This study evaluated the efficacy and safety of adding ticagrelor to low-dose aspirin in stable patients with a history of myocardial infarction. Over 18,000 patients were randomly assigned to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo twice daily in addition to standard medical therapy including aspirin. The primary outcome was a composite of cardiovascular death, myocardial infarction, and stroke. The results showed that ticagrelor at either dose reduced the risk of the primary outcome compared to placebo by 16-19% with no significant difference between the two ticagrelor doses. Ticagrelor increased the risk of TIMI major bleeding but not fatal bleeding or intracere

1. Journal club : dual antiplatelets therapy
Post AMI
Mahajna Muhammad
Sackler faculty of medicine
Tel-Aviv-Uni
2015
This article was published on March 14,
2015, at NEJM.org.
DOI: 10.1056/NEJMoa1500857

2. This article was published on March 14,
2015, at NEJM.org.
DOI: 10.1056/NEJMoa1500857

3. Introduction and background

5. N=18,000

6. An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
TIMI Study Group
Eugene Braunwald (Chair)
Marc P. Bonaca (Co-PI)
S Morin & P Fish (Operations)
Executive Cmte
Eugene Braunwald (Chair)
Deepak L. Bhatt
Ph. Gabriel Steg
Sponsor: AstraZeneca
Peter Held
Per Johanson
Barbro Boberg
Independent Data Monitoring Cmte
Jeffrey L. Anderson (Chair)
Freek W.A.Verheugt
David L. DeMets
Marc S. Sabatine (PI)
Stephen D. Wiviott (CEC Chair)
SA Murphy & Kelly Im (Statistics)
Marc S. Sabatine
Marc Cohen
Robert Storey
Eva Jensen
Ann Maxe Ahlbom
Olof Bengtsson
Terje R. Pedersen
Harvey D. White

7. Hypothesis
The addition of ticagrelor to standard therapy
(including 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. Global enrollment

9. Methods
Study design and oversight
Study population
Randomization and study treatment
End points
Statistical analysis

10. Trial design
Overall 33 months follow up
Bonaca MP et al. Am Heart J 2014;167:437-44

11. Ascertainment for primary endpoint was complete
for 99% of potential patient-years of follow up
Randomized 21,162 patients
Ticagrelor
90 mg bid
(N=7050)
Ticagrelor
60 mg bid
(N= 7045)
Placebo
(N= 7067)
Follow-up median 33 months (IQR 28-37)
Minimum 16 months, maximum 47 months
Premature perm.
drug discontinuation
12%/yr 11%/ yr 8%/ yr
Withdrew consent 0.7
%
total 0.7% total 0.7% total
Lost to follow-up 3 patients 6 patients 1 patient
Follow up

12. ~65
~24%
~82

13. ~54%
~40%
~6%

14. Key Inclusion & Exclusion Criteria
Bonaca MP et al. Am Heart J 2014;167:437-44

15. Endpoints
Efficacy : hierarchical testing
Primary : cardiovascular death , myocardial infarction ,
stroke
Secondary : all cause mortality + non-coronary ischemic
events , individual ischemic eventsSafety :
Primary : TIMI major bleeding
Other : intracranial hemorrhage , fatal bleeding [ death >7d]

16. TIMI major bleeding scale
http://spo.escardio.org/eslides/view.aspx?eevtid= 33=di&5017

17. Results
Efficacy vs safety

18.  Ticagrelor at any dose >placebo
 60 mg as good as 90 mg
 ~ 15 %-19% relative risk reduction

20. 10.1056/NEJMoa1500857

21. 10.1056/NEJMoa1500857
Duration
Relativeriskreduction
RR -
REDUCTIO
N

22.  Pooled Ticagrelor dose > placebo at coronary,cardiovascular,infarction,stroke
prevention
 90 mg > 60 mg at MI prevention
 60 mg > 90 mg for stoke prevention

24. Bleeding

26. Discussion : limitation , comparison

28.  All trials agree on the benefits of dual anti- platelet therapy after
MI
 DAPT trial :
1) Randomly assigned pts to continuing vs stopping a P2Y12 receptor
antagonist after 12 moths
2) Included pts who had not had clinically significant bleeding.
3) Included pts who were able to keep taking a P2Y12 receptor
antagonist .
4) All above minimize their bleeding complication
 In PEGASUS-TIMI 54 all Pts began treatment with Brilinta
after they complete the guidelines duration of therapy .They
enrolled close to 2 years after MI

29.  Considering side effects [ mainly dyspnea] : PLATO trial > PEGASUS-TIM
1. Less stable Pts in PLATO study [ dyspnea is common during 1 year after
2. PEGASUS-TIMI 54 had more stable Pts [ 3 years after MI]
3. PEGASUS-TIMI 54 reflects the real dyspnea ratio as a complication
 PEGASUS-TIMI 54 : safety profile should not be generalized for
all population
1) High risk of bleeding , previous stroke , anticoagulants usage
were among the exclusion criteria

30. summary

31. • Adding ticagrelor to low-dose aspirin in stable patients with a history of MI reduced
the risk of CV death, MI or stroke
• The benefit of Ticagrelor was consistent at all major groups and sub groups
• Ticagrelor increased the risk of TIMI major bleeding, but not fatal bleeding or ICH
• The two doses of Ticagrelor had similar overall efficacy, but bleeding and other side
effects tended to be less frequent with 60 mg bid dose

32. Thanks 