Ticagrelor vs Prasugrel · Primary EP (CV death, MI and stroke at 15 months) Montalescot G, et al....

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Leonardo De Luca, M.D., Ph.D., F.A.C.C.

Department of Cardiovascular SciencesInterventional Cardiology UnitEuropean HospitalRome, [email protected]

9°MEETING CARDIOLUCCA

CONTROVERSIA D’AUTORE:QUALE TERAPIA ANTIAGGREGANTE NELLO STEMI?

Lucca, Auditorium S. Francesco28-30 Novembre 2013

Ticagrelor vsPrasugrel

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Necessity is the mother of

invention

Plato

The Essence of Plato’s Philosophy

• Effective (in terms of recurrent ischemic events prevention) in the broad spectrum of STEMI pts

• Useful in Primary PCI (life-saving therapy in STEMI)

• Functional and safe in clinical practice

What do we Need from a New OAT in STEMI?

This analysis addresses the subgroup of patients with STE-ACS, defined as typical symptoms plus either persistent ST-elevation of 1 mV for 20 minutes in 2 contiguous leads and planned primary PCI (defined as PCI within the first 24 hours after symptom onset) or new or presumed-new left bundle-branch block (LBBB) and planned primary PCI. A sensitivity analysis also included patients with a discharge diagnosis of STEMI.

Who are STEMI Patients Enrolled in PLATO?

Steg PG et al, Circulation 2010;122:2131

p=0.98

p=0.93

p=0.10

p=0.67

%

PLATO STEMI Subgroup:Procedures

During index hospitalizationSteg PG, et al. Circulation. 2010;122:2131

Ticagrelor in PLATOSTEMI Subgroup

Steg PG, et al. Circulation. 2010;122:2131

N=7544P=0.07

0

Primary Efficacy Endpoint

2

4

8

12

6

10

0

ClopidogrelTicagrelor

6 8 10 12

Cum

ulat

ive

inci

denc

e (%

)

42

N=7544P=0.76

0

Plato Major Bleeding

2

4

8

10

6

0

Clopidogrel

Ticagrelor

6 8 10 12

Cum

ulat

ive

inci

denc

e (%

)

42

interaction P=0.29

1. Was the hypothesis specified a priori?2. Does the interaction test suggest a low likelihood that

chance explains the apparent subgroup effect?3. Is the size of the subgroup effect large?4. Is the interaction consistent across studies?5. Is there indirect evidence that supports the hypothesised

interaction (biological rationale)?

5 Criteria to Assess Credibility of Subgroup Analys esIs a Subgroup Effect Believable?

Sun X, et al. BMJ 2010;340:c117

pPCI

RISK

Death Rate Reduction in PLATO..Beyond Primary PCI

p=0.07 p=0.04

Steg PG, et al. Circulation 2010;122:2131Wallentin L, et al. N Engl J Med 2009;361:1045

� …of course, we cannot completely rule out the possibility it is a play of chance

� But consistent in ALL explored subgroups…

� …greater relative and absolute benefit than non-fatal endpoints…in a 18,000 pts study!

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PLATO STE-ACS: Sensitivity analyses in patients diagnosed with STE-ACS/STEMI

CharacteristicInteraction

p valueHR (95% CI)

Ticagrelor better Clopidogrel better

0.5 1.0 2.00.2

Ticagrelor Clopidogrel

LBBB at presentation

Persistent STE at presentation

0.91

Diagnosis of STEMI at discharge only

14.5 14.5

8.9 10.4

8.4 12.5

Definition of STE-ACS/STEMI

0.89 (0.59–1.34)

0.87 (0.74–1.02)

0.67 (0.44–1.02)

720

6824

886

n

Primary efficacy endpoint at month 12 (%)


As it was expected that some patients may not receive an initial diagnosis of STEMI, but may be diagnosed with STEMI upon discharge, sensitivity analyses were planned and performed to explore the consistency of the results using different definitions of the STE-ACS/STEMI population – in particular, analysing the group of patients with a diagnosis of STEMI at discharge only[Steg 2010:D,E]

• In addition to the 7544 patients with an initial diagnosis of STE-ACS (i.e. patients presenting with STE or LBBB), an additional 886 patients who received a diagnosis of STEMI upon discharge[Steg 2010:H]

• In the sensitivity analyses, the effect on the primary efficacy endpoint was similar for patients with STE at presentation, those with LBBB at presentation, and patients who had a diagnosis of STEMI at discharge only[Steg 2010:S]

Steg PG, et al. Circulation 2010;122:2131–2141.

9

1010

Switching in the STEMI Populations of PLATO and TRITON Trials

PLATO TRITON

Steg PG et al, Circulation 2010;122:2131 Montalescot G, et al. Lancet 2009;373:723

%

600 mg ClopidogrelUp to 24 hrs

%

Clopidogrel LDUp to 24 hrs

This presentation is provided as background training for speakers

PLATO was not designed or powered to demonstrate the efficacy or safety of BRILINTA compared with clopidogrel in specific subgroups. Subgroup analyses were performed to evaluate consistency of results in different cohorts. Analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Some subgroups were based on post-randomized determinations

•Any information contained in this presentation that is not contained in a promotional slide deck must not be shared proactively during speaker programs

Information from this presentation that is consistent with the Prescribing Information for BRILINTA may be shared in a specific response to an unsolicited question from the audience

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12

STEMI With Planned PCI in the PLATOEfficacy – Clopidogrel Loading Dose

Steg et al. Circulation. 2010;122:2131

Multitude subsists

simultaneously with

the one.

Plato


ACS

STEMI

Sample Size Calculation and p Values

p for Interaction

SUBGROUP

PLATO

ACS

STEMI


NSTE-ACS

STEMI30% of total

TRITON TIMI-38


p Valuefor Superiority

COHORT

TRITON TIMI-38, STEMI CohortPrimary EP (CV death, MI and stroke at 15 months)

Montalescot G, et al. Lancet 2009;373:723Time (Days)

5

10

15

00 50 100 150 200 250 300 350 400 450

Pro

port

ion

of p

atie

nts

(%)

9.5

6.5

12.4

10.0p=0.02

ClopidogrelPrasugrel

N=3534

This analysis addresses the subgroup of patients with STE-ACS, defined as typical symptoms plus either persistent ST-elevation of 1 mV for 20 minutes in 2 contiguous leads and planned primary PCI (defined as PCI within the first 24 hours after symptom onset) or new or presumed-new left bundle-branch block (LBBB) and planned primary PCI. A sensitivity analysis also included patients with a discharge diagnosis of STEMI.

Not All STEMI Patients Are Alike


We divided participants into two strata:(1)those enrolled within 12 h of onset of symptoms (primary PCI); and (2) those enrolled between 12 h and 14 days after symptom onset (secondary PCI).

Patients undergoing secondary PCI included those who had recurrent ischaemia after initial management or those whose treating doctor chose to pursue an invasivestrategy as part of routine management, even without recurrent ischaemia

Montalescot G, et al. Lancet 2009;373:723

PLATO

TRITON TIMI-38

Ioannidis JP, et al. Am Heart J 2007;154:1065

Death

Is PCI for Late Reperfusion after STEMI Useful?

Primary PCI n=2,438

“Secondary” PCI n=1,044

Clopidogrel Prasugrel Clopidogrel Prasugrel

30 Days

1o – CV death/MI/stroke 8.2% 6.6% 12.3% 6.4%

2o – CV death/MI/UTVR 7.4% 6.8% 12.1% 6.6%

Non-CABG TIMI major bleed 1.5% 1.2% 1.0% 0.5%

15 Months

1o – CV death/MI/stroke 11.6% 10.2% 14.1% 9.6%

2o – CV death/MI/UTVR 11.2% 9.9% 13.9% 9.0%

Non-CABG TIMI major bleed 1.9% 3.1% 2.5% 0.9%

Outcomes in TRITON STEMI Cohort

P = NS

P = NS

P =NS

P = NS

P = NS

P = NS

P = 0.0008

P = 0.0016

P = NS

P = 0.0154

P = 0.009

P = NS

20

Spontaneous (type 1) MIProcedural-Related (types 4-5) MI

Effect of Prasugrel on Spontaneous and Procedural MI in the TRITON TIMI-38

Morrow DA, et al. Circulation. 2009;119:2758

By design of the trial, the majority of periprocedu ral events occurred with revascularization procedur es for the qualifying event performed at the time of randomiza tion. In contrast, the

majority of spontaneous (type 1) MIs occurred after 30 days.

Which K-M curves resemble STEMI curves?

Spontaneous (type 1) MIProcedural-Related (types 4-5) MI

Effect of Prasugrel on Spontaneous and Procedural MI in the TRITON TIMI-38

Morrow DA, et al. Circulation. 2009;119:2758

By design of the trial, the majority of periprocedu ral events occurred with revascularization procedur es for the qualifying event performed at the time of randomiza tion. In contrast, the

majority of spontaneous (type 1) MIs occurred after 30 days.

Which K-M curves resemble STEMI curves?

Long-Term CV Mortality After Procedure-Related or Spontaneous MI in ACS

A Collaborative Analysis of Individual Patient Data From the FRISC, ICTUS, and RITA-3 Trials

Damman P, et al. Circulation. 2012;125:568

%

Periprocedural MI at 30 Daysin the STEMI Cohort of the TRITON TIMI-38

25

TRITON-TIMI 38 Enrollment Schema

adapted from Wiviott SD et al. Am Heart J 2006;152:62 7TRS=Timi Risk Score

UA/NSTEMI < 72 h after symptom onset AND TRS>3

STEMI 12h-14 d afterSymptom onset (post-STEMI)

STEMI < 12 h after symptom onset (Primary PCI)

Diagnostic Catheterization

Randomize (stratified by presenting syndrome)

Loading dose of study drug

PCI* No PCI

Daily maintenance study drug and long-term follow-u p

Do not randomize

PCI planned

Medical Rx or CABGplanned

•Adjunctive medical Rx •and device selection

•at physician discretion

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26

TRITON-TIMI 38 Enrollment Schema

adapted from Wiviott SD et al. Am Heart J 2006;152:62 7TRS=Timi Risk Score

UA/NSTEMI < 72 h after symptom onset AND TRS>3

STEMI 12h-14 d afterSymptom onset (post-STEMI)

STEMI < 12 h after symptom onset (Primary PCI)

Diagnostic Catheterization

Randomize (stratified by presenting syndrome)

Loading dose of study drug

PCI* No PCI

Daily maintenance study drug and long-term follow-u p

Do not randomize

PCI planned

Medical Rx or CABGplanned

•Adjunctive medical Rx •and device selection

•at physician discretion

26


2.6% Difference

NNT: 38


5

10

15

00 50 100 150 200 250 300 350 400 450

Pro

port

ion

of p

atie

nts

(%)

9.5

6.5

12.4

10.0

p=0.02RRR=21%


3% Difference

NNT: 33

p=0.002RRR=32%


2.6% Difference

NNT: 38


5

10

15

00 50 100 150 200 250 300 350 400 450

Pro

port

ion

of p

atie

nts

(%)

9.5

6.5

12.4

10.0

p=0.02RRR=21%


3% Difference

NNT: 33

p=0.002RRR=32%


3% Difference

NNT: 332.6% Difference

NNT: 38


5

10

15

00 50 100 150 200 250 300 350 400 450

Pro

port

ion

of p

atie

nts

(%)

9.5

6.5

12.4

10.0

p=0.02RRR=21%

p=0.002RRR=32%



3% Difference


NNT: 38


5

10

15

00 50 100 150 200 250 300 350 400 450

Pro

port

ion

of p

atie

nts

(%)

9.5

6.5

12.4

10.0

p=0.02RRR=21%

p=0.002RRR=32%



3% Difference


NNT: 38


5

10

15

00 50 100 150 200 250 300 350 400 450

Pro

port

ion

of p

atie

nts

(%)

9.5

6.5

12.4

10.0

p=0.02RRR=21%

p=0.002RRR=32%



3% Difference


NNT: 38


5

10

15

00 50 100 150 200 250 300 350 400 450

Pro

port

ion

of p

atie

nts

(%)

9.5

6.5

12.4

10.0

p=0.02RRR=21%

p=0.002RRR=32%


Is Triton Supporting the Need for Prolonged Prasugrel in STEMI ???

TRITON TIMI-38, STEMI CohortDo We Need a Fair Comparison with Clopidogrel?

TRITON TIMI-38, STEMI CohortDo We Need a Fair Comparison with Clopidogrel?

There is a solution to

every problem:

your solution, my solution

and the right solution

Plato


The STEMIWorld

The STEMIWorld

Thrombolysis/Rescue PCI/Pharmacoinvasive

Primary PCI

Secondary PCIConservative RxCABG

The STEMIWorld

Primary PCI

Secondary PCIConservative Rx

Ticagrelorin PLATO


CABG

The STEMIWorld

Primary PCI

Secondary PCIConservative Rx

Prasugrelin TRITON


CABG

TicagrelorPrasugrel

Clopidogrel

OAT in STEMI

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Ticagrelor vs Prasugrel · Primary EP (CV death, MI and stroke at 15 months) Montalescot G, et al....

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