction in patients with stroke/TIA using a randomized,
double-blind aspirin-controlled clinical trial. The investigator's hypothesis is that
clopidogrel treatment will lead to decreased incidence of SBIs in patients with
non-lacunar stroke/TIA treated over a two-year period.
Consecutive eligible patients admitted with ischemic stroke or TIA to the Neurology
service qualifying for the study (see inclusion and exclusion criteria separately) will
be randomized to either clopidogrel or aspirin, stratified by sex. The study
statisticians will create the randomization sequence using randomly chosen block sizes of
four or six and will implement the sequence concealment. These doses are part of the
recommended guidelines for secondary stroke prevention and both medications are FDA
approved for secondary stroke prevention.
All patients will be followed by the research team in conjunction with regularly
scheduled outpatient visits for up to one year independent of the current study. After
the 12-month time point, the investigators will maintain phone contact with each patient
for an additional 12 months to decrease loss to follow-up. Prior to the 24-month time
point, the PI/Research Assistant will order a repeat non-contrast MRI for each patient.
Initial and repeat MRI images will be independently reviewed after the repeat scan is
completed at 24 months by two experienced stroke specialists while blinded to the
coated-platelet levels and treatment arm. The initial and repeat MRI will be compared for
the presence of new (interval) SBIs in order to determine SBI incidence.
SBIs will be identified on MRI studies, using a 1.5 Tesla magnet, based on published
guidelines as focal (ovoid or irregularly shaped), 3mm, cavitary lesions, displaying T1
hypointensity and T2 hyperintensity features, and hypointense on FLAIR sequences. In
addition, the cortical SBIs (10% of lesions) may also display some focal atrophic changes
of the cerebral cortex in the area surrounding the infarct. These lesions have a chronic
appearance, can be easily distinguished from acute ischemic changes through the use of
DWI and ADC images and have no corresponding, clinically apparent, cerebrovascular
ischemic event noted in the patient's history.
Using electronic medical records, the investigators will collect the following data:
prescription medicines, age, sex, race, ethnicity, past medical history, type of stroke,
National Institutes of Health Stroke Scale (NIHSS) score upon admission, results of
diagnostic studies performed for stroke, vascular risk factors (diabetes, hypertension,
large-artery artery disease, atrial fibrillation, prior stroke/TIA, hypercholesterolemia,
obesity, cardiac disease, aortic arch plaque, smoking, alcohol consumption),
hematological parameters (total platelet count, mean platelet volume, white blood cell
count and hemoglobin), and coagulation studies (PT, PTT and INR).
Because prior research linked interval development of SBIs with decline in cognitive
function, patients will be screened for cognitive impairment at discharge using the MoCA
test. Those with abnormal MoCA results (<26/30 points) will be referred to the Memory
Loss clinic for memory loss assessment, including neuropsychological testing. At the end
to the follow-up period repeat neuropsychological testing will be performed in
individuals who were evaluated initially and compared to the initial results. The
investigators will also repeat cognitive screening with MOCA in patients who scored
within normal range initially, and those with abnormal results at 24 months will undergo
memory loss assessment.
Statistical analysis:
A target sample size of 152 participants (76 clopidogrel and 76 aspirin) over 1.5 years
(8.4 patients/month) is sufficient to provide preliminary estimates of the effect size
and variation in efficacy, as well as feasibility information regarding the conduct of
the clinical trial. This calculation provides 80% power to detect a 65% reduction in the
hazard of SBI for those receiving clopidogrel versus aspirin, assuming a 2-sided 0.05
alpha level, loss-to-follow-up and death rates of 10%, and follow-up for 24 months. Even
if the effect size observed in the clinical trial is not as large, the trial will still
generate valuable estimates of effect size and variation for efficacy, as well as
feasibility information. These estimates can be used to design a larger, more definitive
clinical trial.
The time to incident SBI distribution will be compared between the clopidogrel and
aspirin arms using a log-rank test. Adverse event will be compared between the treatment
groups using a Chi-square test, or Fisher's exact test for rare events. Analyses will be
based on the intention-to-treat principle. A separate per-protocol analysis, analyzing
data from all patients who adhered to the study medication will be performed. No formal
interim efficacy analyses will be performed. Data quality, protocol implementation,
retention and patient adherence and adverse events will be summarized every six months.
Statistical significance will be set at p<0.05. A multiple imputation method will be used
to impute missing data.
Anticipated findings:
The investigators anticipate that treatment with clopidogrel at standard dose for
secondary stroke prevention will lead to a significant decrease in the incidence of SBIs
as compared to treatment with aspirin. The current data will provide proof of concept for
future larger trials with more extended follow-up time that are able to also evaluate
reduction on key cardiovascular outcomes, such as stroke, myocardial infarction and
sudden death. In addition, key data regarding clinical and imaging features of patients
with SBI and progression of cognitive impairment will be obtained.
