Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLAT elet Inhibition and patient O utcomes trial Outcomes in patients

Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLATelet Inhibition and patient Outcomes trial

Outcomes in patients with a Planned Invasive Strategy

The PLATO trial was funded by AstraZeneca

Dr. Cannon discloses research grants/support from the following companies: Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, GlaxoSmithKline, Intekrin Therapeutics, Merck, Merck/Schering Plough Partnership, Novartis and Takeda; and equity in Automedics Medical Systems

Invasive

InvasivePLATO background

• In STEMI and UA/NSTEMI, current guidelines recommend 12 months of aspirin and clopidogrel

• Efficacy of clopidogrel is hampered by – slow and variable transformation to the active

metabolite (e.g. 2C19) – modest and variable platelet inhibition – risk stent thrombosis and MI in poor responders– Irreversible effect – and increased risk of bleeding if

urgent CABG is required

PLATO = PLATelet inhibition and patient Outcomes; NSTEMI = non-ST segment elevation; STEMI = ST segment elevation; ACS = acute coronary syndromes; MI = myocardial infarction

Invasive

Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist

Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)

• Direct acting – Not a prodrug; 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

InvasivePLATO study design

6–12 months treatment

PCI = percutaneous coronary intervention; CV = cardiovascular; PI = principal investigator

NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624)Clopidogrel-treated or -naive; randomized <24 hours of index event

At randomization, 13,408 (72%) of patients were specified by the Investigator: intent for invasive strategy

Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding

Clopidogrel (n=6,676)If pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,

then 75 mg qd maintenance;(additional 300 mg allowed pre-PCI)

Ticagrelor (n=6,732)180 mg loading dose, then

90 mg bid maintenance;(additional 90 mg pre-PCI)

InvasiveBaseline and index event characteristics

CharacteristicTicagrelor(n=6,732)

Clopidogrel(n=6,676)

Median age, years 61.0 61.0 Age ≥75 years, % 12.5 13.9Women, % 25.2 25.3Diabetes mellitus 22.8 23.7

History, % Myocardial infarction Percutaneous coronary intervention Coronary-artery bypass graft

17.114.15.3

17.013.35.7

ECG and Troponin at entry, % Persistent ST-segment elevation ST-segment depression T-wave inversion

48.452.8 28.7

49.354.029.4

Troponin-I positive (central lab, first) % 82.3 84.0

Median time from chest pain to rand., h 8.8 9.0

InvasiveProcedures and timing*

ProcedureTicagrelor(n=6,732)


Invasive procedures at index hospitalization, % (n) Coronary angiography Median (IQR), hours PCI during index hospitalization % (n) Median (IQR), hours

UA/NSTEMI – PCI % (n) Median (IQR), hours

STEMI - Primary PCI % (n) Median (IQR), hours Coronary by-pass surgery pre-discharge % (n) Median (IQR), hours

96.8 (6514)0.62 (0.10, 3.70)

76.7 (5166)0.77 (0.30, 2.75)

63.8 (1882)2.63 (0.78, 21.10)

83.2 (3138)0.47 (0.23, 0.95)

5.5 (372)117 (47, 216)

96.9 (6471)0.62 (0.12, 3.65)

77.1 (5148)0.78 (0.32, 2.65)

64.8 (1854)2.60 (0.87, 21.30)

82.7 (3149)0.48 (0.23, 0.95)

6.1 (410)121 (48, 218)

* Time between randomization and first procedure

InvasiveCo-medication

MedicationTicagrelor(n=6,732)


Anti-thrombotic treatment in hospital, %

Aspirin

Unfractionated heparin

Low molecular weight heparin

Fondaparinux

Bivalirudin

GP IIb/IIIa inhibitor

97.7

35.1

41.1

1.6

1.2

19.7

97.9

36.0

40.9

1.8

1.3

20.3

Other medication in hospital or at discharge, %

Beta-blockade

ACE /ARB

Cholesterol lowering (statin)

Proton pump inhibitor

85.5

87.0

95.4

54.4

86.1

86.8

95.5

53.7

Invasive

TreatmentTicagrelor(n=6,732)


Clopidogrel % Prior to hospitalization 7.3 6.7

Open-label Clopidogrel pre-Randomization, % None or missing information 75 mg 300 mg 600 mg

55.38.3

19.317.1

54.78.119.816.6

Study drug Clopidogrel (or placebo for Tic) in first 24 h None 75 mg 300 mg 600 mg

Total Clopidogrel (OL+IP) pre-Randomization to 24 h 300 mg 600 mg

Premature discontinuation of study drug, %

1.544.246.48.0

69.130.9

23.1

1.444.246.58.0

69.930.1

21.8

Clopidogrel / Ticagrelor treatment

InvasivePrimary endpoint: CV death, MI or stroke

0

0

5

10

15

60 120 180 240 300 360

Days after randomization

K-M

est

ima

ted

rat

e (%

per

ye

ar)

HR: 0.84 (95% CI = 0.75–0.94), p=0.0025

9.02

10.65Clopidogrel

Ticagrelor

No. at risk

Clopidogrel

Ticagrelor

6,676

6,732

6,129

6,236

6,034

6,134

5,881 4,815

4,889

3,680

3,735

2,965

3,0485,972

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Invasive

Hierarchical testing of major efficacy endpoints

Endpoint*Ticagrelor(n=6,732)


HR for ticagrelor(95% CI) p value†

Primary objective, %

CV death + MI + stroke 9.0 10.7 0.84 (0.75–0.94) 0.0025

Secondary objectives, %

Total death + MI + stroke

CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events

MI

CV death

Stroke

9.4

13.2

5.3

3.4

1.2

11.2

15.3

6.6

4.3

1.1

0.84 (0.75–0.94)

0.85 (0.77–0.93)

0.80 (0.69–0.92)

0.82 (0.68–0.98)

1.08 (0.78–1.50)

0.001

0.0005

0.002

0.025

0.646

Total (all-cause) death 3.9 5.1 0.81 (0.68–0.95) 0.010

*The percentages are K-M estimates of the rate of the endpoint at 12 months. Patients could have had more than one type of endpoint. †By univariate Cox model

Invasive

No. at risk

Clopidogrel

Ticagrelor

6,676

6,732

6,157

6,268

6,062

6,173

5,917


4,849

4,924

3,706

3,766

2,987

3,078

0 60 120 180 240 300 360

8

6

4

2

0

Cu

mu

lati

ve i

nci

de

nce

(%

)

Clopidogrel

Ticagrelor

5.3

6.6

6,010

0 60 120 180 240 300 360

8

4

2

0

Clopidogrel

Ticagrelor3.4

4.3

6

6,676

6,732

6,376

6,439

6,332

6,375

6,209


5,114

5,141

3,917

3,591

3,164

3,2336,241

Myocardial infarction Cardiovascular death

Cu

mu

lati

ve i

nci

de

nce

(%

)

HR 0.80 (95% CI = 0.69–0.92), p=0.002 HR 0.82 (95% CI = 0.68–0.98), p=0.025

InvasiveAll-cause mortality

6

4

2

0

0 60 120 180 240 300 360

Clopidogrel

Ticagrelor


K-M

est

ima

ted

rat

e (%

per

ye

ar)

5.08

3.94

HR 0.81 (95% CI = 0.68–0.95), p=0.01

No. at risk

Clopidogrel

Ticagrelor

6,676

6,732

6,376

6,439

6,331

6,375

6,209 5,114

5,141

3,917

3,951

3,164

3,2336,241

InvasiveStent thrombosis

Ticagrelor

(n=6,732)

Clopidogrel

(n=6,676)

HR for

ticagrelor

(95% CI)

p

value*

Stent thrombosis, %

Definite

Probable or definite

Possible, probable, or definite

1.0

1.7

2.2

1.6

2.3

3.1

0.62 (0.45–0.85)

0.72 (0.56–0.93)

0.72 (0.58–0.90)

0.003

0.01

0.003

¶ Evaluated in patients with any stent during the study

Time-at-risk is calculated from the date of first stent insertion in the study or date of randomization* By univariate Cox model

InvasivePrimary efficacy endpoint by clopidogrel loading dose

Ticagrelor better Clopidogrel better

0.5 1.0 2.00.2

Ti. Cl.Total

Patients

KM % atMonth 12

HR (95% CI)

Hazard Ratio

(95% CI)

Clopidogrel loading dose (Pre-rand. + Study drug)

Characteristic

4091 8.0 9.5 0.83 (0.67, 1.03)600 mg9.5 11.2 0.85 (0.74, 0.96)300 mg

p value(Interaction)

0.917

9314

InvasivePrimary safety event: Major bleeding*

No. at risk

Clopidogrel

Ticagrelor

6,585

6,651

5,215

5,235

4,984

4,947

4,786


3,753

3,726

2,754

2,741

2,496

2,503

0 60 120 180 240 300 360

10

5

0

15

Clopidogrel

Ticagrelor

11.6

11.5

4,755

K-M

est

imat

ed r

ate

(% p

er y

ear)

HR 0.99 (95% CI = 0.89–1.10), p=0.88

* PLATO definitions

InvasiveLife-threatening or fatal bleeding*

K-M

est

imat

ed r

ate

(% p

er y

ear)

No. at risk

Clopidogrel

Ticagrelor

6,585

6,651

5,400

5,387

5,180

5,113

5,009

Days from first IP dose

3,934

3,890

2,898

2,866

2,635

2,634

0 60 120 180 240 300 360

6

2

0

8

4,945

HR 1.04 (95% CI = 0.90–1.20), p=0.61

4

Clopidogrel

Ticagrelor

5.96.0

* PLATO definitions

InvasiveTotal major 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. NEJM 2007;357:2001–15; NS = not significant

NS

NS

NS

NS

NS

0

K-M

est

ima

ted

rat

e (%

per

ye

ar)

PLATO major bleeding

1

2

3

4

5

6

7

8

9

10

12

11

13

TIMI major bleeding

Red cell transfusion

PLATO life-threatening/

fatal bleeding

Fatal bleeding

11.5 11.6

8.0 8.0

8.9 8.8

6.0 5.9

0.2 0.3

TicagrelorClopidogrel

Invasive

TicagrelorClopidogrel

NS

NS

NS

0

K-M

est

imat

ed r

ate

(% p

er y

ear)

PLATO major bleeding

1

2

3

4

5

6

7

8

9

10

12

11

13

TIMI major bleeding

11.5 11.6

8.0 8.0

2.93.2

GUSTO severe bleeding*

4.7

4.1

2.8 2.3

1.9

1.7

Non-CABG and CABG-related major bleeding

No

n-C

AB

GC

AB

G

*Preliminary – from eCRF

InvasiveBradycardia-related events and other findings

All patientsTicagrelor(n=6,732)

Clopidogrel(n=6,676) p value*

Bradycardia-related event, %

Any bradycardia event

Symptomatic event

Sick sinus syndrome or sinus pause

AV Block II-III

Temporary pacemaker used

Permanent pacemaker implanted

Considered serious adverse event

5.5

2.1

0.4

0.5

0.8

0.5

1.0

5.1

2.4

0.4

0.4

0.6

0.5

1.1

0.26

0.24

0.89

0.15

0.26

1.00

0.73

All patientsTicagrelor(n=6,732)

Clopidogrel(n=6,676) p value*

Dyspnea, %

Any dyspnea event

Requiring discontinuation of study-

treatment

15.4

0.9

10.4

0.3

<0.0001

< 0.0001

*p values calculated using Fisher’s Exact test

InvasiveTherapeutic considerations

• Based on 1,000 patients admitted to hospital for ACS and planned for invasive strategy, using ticagrelor instead of clopidogrel for 12 months resulted in

– 11 fewer deaths

– 13 fewer myocardial infarctions

– 6 fewer cases with stent thrombosis

– No increase in major bleeding or need for transfusion

– 6 patients may switch to thienopyridine treatment because of reversible symptoms of dyspnoea

• Treating 59 patients with ticagrelor instead of with clopidogrel for one year will prevent one event of CV death, MI or stroke

• Treating 88 will save one life (in one year)

InvasiveConclusions

Ticagrelor, the reversible, more intense P2Y12 antagonist,

is a more effective alternative to clopidogrel for one year

in ACS patients managed with an invasive strategy,

for the continuous prevention of ischemic events,

stent thrombosis and death

without an increase in major bleeding

Documents

Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLAT elet Inhibition and patient O utcomes trial Outcomes in patients