ticagrelor in acute myocardial infarction
TRANSCRIPT
BACKGROUND• POTENTIAL BENEFITS OF DUAL ANTIPLATELET THERAPY
BEYOND 1 YEAR AFTER AN MI HAS NOT BEEN STUDIED• PATIENTS WITH MI ARE AT INCREASED RISK OF RECURRENT
ISCHAEMIC EVENTS• INTENSIVE SECONDARY PREVENTION IS THEORETICALLY
BENEFICIAL
• FINDING AN IDEAL DRUG WITH BEST RISK-BENEFIT RATIO IS A CHALLENGE
Ticagrelor (AZD 6140): oral reversible P2Y12 antagonist
Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)
• Direct acting – Not a pro-drug; does not require metabolic activation
– Rapid onset of inhibitory effect on the P2Y12 receptor
– Greater inhibition of platelet aggregation than clopidogrel
• Reversibly bound– Degree of inhibition reflects plasma concentration– Faster offset of effect than clopidogrel – Functional recovery of circulating platelets within ~48 hours
OH
OH
O
OH
N
S
NH
NN
NN
F
F
PLATO background Clopidogrel has been studied extensively and used to treat millions of
ACS patients successfully, but its efficacy is hampered by slow and variable transformation to the active metabolite
modest and variable platelet inhibition
risk of stent thrombosis and MI in poor responders
irreversible effect – and increased risk of bleeding if urgent CABG is required
In patients with an urgent need for CABG, clopidogrel is recommended to be withdrawn 5 days prior to surgery
Clinical reality often require surgery earlier and a rapid offset of the antiplatelet therapy is preferred
CV death post-CABG
0 1 2 3 4 5 6 7 8 9 10 11 12
8
7
6
5
4
3
2
1
0
Months from CABG procedure
HR: 0.52 (95% CI = 0.32–0.85), p=0.009
No. at risk
Clopidogrel
Ticagrelor
629
629
565
583
539
557
472 404
415
269
291
130
119491
7.9
4.1
Clopidogrel
Ticagrelor
K-M
est
imat
ed r
ate
(%)
All cause mortality post-CABG
0 1 2 3 4 5 6 7 8 9 10 11 12
10
9
8
7
6
5
4
3
2
1
0
629 583 557 491 415 291 119629 565 539 472 404 269 130
MonthsNo. at riskTicagrelorClopidogrel
Clopidogrel
Ticagrelor4.7
9.7
HR: 0.49 (95% CI 0.32–0.77), p<0.01
K-M
est
imat
ed r
ate
(%)
Primary endpoint: CV death, MI or stroke
0 1 2 3 4 5 6 7 8 9 10 11 12
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
Months from CABG procedure
HR: 0.84 (95% CI = 0.60–1.16), p=0.29
No. at risk
Clopidogrel
Ticagrelor
629
629
541
543
516
519
448 386
386
255
268
125
108458
13.1
10.6
Clopidogrel
Ticagrelor
K-M
est
imat
ed r
ate
(%)
CABG-related bleeding
Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. New Eng J Med. 2007;357:2001–15; NS = not significant
NS
NS
NS
NS
NS
0
K-M
est
ima
ted
rat
e (%
per
ye
ar)
Major CABG-related bleeding
10
20
30
40
50
60
70
80
100
90
CABG-related TIMI major bleeding
CABG-related TIMI minor bleeding
CABG-related GUSTO severe
bleeding
CABG-related fatal bleeding
81.2 80.1
59.3 57.6
21.0 21.6
10.6 12.2
0.8 1.0
TicagrelorClopidogrel
Conclusions
In ACS patients undergoing CABG within 7 days after stopping treatment with ticagrelor – a reversible, more
intense P2Y12 receptor antagonist – is associated with
substantially fewer deaths – both total and CV
no change in the overall risk of CABG-related bleeding
In ACS patients undergoing CABG surgery, ticagrelor is a
more effective alternative to clopidogrel for the continuous
prevention of cardiovascular and total death without
an increase in major bleeding
• 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
HYPOTHESIS
• Age >65yrDMsecond prior spontaneous MImultivessel CADChronic renal dysfunction
ATHEROTHROMBOTIC RISK FACTORS
• PrimaryCardiovascular death / MI /
Stroke
SecondaryCV death ; all cause mortality
ENDPOINTS : EFFICACY
• Adding ticagrelor to low-dose aspirin in stable patients with a history of MI reduced the risk of CV death, MI or stroke
•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
SUMMARY
conclusion
Long-term dual antiplatelet therapy with low-dose aspirin and ticagrelor should be considered in appropriate patients with a myocardial infarction.
60mg dose may offer a more attractive benefit-risk profile