DSMB Interim Analyses

The primary objective of this study ist to test the hypothesis that ticagrelor is superior to Aspirin (ASA) fort he prevention of major cardio- and cerebrovascular events (MACCE) in patients undergoing artery bypass operation.

The primary efficiacy MACCE-endpoint is the composite of cardiovascular death, myocardial infarction, recurent revascularisation, and stroke at twelve month after coronary artery bypass operation.

For stable patients who underwent coronary bypass operation, Aspirin alone currently represents the gold standard of antiplatelet treatment.

The CABG substudy of the PLATO-trial (http://www.nejm.org/doi/full/10.1056/NEJMoa0904327) comprising more than 1200 patients has convincingly shown a high significant reduction of cardiovascular and all-cause mortality for patients recieving Aspirin and Ticagrelor as compared to those subjects randomized to Aspirin plus Clopidogrel. Moreover the results of the PLATO CABG substudy showed that benefits of Ticagrelor increase with decreasing Aspirin doses. Therefore Ticagrelor monotherapy (2x 90mg/day) appears to offer the best balance of safety with anticipated improved efficacy over Aspirin (1x 100mg/day) alone, but until now there are no further data available to support this hypothesis.

Hence this study (TiCAB) is assigned as a pivotal efficacy and safety study of Ticagrelor in patients undergoing coronary artery bypass operation and to test the hypothesis that ticagrelor is superior to Aspirin for the prevention of major cardio- and cerebrovascular events (MACCE) in this patient population.

The TiCAB trial is designed as a randomized, double-blind, double-dummy, parallel group, phase III, multicenter study, comparing the efficacy and safety of Ticagrelor 90mg administered twice daily with Aspirin 100mg once daily, for the prevention of MACCE within the first year after CABG operation.

Inclusion Criteria:

1. Patients 18 years of age or older

2. Informed, written consent by the patient

3. Indication for CABG surgery:

   • coronary three vessel disease, or
   • left main stenosis, or
   • two vessel disease with impaired left ventricular function (<50%)

Exclusion Criteria:

1. Cardiogenic shock, haemodynamic instability

2. Indication for oral anticoagulation or dual antiplatelet therapy that can not be stopped after CABG

3. Need for concomitant non-coronary surgery (e.g. valve replacement)

4. Intolerance of or Allergy to Ticagrelor or ASA or any of their ingredients

5. History of bleeding diathesis within three months prior presentation

6. History of significant gastrointestinal bleeding within six months prior presentation

7. History of intracranial hemorrhage

8. History of moderate to severe liver impairment (Child Pugh B or C)

9. Chronic renal insufficiency requiring dialysis

10. Patient with an increased risk of bradycardic events (e.g. patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree AV block or bradycardic-related syncope)

11. Known, clinically important thrombocytopenia (i.e. <100.000/µl)

12. Known, clinically important anaemia (i.e. <10mg/dl)

13. Participation in another investigational drug or device study in the last 30 days

14. Pregnancy or lactation (for premenopausal women 2 methods of reliable contraception, one of which must be barrier method, are required); in women with childbearing potential a pregnancy test is mandatory

15. Concomitant oral or intravenous therapy (see examples below) with strong CYP3A inhibitors, CYP3A substrates with narrow therapeutic indices, or strong CYP3A inducers which cannot be stopped for the course of the study

    • Strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, over 1 litre daily of grapefruit juice.
    • Substrates with narrow therapeutic index: cyclosporine, quinidine.
    • Strong inducers: rifampin/rifampicin, phenytoin, carbamazepine.

16. Life expectancy less than 12 months that may result in protocol non-compliance or a risk for being lost to follow-up, active cancer

17. Indication for major surgery (e.g. cancer treatment, carotid surgery, cerebral surgery, major vascular surgery)

18. Previous enrollment or randomization of treatment in the present study.