Clinical trial NCT02550301: Does Mean Platelet Volume Change With Clopidogrel
Official title: Prospective Pilot Study- Does Mean Platelet Volume Change With Clopidogrel in Patients With Stable Angina Undergoing Percutaneous Coronary Intervention?
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Stable Angina
Keywords: mean platelet volume
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
First posted: 2015-09-15
Enrollment: 100
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Consecutive patients who are clopidogrel naïve, electively listed for coronary angiography and Percutaneous Intervention (PCI) at PMCC, Toronto General Hospital (TGH), will be prospectively enrolled in this pilot study

Brief summary: Platelets play a major role in thrombus formation and platelet size, measured by Mean Platelet Volume (MPV) correlates with platelet activity. MPV is increased in patients with Myocardial Infarction (MI) and is an independent predictor of adverse events in patients with ST Elevation Myocardial Infarction (STEMI) . Data on MPV in patients with stable angina is limited.

Aspirin and clopidogrel are antiplatelet agents administered routinely to patients undergoing PCI and are required for stent patency. MPV is not known to be affected by low dose Aspirin. Treatment with clopidogrel is thought to reduce MPV in-vitro but the magnitude of this reduction in MPV is unclear, especially in patients with stable angina undergoing PCI. An inverse correlation also exists between MPV and platelet count .

The investigators aim to assess if a change occurs in MPV (∆ MPV) after routine clopidogrel administration in patients with stable angina undergoing PCI.

Detailed description: This is a prospective, observational study. The investigators aim to conduct this pilot study to assess if there is a change in MPV (∆ MPV) after routine clopidogrel in patients with stable angina undergoing PCI.

Reduced responsiveness to clopidogrel (otherwise known as clopidogrel resistance) is well documented. Clopidogrel resistance can result in adverse long term effects including stent thrombosis and mortality. Diagnosis of clopidogrel resistance requires special analyzers and reagents . There are potential cost factors involved with the analyzers and reagents used for testing resistance. There are no known clinical or biochemical markers of clopidogrel resistance.

If our pilot study results demonstrate that MPV does change (∆MPV) after clopidogrel, then a prospective trial can be conducted in future to correlate ∆MPV with clopidogrel resistance measured by analyzer tests. This could establish ∆MPV as a potential cheap, effective biochemical marker for clopidogrel resistance.

If the investigators are successful in demonstrating a change in MPV with clopidogrel, our pilot study will facilitate conducting future larger studies to demonstrate correlation between ∆MPV and clopidogrel resistance. This could establish ∆MPV as a potential cheap, effective biochemical marker for clopidogrel resistance with resultant benefit to subjects and the institution.

All clopidogrel naive patients with stable angina symptoms who are electively listed for coronary angiography and PCI at Peter Munk Cardiac Centre (PMCC), Toronto General Hospital (TGH), will be included in this pilot study. This pilot study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and University Health Network (UHN) policy

Study hypothesis. The investigators hypothesize that MPV values remain the same after clopidogrel in patients with stable angina undergoing PCI and aim to disprove the hypothesis

Study Design This prospective pilot study will include consecutive clopidogrel naïve patients with stable angina symptoms, who are electively listed for coronary angiography and PCI at Peter Munk Cardiac Centre (PMCC), Toronto General Hospital (TGH), will be prospectively included in this pilot study. These patients are given a routine loading dose of clopidogrel 600milligrams (mg) followed by a daily dose of clopidogrel 75mg daily after they undergo PCI (as per protocol for all patients who undergo PCI). Complete Blood Count (CBC) is performed routinely in patients prior to the loading dose of clopidogrel (day 0) and on one occasion post PCI as per UHN standard of care. MPV and platelet count are automatically generated during analysis of CBC.

Ten milliliters (mls) of blood will be drawn from eligible, consented patients at the time of the admission, collected in ethylenediamine tetraacetic acid (EDTA) tubes, and tested for CBC. Platelets have an average life span that can vary from 8-10 days or 10-36 days12. To minimize this bias, three additional MPV samples will be collected on day 1, day 7 and day 30 post PCI.

The samples will be analyzed within 2 hours of venipuncture to minimize artefactual increase in MPV with prolonged exposure to EDTA in the collection tubes .

Change in MPV (∆MPV) and change in platelet count (∆Platelet count) will be calculated as follows:

* MPV = MPV on admission - Mean MPV after clopidogrel
* Platelet count = Platelet count on admission - Mean Platelet count after clopidogrel These results will be correlated with adverse events (readmission and MI) at 30 days by collecting data regarding readmission and cardiac blood tests (for MI) from the electronic patient record (EPR) system online. The universal definition of MI will be adhered to .

Platelet inhibition occurs within 2 hours of a loading dose but reaches a steady state from 3 to 7 days. Repeated samples will ensure the effect of a steady level of clopidogrel on MPV and reduce bias.No change in intervention or medication will occur-all patients will receive treatment according to the UHN standard of care. No randomization or blinding is involved in this pilot study.

The expected duration of participation will be up to 1 month after the index procedure as repeat blood tests are required at day 7 and day 30 after the procedure and adverse events are assessed at day 30.

Patients discharged on the day of the procedure need to return for blood tests the following day, on day 7 and day 30 after the PCI (3 visits). Patients discharged on the day after the procedure will need to return for blood tests on day 7 and day 30 after the PCI (2 visits).

This will involve travel time (approximately 1 hour each way) and time to give the blood sample (30 minutes inclusive of waiting time) equal to a total of 2.5 hours for each visit. Patients will have an overall time commitment of 7.5 hours for 3 visits or 5 hours for 2 visits.

Statistics MPV is automatically analyzed (on a CBC sample) by the Abbott CELL-DYN Sapphire@ analyzer at the TGH laboratory.

The sample size was estimated using the formula:

Z = 1.96 for 95% Confidence Interval (CI) σ = standard deviation (SD) of the outcome variable = 0.219 fl for MPV (Hematology Laboratory Quality Control (QC) for MPV analyzed by Abbott CELL-DYN Sapphire@ (8.46 fl). E (5%) = desired margin of error

In order to ensure that the 95% confidence interval estimate of the MPV in adults with stable angina undergoing PCI is within 0.219 femtolitre (fl) of the true mean MPV, a sample size of 74 patients is required for this pilot project.

Assuming an attrition rate of 30%, a sample size of 100 patients would be required. The formula has taken into account the QC mean obtained for the Abbott CELL-DYN Sapphire@. An attrition rate of 30% was taken into account for patients who may not be able to return for the repeat blood tests.

In addition to determining if MPV changes after clopidogrel or not, ∆MPV will be correlated with the presence of clopidogrel using Receiver Operating Curves (ROC) as will ∆Platelet count. The study will be terminated on completion of collection of 4 blood samples at pre-specified time points in 74 patients (actual calculated sample size) with stable angina undergoing angiography and PCI.

All eligible patients (as per the inclusion criteria) will be included in the trial.

Only persons involved in this pilot study (i.e. PI, Co-PI, research fellows and research nurse) will have access to the source data and documents which will be maintained in a secure location at the PMCC site. Any electronic data will be on specific UHN designated on-site computers, password protected and only accessible to the designated research team.

Review and Assessment of adverse events Adverse effects are not expected at the time of blood collection. A designated contact telephone number for the research nurse will be made available to the participating patients in the event of rare adverse effects such as fainting at the time of blood collection, bruising or infection at the access site.

Consent process Patients will be consented prior to the procedure - the background of the proposed study and the relative benefits and risks of the study will be clearly explained to the patient prior to the procedure on the day. If the patient's native language is not English or the patient does not speak/understand English, then a UHN designated native language translator will be involved for purposes of consent. Patients must sign the consent form prior to enrollment. A UHN prototype consent form prototype will be used for this purpose.

Co-ordinated Approval Process for Clinical Research (CAPCR) form has been submitted for and approved by the Research Ethics Board (REB)

Financing: Funding will be obtained (internally) from the Cardiology Division, PMCC, TGH.

Eligibility criteria: Inclusion Criteria:

* \> 18 years old
* Able to attend for follow up blood tests
* Able to provide written informed consent

Exclusion Criteria:

* \<18 years of age
* Unable to attend for follow up blood tests on days 1, 7 and 30
* Already on clopidogrel at least 1 day prior to presenting for angiography/PCI
* Those who undergo only diagnostic angiography
* History of Myocardial Infarction (MI) in last 1 year
* Anemia (Hb\<100)
* Abnormal (low or high out of range) platelet counts
* Diabetes Mellitus
* Known liver disease
* Known severe renal impairment (eGFR \<30ml/min/1.73m2)
* Known pregnancy
* On Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) or steroids
* Known connective tissue disease
* Acute ongoing infections or bleeding
* On oral anticoagulant treatment in the last 1 week
* Pro-coagulant blood disorder
* Known immunosuppressed states
* Treatment with GpIIb/IIIa inhibitor in the last week prior to presentation
* Patients involved in other trials

Primary outcomes:
measure: Change in MPV (∆MPV) with clopidogrel in stable angina patients undergoing PCI.
timeFrame: 30 days
Secondary outcomes:
measure: Change in Platelet count (∆ platelet count) with clopidogrel in stable angina patients
timeFrame: 30 days
measure: Correlation between ∆MPV and adverse events (readmission and Myocardial Infarction) at 30 days
timeFrame: 30 days
Other outcomes:
Locations:
Study officials:
affiliation: University Health Network, Toronto
name: Vladimir Dzavik, MD,FRCPC
role: PRINCIPAL_INVESTIGATOR
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