Trattamento antiaggregante orale precoce nel paziente

NSTEMI: il trial DUBIUS

Giuseppe Musumeci

USC Cardiologia

Ospedale Santa Croce e Carle Cuneo

Como 1 Aprile 2017

➢ Ticagrelor > clopidogrel up (< 10 days) or dowstream (as switch)

➢ D/MI/stroke -2.1% vs -2.5% ARR (-18% RRR)

➢ Major bleeding + 0.4% vs +0.8% ARR (+4% vs +7% RRR)

➢ Non-CABG major bleeding + 0.7% vs +1% (+19% vs +28% RRR)

➢ Prasugrel > clopidogrel only dowstream

➢ D/MI/stroke -2.2% vs -0.1% ARR (-19% vs -2% RRR)

➢ Non-CABG major bleed + 0.6% vs +0.8% (+32% vs +195% RRR)

NSTE-ACS

Coro

MedicalRx

PCI

CABG

MedicalRx

Ho

spital

NSTE-ACS: Strategies and Timing

Pre treatment with DAPT

EYESHOT

Registry

* In addition to other standard therapies.

* Patients did not receive open-label thienopyridine before PCI.

Mehta SR et al for the CURE Investigators. Lancet. 2002

Days of follow-up

Composite of MI, urgent revascularization or cardiovascular death at 30 Days

0 5 10 15 20 25 30

0.0

0.02

0.04

0.06

0.08

Cu

mu

lati

ve

Ha

zard

Ra

te

44%Relative Risk

Reduction

p=0.017

(0.35-0.90)

Clopidogrel

pretreated

Placebo

pretreated

Pre-Treatment with Clopidogrel Prior to PCI and Stenting in ACS Patients

CREDO – clopidogrel loading dose timing

and MACE at 28d in per protocol patients (n=1762)

-2

-3

-4

-5

-6305 10 15 20 250

Hours prior to PCI of study drug loading dose

Log odds of death, MI or urgent TVR at 28

daysPlacebo

Clopidogrel

P=0.020for treatment / timing

interaction

Bellemain-Appaix A, et al. JAMA. 201terial2;308

Supplemental material,

Clopidogrel and Pre-Treatment in PCI: A Meta-Analysis

Prasugrel 30 mg

Prasugrel 60 mg Prasugrel 30 mg

Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days

PCI

1° Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa bailout, at 7 days

Placebo

Coronary

Angiography

n~4100 (event driven)

Coronary

Angiography

PCI

CABG

or

Medical

Management

(no prasugrel)

CABG

or

Medical

Management

(no more prasugrel)

Montalescot G et al. Am Heart J 2011;161:650

Randomize 1:1Double-blind

NSTEMI + Troponin ≥ 1.5 times ULN local lab valueClopidogrel naive or on long term clopidogrel 75 mg

ACCOAST

Design Schema

Days From First Dose

0 5 10 15 20 25 30

En

dp

oin

t (%

)

0

5

10

15

1996

2037

1788

1821

1775

1809

1769

1802

1762

1797

1752

1791

CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout

1621

1616

No. at Risk, Primary

Efficacy End Point:

No pre-treatment

Pre-treatment

Pre-treatment10.810.0

Pre-treatment

Hazard Ratio, 0.997 (95% 0.83, 1.20)P=0.98P=0.81

(95% 0.84, 1.25) Hazard Ratio, 1.02

No Pre-treatment10.8

9.8No Pre-treatment

1° Efficacy End Point @ 7 + 30 days

(All Patients)

Montalescot G, et al. N Engl J Med 2013;369:999

All TIMI (CABG or non-CABG) Major

Bleeding (All Treated patients)

Days From First Dose

0 5 10 15 20 25 30

En

dp

oin

t (%

)

0

1

2

3

4

5

All TIMI Major Bleeding

Pre-treatment2.9

Pre-treatment2.6

No Pre-treatment1.5

No Pre-treatment1.4

19962037

19471972

13281339

12971310

12881299

12841297

12631280

No. at Risk, All TIMI Major Bleeding:No pre-treatmentPre-treatment

Hazard Ratio, 1.97 (95% 1.26, 3.08)P=0.002

Hazard Ratio, 1.90(95% 1.19, 3.02) P=0.006

Montalescot G, et al. N Engl J Med 2013;369:999

Evidence (NSTEMI) upstream vs

downstream?

Clopigogrel: Upstream flawed superiority UP vs DOWN

Prasugrel: Downstream > Upstream

Ticagrelor: Downstream > Upstream unsettled

“STEMI no overall advantage”

GPI:

I IIa IIb III

AWhen coronary anatomy is

not known.

Antiplatelet in NSTEACS

I IIa IIb III

B

I IIa IIb III

BTicagrelor (180 mg LD, 90 mg bid) is recommended, in the absence of contraindications, for all pts at moderate-to-high risk of ischaemicevents, regardless of initial treatment strategy and including those pretreated with clopidogrel

I IIa IIb III

B

Prasugrel (60 mg LD, 10 mg daily dose) is recommended in patients who are proceeding to PCI if no contraindication

Clopidogrel (300–600 mg LD, 75 mg daily dose) is recommended for pts who cannot receive ticagrelor or prasugrel or who require oral anticoagulation

It is not recommended to administer prasugrel in pts in whom coronary anatomy is not known

ESC guidelines, 2015

I IIa IIb III

B

“…As the optimal timing of ticagrelor or clopidogrel administration in

NSTE-ACS patients scheduled for an invasive strategy has not been

adequately investigated, no recommendation for or against

pretreatment with these agents can be formulated”

Unknown issues

➢ UPSTREAM Tica > DOWNSTREAM Tica?

➢ DOWNSTREAM Tica > DOWNSTREAM Prasugrel?

➢ UPSTREAM Tica > DOWNSTREAM Prasugrel?

RANDOMIZED CONTROLLED TRIAL

Downstream versus Upstream strategy for the

administration of P2Y12 receptor Blockers In

non ST elevated acUte coronary Syndromes

with initial invasive indication.

PI G. Tarantini

Co-PI G. Musumeci

DUBIUS TRIAL

Downstream versus Upstream strategy for the administration of P2Y12 receptor Blockers In non ST elevated acUte coronary Syndromes with initial invasive indication

HYPOTHESES:1. Superiority of downstream vs upstream strategy2. Non inferiority of Prasugrel vs Ticagrelor

CO-PRIMARY (powered) HYPOTHESES

1. Superiority of the downstream administration strategy for P2Y12 receptor blockers over the upstream administration strategy (ticagrelor only) in terms of NACE at 30 days

2. Non inferiority of Prasugrel vs Ticagrelor in the PCI group of the downstream strategy arm in terms of NACE at 30 days.

PRIMARY ENDPOINT: NACE

Net Adverse Cardiac Events (NACE):

Death from vascular causes (cardiovascular or cerebrovascular, without another known cause)

non fatal MI

non fatal stroke

BARC major bleedings (type 3, 4 and 5)

SECONDARY ENDPOINTS

• Death from vascular causes

• MI

• Stroke

• TIA

• Severe recurrent ischemia

• Recurrent ischemia or other arterial thrombotic event

• Death from any cause.

• Stent thrombosis (possible, probable, or definite).

• Target vessel revascularization (TVR).

• Target lesion revascularization (TLR).

• NACE occurred between admission and revascularization

• BARC type 2, 3, 4 and 5 bleeding

• All TIMI major, major-life-threatening, and minor bleeding

• STEEPLE major and minor bleedings

• Compliance to mandated antiplatelet therapy

INCLUSION CRITERIA

1. Age ≥ 18

2. Non ST elevated acute coronary syndrome (unstable angina, non ST elevated myocardial infarction), with an onset of symptoms during the previous 72 hours.

3. An initial invasive strategy is chosen (the patient is expected to undergo coronary angiography within 72 h from admission).

4. Subject is able to start therapy with a new P2Y12 inhibitor (prasugrel or ticagrelor) OR is on a maintenance dose of clopidogrel or ticlopidine and is able to switch to a new P2Y12 inhibitor (prasugrel or ticagrelor).

3. Patient agrees to comply with follow-up evaluations.

MAIN EXCLUSION CRITERIA (1)1. Known hypersensitivity/contraindication to aspirin, clopidogrel, prasugrel, ticagrelor,

heparin or bivalirudin, or sensitivity to contrast media, which can't be adequately pre-medicated.

2. Platelet count <100,000 cells/mm³ or >700,000 cells/mm³, or a white blood cell (WBC) count <3,000 cells/mm³ within 7 days prior to index procedure.

3. Fibrinolytic therapy within 24 hours before randomization.

4. Concomitant therapy with a strong cytochrome P-4503A inhibitor or inducer.

5. Serum creatinine level >170 micromol/L within 7 days prior to index procedure.

6. Subject is receiving chronic anticoagulation therapy.

7. Subject is already receiving ticagrelor or prasugrel.

8. Shock.

MAIN EXCLUSION CRITERIA (2)

9. History of stroke or TIA

10. Active peptic ulcer or upper gastrointestinal bleeding within prior 6 months.

11. History of bleeding diathesis or coagulopathy or will refuse blood transfusions.

12. Planned elective surgery within 12 months after the procedure requiring discontinuation of any antiplatelet drugs.

13. Pregnant or nursing subjects

14. Other medical illness (e.g., cancer or congestive heart failure) or known history of substance abuse (alcohol, cocaine, heroin etc.)

15. Subject is belonging to a vulnerable population

16. Currently participating in investigational drug or device trial

FOLLOW UP

30 ± 7 days: office visit✓ Adverse events with related laboratory tests results, ECGs, details of any subsequent repeat

coronary angiography and results of such, if applicable.✓ Compliance to protocol required anti-platelet medications✓ Use and changes in chronic anti-platelet medications

12 months ± 30 days: office visit✓ Adverse events with related laboratory tests results, ECGs, details of any subsequent repeat

coronary angiography and results of such, if applicable.✓ Compliance to protocol required anti-platelet medications.✓ Use and changes in chronic anti-platelet medications.

STUDY CONDUCTION

SCTB@DCTV (Service of Clinical Trials and Biometrics)Dept. of Cardiac, Thoracic and Vascular Sciences, University of Padova

Randomization and e-CRF service (Red-Cap and Open-Clinica based)Study design and sample size calculationAssistance for regulatory aspects and ethical committee submission processStatistical plan (SAP), analysis and reporting (R and SAS)Risk-based monitoring

Public, University-level no-profit serviceResearch- and innovation-oriented approachLinked with advanced teaching (clinical epidemiologists, clinical researchers, research nurses, advanced biostatisticians)Master I level (Biostatistics for medical writing)Master II level (Advanced topis in biostatistics for clinical trials)

Information

rate

sign.level

one-sided

a

spent

stage

n1

sizes

n2

0.333 0.0003 0.0005 382.0 382.0

0.667 0.0071 0.0143 382.0 382.0

1.0 0.0225 0.0500 382.0 382.0

(FDA recommended) Adaptive trial design

• Primary end-point NACE event rate at 30 days (up- vs. down-stream)

After first 382 patients (per group), analysis of NACE

Stopping allowed for futility or proven benefit

• If no stop, study continues after sample size reassessment

Stopping allowed for futility or proven benefit

• If no stop, study continues to the end after sample size reassessment

LOMBARDIA

- A.O. di Desio e Vimercate

- A.O. Papa Giovanni XXIII

- A.O. Treviglio

- Centro Cardiologico Monzino

- A.O. Fatebenefratelli

- Policlinico San Matteo -

Fondazione IRCCS

- Ospedale Bassini

- Ospedale Niguarda Ca'

Granda

- Policlinico San Marco

ZIngonia

- A.O.S. Antonio Abate

- Humanitas

- Ospedale di Vimercate

- Istituto Scientifico Ospedale

San Luca

- Ospedale San Gerardo

- Ospedale Maggiore

- San Donato

PIEMONTE

- Ospedale degli Infermi

- Ospedale Maria Vittoria

- S.Giovanni Bosco

- Ospedale Maggiore

della Carità

- AO Ordine Mauriziano

di Torino

- P.O. Domodossola e

Verbania

LIGURIA

- Ospedale Galliera

- Ospedale San Paolo - ASL 2

Savonese

EMILIA ROMAGNA

- Policlinico S. Orsola –

Malpighi

- Ospedale G.B. Morgagni -

L. Pierantoni

- Ospedale Infermi – Rimini

- AOU Ferrara

- AO-IRCCS Santa Maria

Nuova

CAMPANIA

- A.O.S.G.Moscati

- A.O. Monaldi

- AO Universitaria Federico II

- Ospedale Cardarelli

TOSCANA

- A.O. Senese

- Azienda USL 9

- Azienda USL 4

- Ospedale del Cuore

- Azienda USL 6

- Azienda Ospedaliero-

Universitaria PisanaABRUZZO

- Ospedale Spirito Santo

CALABRIA

- A.O. di Cosenza

- AO Mater Domini di

Catanzaro

- S. Anna Hospital

PUGLIA

- Ospedale Civile Lorenzo

Bonomo

- Ospedale Casa Sollievo

Della Sofferenza

- San Paolo

LAZIO

- Ospedale Sandro Pertini

- Policlinico Casilino

- Ospedale S. Andrea

- Ospedale S. Spirito

VENETO

- Azienda ULSS 9 Treviso

- Azienda ULSS 13 Mirano

- Ospedale San Giacomo

- Ospedale Civile Santa Maria

della Misericordia

- Azienda ULSS 17 Schiavonia

- Casa di Cura Dott.

Pederzoli

SICILIA

- A.O. Universitaria Gaetano

Martino

- Ospedale 'Civile Maria

Paternò Arezzo

- P.S. S.Elia

- A.R.N.A.S. Ospedali Civico

- San Giovanni – ASP 1

SARDEGNA

- Ospedale San Francesco

- Ospedale Sirai

MARCHE

- Ospedale Civile di Macerata

TRENTINO

-Ospedale S.Maria del Carmine

ABRUZZO

-ASL 1 Avezzano – Sulmona –

L’Aquila – P.O. S. Filippo e Nicola

FRIULI

-Ospedali Riuniti Di Trieste

Coordinating Center:

PADOVA

711

5

3

4

2

41

16

526

3

16 Centri aderenti: 67

(+25 da GISE 2015)

Arruolati 312 pazienti

Where we find evidence that

upstream > downstream?

Clopigogrel: Upstream flawed superiority UP vs DOWN

Prasugrel: Upstream Harm vs downstream

Ticagrelor: unsettled - “STEMI no overall advantage”

GPI:

Study logistics

Randomization via dedicatedrandomization interface (PC and

mobile)

Data collection via on-line Red-Cap platform

Pt Rand (1) at first contact

to upstream vs downstream

Pt in downstream Rand (2) when decision is taken on PTCA

Discharge

30 days follow-up

1-year follow-up

Risk-based monitoring via centralizeddata flow-analysis and feedbacks to

centers

Adaptive ad-interim analysis (3 stages)

42

32

30 0 0 0 0 0

ARRUOLAMENTO ATTIVO

CENTRI APPROVATI (n=19)

Messina, G. Andò

Gallarate, S.I. Caico

Milano - Monzino, D. Trabattoni

Ragusa, A. Nicosia

Roma - Casilino, R. Della Bona

Roma - Pertini, S. Rigattieri

Cinisello Balsamo, S. Pierini

Mirano, C. Penzo

Treviglio, P. Sganzerla

Nuoro, G. Casu

ATTIVAZIONE IN CORSO

Different Use of GPIs in Trials

NSTEACS

ASAUFH or LMWH

GPI

PCICABG

Medical Tx

GPI

PCIASAUFH or LMWH

NSTEACS, STEMIHigh-risk, Elective

Cath-Lab

CCU / ER

Redefining GP IIb/IIA issues

NSTEACSGPI

GPI

EARLY ACS TIMACS

Bellemain-Appaix A, et al. JAMA. 2012;308:2507

Clopidogrel and Pre-Treatment in PCI: A Meta-Analysis

ISAR REACT 5

STEMI + NSTEACS

Single randomized:Ticagrelor vs. prasugrel

Stratified but not powered per single ST type

Composite primary endpoint:ischemic events onlyat 12 months

ESC 2015 UA/ NSTEACS guidelines

“UP versus Down -stream” strategy

ESC guidelines, 2015

“NO recommendation for or against pretreatment

with TICA or Clopidogrel can be formulated”

When upstream is selected

“optimal timing of TICA or CLOP administration in

NSTE-ACS patients scheduled for an invasive

strategy has not been adequately investigated”

Where we find evidence that

upstream > downstream?

Clopigogrel: Upstream flawed superiority UP vs DOWN

Prasugrel: Upstream Harm vs downstream

Ticagrelor: unsettled - “STEMI no overall advantage”

GPI: Upstream harm vs downstream

I IIa IIb III

A

I IIa IIb III

CGPIIb/IIIa inhibitors during PCI should be considered for bailout situations or thrombotic complications.

It is not recommended to administer GPIIb/IIIa inhibitors in patients in whom coronary anatomy is not known.

ESC guidelines, 2014 and 2015

GP IIb/IIIa in NSTEACS

GP IIb/IIIa in STEMI

I IIa IIb III

B

I IIa IIb III

CGP IIb/IIIa inhibitors should be considered for bail-out or evidence of no-reflow or a thrombotic complication.

Upstream use of a GP IIb/IIIa inhibitor (vs. in-lab use) may be considered in high-risk patients undergoing transfer for primary PCI.

Study timeline

PD Ethical Committee Approval

Study Start

1-year pts enrollment 1-year follow-up

Dec 2015

Study End

Dec 2017

Information

rate

sign.level

one-sided

a

spent

stage

n1

sizes

n2

0.333 0.0003 0.0005 382.0 382.0

0.667 0.0071 0.0143 382.0 382.0

1.0 0.0225 0.0500 382.0 382.0

Adaptive trial design

• Primary end-point NACE event rate at 30 days (up- vs. down-stream)

After first 382 patients (per group), analysis of NACE

Stopping allowed for futility or proven benefit

• If no stop, study continues after sample size reassessment

Stopping allowed for futility or proven benefit

• If no stop, study continues to the end after sample size reassessment

NSTE-ACS

EYESHOT

Registry

Coro

MedicalRx

PCI

CABG

MedicalRx

Ho

spital

Pre treatment with DAPT

NSTE-ACS: Strategies and Timing

ACCOAST trial

Time to TX - Outcomes

STATISTICAL ASSUMPTIONS

✓ The study is powered for all co-primary endpoints based on the expectedincidence at 30 days of NACE

✓ Primary analysis: by intention-to-treat.

First target: superiority of downstream over upstream strategy.

α = 0.05 Power 0.80 NACE rate of 0.08 in downstream and 0.115 in upstream arm (odds ratio of 1.4) Drop-out rate of about 10%

Total sample size of 2520 patients (1260 upstream + 1260 downstream).

STATISTICAL ASSUMPTIONS (2)

Second target: non inferiority of Prasugrel vs Ticagrelor within the PCI group of the downstream strategy arm.

Assuptions:

At least 80% of the patients will have an indication to PCI

NACE rate of 0.05 for Ticagrelor and 0.085 for Prasugrel (odds ratio 1.7)

Two-sided non-inferiority test to reject the hypothesis H0: π2 –π1 > 0.01

Prasugrel and Ticagrelor will differ for no more than 1% in terms of NACE

α = 0.025

Power 0.805

A sample size of 1000 patients (500 Prasugrel + 500 Ticagrelor) is required in the PCI group of the downstream arm

If non-inferiority will be met, superiority will be tested

Clopidogrel and Pre-Treatment in PCI:

A Meta-Analysis

8608 patients out of 7 RCTs undergoing PCI, including NSTEACS, STEMI, and elective PCI

PCI Cure

Relative Weight, % 43.1 49.7

Bellemain-Appaix A, et al. JAMA. 2012;308:2507

Ab

solu

te r

isk,

%

OR: 0.80

P=0.17

OR: 0.77

P<0.001

NNT: 40

0.4 0.6 0.8 1.0 1.2

Hazard Ratio (95% CI)

RRR: –13.4%

p=0.60

RRR: 38.6%

p=0.05

RRR: 18.5%

P=.23CREDO Overall

Steinhubl SR, et al. JAMA. 2002;288:2411

CREDO Study: Timing of

Loading Dose and 28-Day Endpoint

Timing N Pretreat No Pretreat

3–<6 h 893 7.9 7.0

≥6–24h 851 5.8 9.4

Clopidogrel No

Trial Pretreatment Pretreatment

PCI-CURE 3.6 5.1

CREDO n/a n/a

PCI-CLARITY 4.0 6.1

Overall 3.7 5.5

Meta-Analysis of Clopidogrel Pretreatment

CV Death or MI after PCI (%)

MI before PCI (%)

1.00.25 2.00.5

1.00.25 2.00.5OR (95% CI)

OR (95% CI)

OR: 0.67

p=0.005

Favors

Pretreatment

Favors

No Pretreatment

OR: 0.71

p=0.004

Sabatine MS, et al. JAMA 2005;294:1224

Clopidogrel NoTrial Pretreatment Pretreatment

PCI-CURE 2.9 4.4

CREDO 6.0 7.1

PCI-CLARITY 3.3 5.4

Overall 3.9 5.5

Bellemain-Appaix A, et al. JAMA. 2012;308:2507

Clopidogrel and Pre-Treatment in PCI:

A Meta-Analysis

STABLE

ACS