This study evaluated the addition of ticagrelor at doses of 90 mg or 60 mg twice daily to low-dose aspirin in reducing cardiovascular events in patients with a history of myocardial infarction 1 to 3 years prior. Over a median follow-up of 33 months, both ticagrelor doses significantly reduced the primary composite outcome of cardiovascular death, myocardial infarction, or stroke compared to placebo. However, both ticagrelor doses increased the risk of TIMI major bleeding compared to placebo. The 60 mg dose resulted in lower rates of bleeding and dyspnea with similar efficacy compared to the 90 mg dose.

2. Introduction
Myocardial Infarction
• Necrosis of a region of the myocardium
secondary to prolonged ischemia.
• Patients who have had a myocardial infarction are at
heightened risk for recurrent ischemic events.

3. Introduction (cont.)
•Aspirin reduces the risk of ischemic events.
•Practice guidelines in the United states and Europe
currently recommend treatment with a P2Y12 receptor
antagonist for up to 1 year after a myocardial infarction.

4. Introduction (cont.)
Ticagrelor
• Potent, reversibly-binding, direct-acting P2Y12
receptor antagonist.

5. Introduction (cont.)
Ticagrelor
• When added to aspirin for 1 year after an ACS,
at a dose of 90 mg twice daily reduced the rate of major
adverse cardiovascular events, as compared with
clopidogrel at a dose of 75 mg once daily.

6. PEGASUS-TIMI 54
Prevention of Cardiovascular Events in Patients with
Prior Heart Attack Using Ticagrelor Compared to
Placebo on a background of Aspirin-Thrombolysis in
Myocardial Infarction.

7. PEGASUS-TIMI 54
Hypothesis
• The addition of ticagrelor to low-dose aspirin would
reduce the incidence of major adverse cardiovascular
events during long-term follow-up in patients with a
history of MI.

8. PEGASUS-TIMI 54
Evaluated two doses of ticagrelor therapy
90 mg twice daily.
60 mg twice daily.

9. Study design
9
study type
Multi –center ,multi-
country
Randomized
Double
blind
Placebo
controlled

10. Study design
10
Eligibility
Age > or = 50
years old
Both genders
No healthy
volunteers

11. Study design
Inclusion criteria
•Patients with a spontaneous myocardial
Infarction 1 to 3 years before enrollment .
•50 years of age at least , had one of the following
additional high risk features .
11

12. Study design
Inclusion criteria (cont.)
12
High risk features
1-Age of 65 years or older
2-Diabetes Mellitus requiring medication
3-A second prior spontaneous myocardial infarction

13. Study design
Inclusion criteria (cont.)
13
High risk features
4-Multi vessel coronary artery disease
5-Chronic renal dysfunction, estimated creatinine
clearance < 60 ml/min

14. Study design
Exclusion criteria
14
1-Use of aP2Y12 receptor antagonist
2- Dipyridamole , Cilostazole or anticoagulant therapy during
the study period
3-A bleeding disorder or a history of an ischemic stroke or
intracranial bleeding

15. Study design
Exclusion criteria (cont.)
15
4-A central nervous system tumor or an intracranial
vascular abnormality
5-Gastrointestinal bleeding within the previous 6 months
6-Major surgery within the previous 30 days

16. End points
Efficacy
•Primary: cardiovascular (CV) death, MI, or stroke
•Secondary: CV death; all-cause mortality
•Prespecified exploratory: substituting coronary for CV death; other
individual coronary and cerebrovascular ischemic outcomes;
pooling ticagrelor doses
16

17. End points (con.)
Safety
•Primary: TIMI major bleeding
•Other: intracranial hemorrhage (ICH), fatal bleeding
•Aes/saes
17

18. Randomization and study treatment
•Randomization performed with central computerized
telephone or web-based system
•Assignment was double-blinded ,double-dummy (ticagrelor
or clopidogrel)

19. RANDOMIZATION AND STUDY TREATMENT
(con.)
•Patients planning to undergo elective major non CV
procedures were advised to stop the study TTT 5 days
before the procedure and resume it when it was deemed
appropriate by the treating physician
19

20. Eligible patients were randomly assigned
Group 1 Group 2 Group 3
All the patients were to receive low-dose aspirin followed for a median of 33
months
Ticagrelor 90
mg twice
daily
Ticagrelor
60 mg twice
daily
Placebo twice
daily

22. • We estimated a total 1360 primary endpoint events in
order to provide the study with approximately
o 90% POWER to detect a 20% REDUCTION in
risk with the 90-MG DOSE of ticagrelor
o 83% POWER to detect a 19% REDUCTION in
risk with the 60-MG DOSE of ticagrelor

23. •The primary efficacy analysis
•Conducted on an intention-to-treat basis, with each dose
compared with placebo

24. •Safety analyses
oThese analyses included all the events occurring after
receipt of the first dose and within 7 days after receipt of the
last dose of study drug.

25. •Alpha was apportioned to the comparison of each
ticagrelor dose with placebo (with the use of a correlation
of 0.5 between the test statistics)
•A significance level is 0.026

26. •Event probabilities are expressed as kaplan–meier
estimates of cumulative incidence at 36 months.
•Hazard ratios and 95% confidence intervals were
generated with the use of a cox proportional-hazards
model.

27. Results
•Study patients
•Study drug
•Follow up
27

28. Results
•Study patients
•Total of 21,162 patients
• The median time from the qualifying myocardial
infarction to randomization was 1.7 years
•53.6% of the qualifying events were ST-segment
elevation myocardial infarctions.
28

29. Results
•Study patients
•A total of 83.0% of the patients had a history of
percutaneous coronary intervention, and 59.4% had
multivessel coronary artery disease.
•All the patients (99.9%) received aspirin, 75 mg and
100 mg in (97.3%) of patients.
29

30. Results
30

31. Results
31

32. Results
•Study drugs
•The proportions of patients in each group who
discontinued treatment prematurely over the duration
of the trial were:
•32.0% in the group that received 90 mg of ticagrelor
twice daily
•28.7% in the group that received 60 mg of ticagrelor
twice daily
32

33. Results
•Study drugs
•The proportions of patients in each group who
discontinued treatment prematurely over the duration
of the trial were:
•21.4% in the placebo group
33

34. Results
•Study drugs
•The majority of premature discontinuations in the two
ticagrelor groups were due to adverse events
34

35. Results
•Study follow up
•The median duration of follow-up was 33 months
(interquartile range, 28 to 37)
•Resulting in 56,004 patient-years of follow-up
•Ascertainment of the primary end point was complete for
99.2% of the potential patient-years of follow-up
35

36. Results
•Efficacy
•The two ticagrelor doses each significantly reduced
the rate of the primary composite end point of
•Cardiovascular death
•Myocardial infarction
•Stroke
36

37. Results
•Efficacy
37

38. 38
Results
•Efficacy

39. Results
39
Safety
Bleeding
TIMI major bleeding
(primary safety end point)
TIMI minor bleeding
Bleeding requiring transfusion
Bleeding leading to study-drug
discontinuation
Significantly higher
with two ticagrelor
doses than with
placebo

40. Results
40
Safety
Bleeding
Fatal bleeding or nonfatal
intracranial hemorrhage
Did not differ significantly
between either ticagrelor
dose group and placebo

41. Results
41
Safety

42. Results
42
Safety
Other adverse event
Dyspnea
Renal event
Bradyarrhythmia
Gout
Significantly more frequent with
ticagrelor than with placebo
There were no notable differences
between either ticagrelor dose group
and placebo
Significantly more frequent with
ticagrelor than with placebo

43. Results
43
Safety

44. Discussion
• Efficacy
The results of the PEGASUS-TIMI 54 trial
provide prospectively defined evidence affirming
the hypothesis that long-term, intensive platelet
inhibition with ticagrelor reduces ischemic
events in patients with prior myocardial infarction.
44

45. Discussion
•Safety
The study protocol excluded patients with recent bleeding,
prior stroke, or the need for oral anticoagulant therapy.
So, the safety profile of long-term ticagrelor that was
observed should not be generalized to other populations at
heightened risk for bleeding.
45

46. Discussion
The rates of drug discontinuation because of dyspnea observed
with ticagrelor in this trial were higher than those observed in the
Study of Platelet Inhibition and Patient Outcomes (PLATO).
46
PEGASUS – TIMI 54 trialPLATO trial
Patients were stable , so
dyspnea was more surprising and
more likely to lead to drug
discontinuation .
Patients included were with acute
coronary syndromes , so dyspnea
is common with their acute illness.

47. Discussion
The two ticagrelor doses were associated with a similar magnitude
of efficacy.
However, the rates of bleeding and dyspnea were numerically
lower with the 60-mg dose of ticagrelor than with the 90-mg dose,
resulting in a lower rate of discontinuation of the study drug and a
better safety profile with the 60-mg dose.
47

48. Conclusion
The addition of ticagrelor, at a dose of 90 mg twice daily or 60
mg twice daily, to low-dose aspirin reduced the risk of
cardiovascular death, myocardial infarction, or stroke
and increased the risk of TIMI major bleeding among patients
who had had a myocardial infarction one to three years earlier.
48

49. Recommendation
The two ticagrelor doses were studied on a
background of low-dose aspirin, as is
recommended for patients with stable
ischemic heart disease .
49

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