Platelet Hyperreactivity to Aspirin and Stroke (PLARAS)
|First Received Date ICMJE||October 2, 2008|
|Last Updated Date||June 20, 2013|
|Start Date ICMJE||July 2009|
|Primary Completion Date||June 2013 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Correlation between platelet hyperreactivity and the sum of clinical outcomes (sum of death, TIA, stroke and acute coronary syndromes) in 3, 12, 24, and 36 months [ Time Frame: Three, 12, 24, and 36 months ] [ Designated as safety issue: No ]|
|Original Primary Outcome Measures ICMJE
|Change History||Complete list of historical versions of study NCT00766896 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Platelet Hyperreactivity to Aspirin and Stroke|
|Official Title ICMJE||Platelet Hyperreactivity to Aspirin and Stroke: A Prospective Study With Clinical Outcomes|
Aspirin is the anti-thrombotic therapy of choice for patients in the acute or chronic phase of vascular, cardiac, and neurological diseases, unless there is a specific indication for sodium warfarin (for instance, cardiac thrombus, chronic atrial fibrillation, cardio-embolic ischemic stroke). Recent studies, including some meta-analyses, suggest that 5-60% of patients with cardiovascular disease who use aspirin show some platelet resistance to the drug. However, the available studies include several methodological errors that make interpretation and practical application difficult. Thus, the incidence and outcome of platelet resistance remain poorly understood, especially in patients with ischemic stroke. Moreover, few studies have included patients in ambulatory follow-up
THERAPY WITH ASPIRIN
The dose of aspirin to be prescribed in this study will be 300 mg orally or by nasogastric tube once a day (assisted therapy), with first dose tomography soon after admission if the patient has no indication of thrombolytic therapy. After the acute phase, patients will receive aspirin at a dose of 200 mg/day. Aspirin will be administered in a "simple" preparation (no buffer, no extended release)
ANALYSIS OF OUTCOME DURING THE HOSPITAL PHASE
The outcomes will be assessed daily during hospitalization until the patient is discharged. The physician, the patient, and the researchers will not have access to the results of tests for platelet function. The number of days of hospitalization will be reviewed, including the number of days of hospitalization in the intensive care unit. Deaths will be analyzed, and the cause of death will be described in detail in each case. Electrocardiograms will be examined by an experienced cardiologist. Echocardiograms will be examined by an experienced cardiologist specializing in this method. Tomography will be examined by an experienced neuroradiologist, and resonance/resonance angiography will be evaluated by another experienced neuroradiologist; both will be blinded to the platelet results. Outcomes will be judged by a committee containing a neurologist, a hematologist, a neuroradiologist, a cardiologist, and an epidemiologist, all of whom will be blinded to the results of platelet function
MONITORING AND MANAGEMENT AFTER HOSPITAL DISCHARGE
Outcomes will be analyzed through interviews 3, 12, 24, and 36 months after the initial neurological event, as well as with monthly telephone interviews. Potential adverse outcomes (death, hospitalization, diagnostic tests conducted, request for treatment of any condition, or new onset of symptoms) will be assessed in detail by the committee of investigators of this study. During this evaluation, the doctor, the patient, and the researchers will not have access to the results of the tests for platelet function. The outcomes will be judged by a committee comprising a neurologist, a hematologist, a neuroradiologist, a cardiologist, and an epidemiologist, all of whom will be blinded to platelet test results Adherence (daily use) will be investigated in an active manner at all return visits and through monthly telephone contact. This study will include interviews with patients and separate interviews with families, in addition to reviews of the package of aspirin. In addition, adherence will be assessed by measuring serum thromboxane B2.
DEFINITION OF HYPERREACTIVITY TO ASPIRIN
COLLECTION OF BLOOD
Blood samples will be collected on arrival at the ED (before the first dose of aspirin), on the fifth day of hospitalization, after three months, and again after 12 months. Samples will be collected between 9 and 12 AM after fasting overnight, except for the sample taken on arrival at the ED. The blood will be collected from the antecubital vein, or another vein if necessary, into bottles of citrate (3.2%; Vacuette, Greiner Bio-One) or directly into the Plateletworks bottle kit. Samples will total approximately 20 ml. The tourniquet will not be applied for more than 30 seconds and movement will not be allowed before or during collection. In order to prevent platelet activation induced by collection, even with the above precautions, the first 5 ml sample will be discarded. The bottles will be filled to the top and gently inverted five times to obtain the correct mixture of blood with anticoagulant. In the Plateletworks test, assays will conducted within 10 minutes of collection; the remaining assays will be conducted within 30 minutes
AGGREGOMETRY BY MEASURING THE IMPEDANCE OF WHOLE BLOOD USING CHRONOLOG MODEL 700 AND SOFTWARE (AGGRO/LINK-8, PA, USA)
After collecting citrated whole blood, the sample will be processed in under 30 minutes. Whole blood will be diluted 1:1 with sterile saline (0.9%) and stimulated with one of several reagents (Chrono-Log, 0.5 mM arachidonic acid, 1 g/L collagen, or 5 g/L collagen). The maximum impedance will be measured using two electrodes immersed in the sample for 6 minutes and expressed as Ω.
PFA-100 (PLATELET FUNCTION ANALYZE-100, SIEMENS, USA)
Blood specimens for PFA-100® assays will be tested according to the manufacturer's instructions. For all samples, the PFA-100® self-test procedure will be run before analysis. Testing will be performed using citrated whole blood with collagen-epinephrine cartridges. Whole blood will be aspirated under conditions of high shear stress through a 150-µm aperture covered with a membrane impregnated with collagen and epinephrine. The time taken to occlude the aperture by a platelet plug will be recorded as the closure time (measured in seconds).
DETERMINATION OF SERUM THROMBOXANE B2 - ELISA
After collection, blood will be immediately centrifuged (+4 °C), and the plasma immediately frozen in liquid nitrogen (-190 °C) and then transferred to a -80 °C freezer. Serum thromboxane B2 will be measured by ELISA in duplicate according to the manufacturer's instructions, and expressed as ng/ml.
PLATELETWORKS (HELENA CORPORATION, USA)
Briefly, after collection of blood in kits containing arachidonic acid, collagen, ADP and EDTA, platelet counts will be made by impedance measurement (Horiba ABX, Montpellier, France), in accordance with the standard protocol of Helena Laboratories (Helena Point of Care ®, Texas, USA). The percentage of platelet aggregation will be calculated using the following formula: % of aggregation = [platelets in EDTA - platelets with agonist]/ platelets in EDTA x 100
VERIFYNOW ASPIRIN, ACCUMETRICS, USA
The VerifyNow Aspirin point-of-care system (Accumetrics, San Diego, CA, USA) is based on turbidimetric optical detection of platelet aggregation in whole blood. Whole blood will be transferred into standard cartridges containing a lyophilized preparation of human fibrinogen-coated beads and arachidonic acid. As aggregation occurs, the system will convert luminosity transmittance results into aspirin reaction units (ARUs).
IMPACT-R, DIAMED, USA
Citrated blood (130 μL) will be placed in the test kit (wells) according to the manufacturer's protocol, and subjected to shear flow using a rotating cone for 2 minutes (1800 s-1). The wells will then be washed and stained with May Grünwald. The adhesion of platelets to the surface will be evaluated using an image analysis system connected to the Impact-R, and the results will be expressed as the percentage of stained area.
For all calculations, will be used the software IBM SPSS 21.0 for Windows (SPSS Inc, Chicago, IL, USA). The database will be created by SPSS Data Entry Builder 4.0 using the double entry input system.
TIMETABLE FOR IMPLEMENTATION OF THE PROJECT
Phase No. of Months Calendar Dates Trial Activities and Estimates
CONFLICT OF INTEREST
There is no external influence or sponsor for the survey, collection, or analysis of data. Similarly, the statistical analysis, preparation and publication of manuscripts will be conducted entirely by the researchers themselves, working together with epidemiologists and statisticians of the Faculty of Medicine, USP. Companies and institutions that provided the kits and equipment for the platelet tests will be described in presentations at conferences and in publications
|Study Type ICMJE||Interventional|
|Study Phase||Phase 4|
|Study Design ICMJE||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Diagnostic
|Intervention ICMJE||Drug: Aspirin (platelet sensitive versus platelet hyperreactivity)
The dose of aspirin to be prescribed in this study will be 300 mg orally or by nasogastric tube once a day (assisted therapy), with first dose tomography soon after admission if the patient has no indication of thrombolytic therapy. After the acute phase, patients will receive aspirin at a dose of 200 mg/day. Aspirin will be administered in a "simple" preparation (no buffer, no extended release).
Other Name: Aspirin resistance
|Study Arm (s)||
|Publications *||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||Completed|
|Completion Date||June 2013|
|Primary Completion Date||June 2013 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years and older (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Brazil|
|Removed Location Countries|
|NCT Number ICMJE||NCT00766896|
|Other Study ID Numbers ICMJE||0292/07|
|Has Data Monitoring Committee||Yes|
|Plan to Share Data||Not Provided|
|IPD Description||Not Provided|
|Responsible Party||Herlon Saraiva Martins, University of Sao Paulo|
|Study Sponsor ICMJE||University of Sao Paulo|
|Information Provided By||University of Sao Paulo|
|Verification Date||June 2013|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP