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Reversal of the Antiplatelet Effects of Ticagrelor in Combination With Aspirin, Using Normal Platelets (REVSTARTS)

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ClinicalTrials.gov Identifier: NCT03005704
Recruitment Status : Unknown
Verified April 2017 by Paul Kruger, Hamilton Health Sciences Corporation.
Recruitment status was:  Recruiting
First Posted : December 29, 2016
Last Update Posted : April 6, 2017
Sponsor:
Information provided by (Responsible Party):
Paul Kruger, Hamilton Health Sciences Corporation

Brief Summary:
The specific objective of this study is to investigate the potential for normal platelets to reverse the inhibition of platelet aggregation in patients treated with ticagrelor in combination with aspirin.

Condition or disease Intervention/treatment Phase
Ticagrelor Aspirin Platelet Dysfunction Due to Drugs Transfusion Drug: Antiplatelet treatment Not Applicable

Detailed Description:

Ticagrelor is one of three commercially available antiplatelet adenosine diphosphate (ADP) antagonists (the other two are clopidogrel and prasugrel). They exert their antiplatelet effects by binding to P2Y12 receptors on the platelet surface. Ticagrelor is used in combination with aspirin to prevent and treat thrombosis in patients with acute coronary syndrome, particularly after stent implantation. ADP antagonists are combined with aspirin because aspirin blocks platelet aggregation by preventing thromboxane production, and blocking two different pathways leads to greater efficacy than either drug used alone. Recent clinical trials indicate ticagrelor in combination with aspirin is more effective for prevention of thrombotic events in patients with symptomatic coronary artery disease than aspirin in combination with clopidogrel, but causes significantly more bleeding. The improved efficacy and reduced safety occurs because ticagrelor causes greater inhibition of ADP-mediated platelet activation. The latter can be reliably measured in the laboratory.

Management of patients who bleed while taking an ADP antagonist in combination with aspirin is challenging because there is no specific antidote, Platelet transfusion has the potential to reverse the effects of clopidogrel or prasugrel and aspirin, but these findings cannot be extrapolated to ticagrelor in combination with aspirin because the pharmacokinetic and pharmacodynamic effects of ticagrelor differ.

Aspirin, clopidogrel active metabolite, and prasugrel active metabolite have half-lives of 15-20 minutes, 30 minutes, and four hours respectively. They are irreversible platelet inhibitors which bind to and permanently block platelet function. After their drug elimination, new platelets which enter the circulation from megakaryocytes in the bone marrow are unaffected. Therefore, after elimination, newly transfused platelets have the potential to restore haemostasis. In contrast, ticagrelor, a reversible platelet inhibitor, has a longer half-life (7.7 to 14.1 hours). As a result of its longer half-life, newly added platelets (both from the bone marrow and transfused platelets) are inhibited by ticagrelor for at least 24 hours after the last dose. Therefore, reversing platelet inhibition and controlling excessive bleeding associated with ticagrelor by platelet transfusion poses a greater challenge than with clopidogrel and prasugrel. Nevertheless, because of its greater efficacy, ticagrelor is preferred over clopidogrel in high risk patients.

Previous studies of platelet transfusion and ev vivo mixing within 24 hours of drug administration have shown than the inhibition of ADP-mediated platelet activation by clopidogrel and prasugrel, but not ticagrelor can be reversed or modulated by the addition of donor platelets. Although reversing the platelet inhibitory effects of ticagrelor might not be possible within 24 hours of stopping the drug, it should be possible in the days that follow. This has not been examined. Accordingly, we propose to perform a study in which we systematically evaluate inhibition of ADP mediated platelet activation, a reliable measure of ticagrelor's antiplatelet activity, when donor platelets are added to the platelets of subjects treated with ticagrelor at time intervals up to 96 hours after their last dose.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Reversal of the Antiplatelet Effects of Ticagrelor in Combination With Aspirin, Using Normal Platelets
Study Start Date : January 2017
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : January 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Antiplatelet Treatment
Subjects will be treated with five days of ticagrelor in combination with acetylsalicylic acid.
Drug: Antiplatelet treatment
Subjects will be treated with ticagrelor in combination with acetylsalicylic acid for five days. Ticagrelor will be administered at a loading dose of 180 mg, followed by 90 mg twice daily maintenance dose. Acetylsalicylic acid will be administered at a dose of 81 mg daily.
Other Name: Ticagrelor and acetylsalicylic acid

No Intervention: Control
Subjects will not receive antiplatelet treatment and their PRP will be used as the source of untreated platelets in laboratory mixing studies.



Primary Outcome Measures :
  1. Reversal of platelet inhibition [ Time Frame: 5 days ]
    The primary outcome is to measure the efficacy of untreated platelets in reversing the platelet inhibition due to ticagrelor in combination with aspirin by ex vivo mixing studies. Increase in platelet aggregation will be measured by light transmission aggregometry after stimulation by adenosine diphosphate, arachidonic acid, and collagen.


Secondary Outcome Measures :
  1. Timing of reversal of platelet inhibition [ Time Frame: 5 days ]
    The secondary outcome measure is to determine the time point post cessation at which untreated donor platelets reverse the antiplatelet effect of ticagrelor in combination with aspirin.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy subjects
  • At least 18 years of age
  • No history of cardiovascular disease
  • Not taking antiplatelet therapy prior to participation

Exclusion Criteria:

  • Known thrombocytopenia, other coagulation disorder such as von Willebrand's disease, haemophilia
  • Allergy or intolerance to ticagrelor or aspirin (if known)
  • Consumption of drugs within the preceding fourteen days that potentially can interfere with metabolism of ticagrelor through CYP3A4, CYP3A or P-glycoprotein (eg, ketoconazole, clarithromycin, nefazodone, ritonavir, atazanavir, diltiazem, amprenavir, aprepitant, erythromycin, fluconazole, verapamil, rifampicin, dexamethasone, phenytoin, carbamazepine, phenobarbital, cyclosporine, simvastatin, atorvastatin, tolbutamide, digoxin)21
  • Previous transfusion or pregnancy (because of potential alloimmunisation)
  • Pregnant or trying to conceive, or breastfeeding
  • Unable or unwilling to give written informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03005704


Locations
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Canada, Ontario
Population Health Research Institute Recruiting
Hamilton, Ontario, Canada, L9L 2X2
Contact: Paul Kruger, MB BS    9059230285    paul.kruger@phri.ca   
Sponsors and Collaborators
Hamilton Health Sciences Corporation

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Responsible Party: Paul Kruger, Dr, Hamilton Health Sciences Corporation
ClinicalTrials.gov Identifier: NCT03005704     History of Changes
Other Study ID Numbers: PopulationHRI
First Posted: December 29, 2016    Key Record Dates
Last Update Posted: April 6, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Paul Kruger, Hamilton Health Sciences Corporation:
Ticagrelor
Acetylsalicylic acid
Platelet transfusion
Reversal
Additional relevant MeSH terms:
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Aspirin
Platelet Aggregation Inhibitors
Ticagrelor
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents