Reversing Ticagrelor's Effects With Fresh Platelets

The current American College of Cardiology/American Heart Association (ACC/AHA) guidelines
for ACS patients requiring CABG surgery after treatment with dual antiplatelet therapy
recommend delaying surgery for 5-7 days after discontinuation of therapy, to allow for the
dissipation of its antiplatelet effects. This treatment-devoid waiting period puts the ACS
patients at risk for further cardiovascular events. Any means to shorten this vulnerable
period would be of critical value. One possibility to speed up the recovery of the inhibited
platelets is to administer infusions of fresh platelets. In fact, platelet transfusions are
frequently administered to patients during surgery who had received prior antiplatelet
therapy. However, the degree to which these transfusions restore platelet function in the
recipient subjects' blood and the time from dosing when they are most effective are unknown.
The timing is critical in scenarios where urgent surgery is required because infusion of
platelets too soon after antiplatelet dosing could render them useless by the residual drug
in circulation.

The aim of the present study is to investigate the restoration of platelet function of
ticagrelor-treated subjects by adding donor platelets to their blood. The study would have 2
arms mimicking different clinical scenarios:

1. Clinical Scenario 1 - Patient given a loading dose (LD) of ticagrelor in the emergency
room, requires surgery: A single LD of ticagrelor (180 mg) with aspirin (325 mg) will be
given to study subjects and platelet testing will be performed after addition of fresh
platelets to their blood ex vivo. Donor platelets will be added at 4-, 6-, 24- and
48-hours post-dose, to assess the time required for normalizing subject's platelet
function after a LD of ticagrelor.

2. Clinical Scenario 2 - Patient on maintenance dosing (MD) of ticagrelor, requires
surgery: Subjects will receive ticagrelor (90 mg twice daily) with aspirin (81 mg once
daily) for 3-7 days. After the last dose, platelet testing will be performed after
addition of fresh platelets to their blood ex vivo, at 4-, 6-, 24- and 48-hours
post-dose to assess the time required for normalizing subject's platelet function after
daily treatment with ticagrelor.

Platelet testing will be carried out using the following methodologies:

1. Platelet Aggregation - VerifyNow P2Y12 assay.

2. Platelet Aggregation - Multiplate Analyzer.

Inclusion Criteria:

- Male or female volunteer between 18 and 75 years old.

- History of stable (i.e. non-acute) cardiovascular disease or the presence of risk
factors for cardiovascular disease (i.e. hypertension, diabetes, hyperlipidemia, high
calcium score and abnormal findings on angiography or stress test).

Exclusion Criteria:

- Conditions associated with hemorrhagic risk, e.g., frequent epistaxis,
gastrointestinal ulcer, hemorrhagic vascular lesions, recent surgery.

- Allergy or hypersensitivity to aspirin or ticagrelor.

- Loss of >400 mL blood or blood donation within past 3 months.

- Positive serology for hepatitis B (HBs Ag) or hepatitis C.

- History of drug abuse or alcohol abuse.

- Positive pregnancy test.

- Evidence of unstable or acute cardiovascular disease (e.g., unstable angina, recent
myocardial infarction, congestive heart failure).

- History of clinically relevant pulmonary, hepatic, gastrointestinal, renal, metabolic,
hematologic, neurologic, respiratory or psychiatric disease, bleeding, acute
infectious disease or signs of acute illness.