PRE/POST DAPT in NSTEMI evidence beyond

any DUBIUS

Giuseppe Tarantini

University of Padua

Clinical History

Male 71 years old

Risk factors:

Hypertension

Carotid Vasculophaty

COPD

Diabetic (IR)

Admitted because of NSTE ACS in our Hospital

EKG

2D-ECHO: EDV 70 ml/m2, EF 57%, anterior hypokinesia

TIMI Risk Score = 5

Death, MI or uTVR: 26% @ 14 days

Grace Risk Score = 134

In-Hospital Death: 4.6 ---- 6-Months Death 12%

Crusade bleeding Score = 40

In-hospital Major Bleeding: 9.2%

Expected cath 12-24 hrs

Up vs Downstream

DAPT?

Risk-based

approach

Trial-based

approach

Risk-based

approach

1.ACS Trial’s MACE rate has fallen over the past 10 years

2.Risk calculator of old data/old drugs may

Overestimate the contemporary ischemic risk

Underestimate the contemporary bleeding risk

3.Risk score is rarely used in trials as enrollment criteria

4.Highest absolute risk do not always predicts greatest

efficacy

5.NACE risk score are absent

6.RC applied to general population pts not enrolled in

trials, do not ensure that pts selected for Tx are those

who benefit

Risk-based

approach

Trial-based

approach

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

A When coronary anatomy is

not known.

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”

Up vs Downstream

DAPT?

RANDOMIZE !

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

Downstream strategy Upstream strategy:

Ticagrelor

if PCI

UA/NSTEMI <72 hours - initial invasive indication

ASA + open label anticoagulants

Randomization

Prasugrel* Ticagrelor

I EP powered for

superiority

II EP powered for

non inferiority

DUBIUS trial n≈ 2528

1st

Primary EP: 30-d NACE (CV death, MI, stroke, BARC 3, 4, 5)

*60 mg oral bolus then 5 mg/die if >75 yrs or < 60 kg

Randomization 2nd II EP powered for

EQUIVALENCE

EQUIVALENCE CALCULATIONS

ASSUMPTIONS: Two-sided equivalence test for rejecting the hypothesis H0: |π2 - π1 |≤ 0.04 (i.e.:

Plasugrel and Ticagrerol will not differ for more than 4% in terms of NACE)

α = 0.05, confidence bounds 0.95

Overall sample size of 1100 patients (550 Prasugrel + 550 Ticagrerol) An incidence rate of rates π1 = 0.05 in Ticagrerol and π2 = 0.085 in Prasugrel (odds ratio

of 1.765) and a true difference in incidence rates of 0.01 between treatment groups

An allocation rate of 1:1

Based on the above assumptions, the power (1 - β) is 0.805.

WHY NACE?

POOLED ANALYSIS - 26452 PCI PATIENTS

Rao SV et al. Am J Cardiol 2005;96:1200-6

Bleedings

increase

mortality ~16x

NACE Rationale in DUBIUS TRIAL:

Bleeding increases directly and indirectly mortality

FDA RECOMMENDATION

Ischemic (efficacy) and Bleeding (safety) endpoints should be

comparable (hard vs hard)

NACE rate should not derived post-hoc (e.g. TRITON

TIMI 38 and PLATO) but prespecified and powered

19

TIMI

GUSTO

CURE

GRACE

STEEPLE

PLATO

Why BARC bleedings

HETEROGENEITY IN PREVIOUS BLEEDING DEFINITIONS

TIMI

CRITERIA

GUSTO

CRITERIA

BARC

LOMBARDIA - A.O Desio

- AO Vimercate

- A.O. Papa Giovanni XXIII

- A.O. Treviglio

- Centro Cardiologico Monzino

- A.O. Fatebenefratelli

- Policlinico San Matteo

- Ospedale Bassini

- Ospedale Niguarda

- Policlinico San Marco

- A.O.S. Antonio Abate

- San Luca – Milano

- Humanitas

- San Gerardo

- San Donato

- Osp Maggiore

PIEMONTE - Ospedale degli Infermi

- Ospedale Maria Vittoria

- Ospedale San Giovanni Bosco

LIGURIA - Ospedale Galliera

EMILIA ROMAGNA - Ospedale degli Infermi

- Ospedale Maria Vittoria

- Ospedale San Giovanni Bosco

CAMPANIA - A.O.S.G.Moscati

- A.O. Monaldi

- Azienda Ospedaliera

Universitaria Federico II

TOSCANA - A.O. Senese

- Azienda USL 9

- Azienda USL 4

- Ospedale del Cuore

- Azienda USL 6

- Azienda Ospedaliero-

Universitaria Pisana

ABRUZZO - Ospedale Spirito Santo di

Pescara

CALABRIA - A.O. di Cosenza

PUGLIA - Anthea Hospital

- Ospedale Civile Lorenzo

Bonomo

- Ospedale Casa Sollievo Della

Sofferenza

LAZIO - Ospedale Sandro Pertini

- Policlinico Casilino

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 Privata Dott.

Pederzoli

SICILIA - A.O. Universitaria Gaetano

Martino

- Ospedale 'Civile Maria Paternò

Arezzo

- P.S. S.Elia

SARDEGNA - Ospedale San Francesco

- Ospedale Sirai

Coordinating Center: PADOVA

47 centri aderenti

Downstream strategy

DUBIUS trial

CURRENT CASE #1

*60 mg oral bolus then 5 mg/die if >75 yrs or < 60 kg

Randomization 1st

PCI

Downstream strategy

Prasugrel*

DUBIUS trial

CURRENT CASE #1

*60 mg oral bolus then 5 mg/die if >75 yrs or < 60 kg

Randomization 1st

Randomization 2nd

After PCI

DISCHARGE DAY 4

TnI peak 0.261 ug/l

2D-ECHO: EDV 72 ml/m2, EF 54%

ASA 100 mg

Prasugrel (10 mg daily)

Norvasc 10 mg, Triatec 5 mg, Torvast 80 mg, Lansoprazolo 30 mg

F-up 4 month – no Events, still on

Prasugrel

2015 2016

DUBIUS – UPDATED TIMELINE

SEPT 2015 AIFA APPROVAL

APRIL 2016 INSURANCE

AVAILABLE FOR ALL CENTERS

MID 2017 STUDY END

30 PTS

ENROLLED IN

PADOVA

NOV 2015 STUDY STARTS IN

PADOVA ONLY

MAY-JULY 2016 STUDY STARTS

IN ALL CENTERS

2017