Ticagrelor in acute myocardial infarction

Dr VIJAYARAJU M.D,Dr VASIF MAYAN

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In patients with an urgent need for CABG, clopidogrel is recommended to be withdrawn 5 days prior to surgery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

background

• 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

TRIAL DESIGN

• Age >65yrDMsecond prior spontaneous MImultivessel CADChronic renal dysfunction

ATHEROTHROMBOTIC RISK FACTORS

• PrimaryCardiovascular death / MI /

Stroke

SecondaryCV death ; all cause mortality

ENDPOINTS : EFFICACY

• PrimaryTIMI major bleeding

OtherICH , Fatal Bleeding

Adverse effects

ENDPOINTS : SAFETY

BASELINE CHARACTERISTICS

PRIMARY ENDPOINT-CV DEATH/MI/STROKE

OTHER OUTCOMES

SAFETY ENDPOINTS

ADVERSE EFFECT ENDPOINTS

• 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