Study of Ticagrelor Versus Aspirin Treatment in Patients With Myocardial Injury Post Major Non-cardiac Surgery

The objective of this pilot study is to establish the rate of cardiovascular events in
patients with elevated troponins levels post major, non-cardiac surgery and to evaluate the
efficacy and safety of ticagrelor treatment compared to aspirin in these patients.

Data from current studies suggest that myocardial injury detected by minor elevations in
troponin levels within 3 days after non-cardiac surgery may occur in 10-24% of patients and
is associated with an increased risk of mortality at 30 days and 1 year. There are no
current guidelines for care of patients with elevated troponin levels in the absence of
acute coronary syndrome (ACS) and it is not certain if this is a modifiable disease process.
Ticagrelor is a direct, reversible inhibitor of the platelet P2Y12ADP-receptor. It has been
shown to be superior to clopidogrel in the setting of ACS. The clinical benefit of treating
patients with port-operative troponin elevation with antiplatelet agents remains unexplored.
The short half-life of ticagrelor makes it favorable to use in this setting.

This is an open label, randomized, parallel group study comparing ticagrelor to aspirin in
patients who experience troponin elevations post major non-cardiac surgery. Patients will be
randomized in an open-label fashion to receive either ticagrelor 90 mg twice daily or
aspirin 81 mg once daily. Patients will be followed for 13 months post randomization (12
months of treatment and a phone call 30 days after study drug discontinuation). The maximum
duration of treatment will be 12 months.

Follow-up visits will occur at Month 1, Month 6, and Month 12. Phone calls will be made at
Month 3, Month 9, and at 30 days after study drug discontinuation.

Up to 1000 patients with post-operative troponin elevation ≥2x ULN within first 7
postoperative days, will be enrolled in the study.

Inclusion Criteria:

1. Written informed consent before any study related procedures are performed.

2. A qualifying post-operative T or I troponin elevation (≥2x ULN of assay within 7 days
of index surgery and during the index hospitalization).

3. Men and women ≥40 years of age if troponin elevation was identified as part of
routine post-operative clinical care OR

4. Men and women ≥55 years of age if troponin elevation was identified post-operatively
as part of screening for the study.

5. Undergone non-cardiac surgery requiring an overnight hospital stay.

6. Women of childbearing potential who are sexually active must have a negative
pregnancy test at enrollment and agree to use adequate contraception from screening
until 30 days after receiving the last dose of study drug.

7. Able to be randomized within 35 days following the index surgery.

Exclusion Criteria:

1. Post-operative ST-elevation Myocardial Infarction (STEMI).

2. Post-operative high-risk non-STEMI, defined as patients with elevated troponin with
either:

1. active Ischemic EKG changes (≥2 mm of ST-segment depression in at least 2
adjacent leads)

2. ongoing hemodynamic instability thought to be ischemia mediated or

3. persistent anginal symptoms.

3. Planned or urgent coronary angiography/revascularization.

4. A current or ongoing indication for dual antiplatelet therapy (DAPT) as determined by
the patient's physician.

5. History of intracranial hemorrhage

6. Bleeding disorder or active bleeding that prevents ticagrelor or aspirin
administration.

7. Taking any of the following medications at the time of randomization: vitamin K
antagonists, dabigatran, rivaroxaban, apixaban, edoxaban , fondaparinux, cilostazol,
vorapaxar or LMWHs.

8. Renal dialysis.

9. Hepatic impairment with transaminase ≥3x ULN at time of randomization.

10. Known contra-indication for use of ticagrelor.

11. Estimated life expectancy of <1 year.

12. Enrolled in another ongoing drug or device research protocol

13. A definite non-ischemic explanation for troponin elevation, such as myocarditis or
pulmonary embolism.

14. A documented hypersensitivity to aspirin.

15. Hypersensitivity to ticagrelor or any component of the product.

16. Neurological or ophthalmic surgery during the index hospitalization.

17. Patients taking strong CYP3A inhibitors and/or CYP3A inducers that cannot be stopped
for the course of the study.