Results From The Minimizing Adverse Haemorrhagic Events By

Transradial Access Site And Systemic Implementation

of Angiox-MATRIXTreatment Duration Program

M. Valgimigli, MD, PhD

Swiss Cardiovascular Center Bern, Inselspital, Bern, Switzerland

on behalf of the MATRIX Group

NCT01433627

Declaration of Interest

I, Marco Valgimigli,

Served as a speaker, or advisor or consultant for:

The Medicines Company and Terumo

Background

The most effective anti-thrombotic regimen for preventing ischemic complications, while limiting bleeding risk, in patients with acute coronary syndromes undergoing invasive managementremains unresolved

Bivalirudin decreases bleeding events as comparedto UFH±GPI but it also increases the hazard of stentthrombosis

Whether prolonging bivalirudin after PCI mitigates ischemic without increasing bleeding risks is unknown

Objectives

To determine whether the use of bivalirudin during intervention followed by a post-PCI infusion of ≥4 hours, as compared to no post-PCI infusion, reduces net adverse cardiovascular events (NACE), defined as the composite of death, MI, stroke, major bleeding, urgent TVR and ST

To determine the impact of post-PCI bivalirudin on each component of the primary endpoint

In a broadly inclusive ACS population undergoinginvasive management via randomly assigned radial or femoral access

1:11:1

1:11:1

NSTEACS or STEMI with invasive managementAspirin+P2Y12 blocker

NSTEACS or STEMI with invasive managementAspirin+P2Y12 blocker

Trans-Femoral Access

Heparin±GPI

BivalirudinMono-Tx

StopInfusion

Prolong≥ 4 hs infusion

1:11:1

Trans-Radial Access

MATRIX ProgramMATRIX Program NCT01433627

http://www.cardiostudy.it/matrix

Lancet. 2015; 385(9986):2465-76

ACC 2015, oral presentation

ACCESS

ANTITHROMBINTYPE

TREATMENT DURATION

Study Organization and SitesSponsor

Clinical Event Committee

P. Vranckx, Chair

S. Leonardi Co-Chair

P. Tricoci

Italian Society of Interventional Cardiology

Grant suppliers: The Medicines Company and Terumo

Principal Investigator: Marco Valgimigli, MD, PhD

Study Director: Maria Salomone. MD, PhD

78 Sites across 4 EU countries recruited patients

Statistical Committee

(CTU)P.Jüni, MD, Chair

M. Rothenbühler

Dik Heg

National Coordinating Investigators and CROs

Paolo Calabrò, MD, PhD, Italy; Trial Form Support Arnoud W J van‘t Hof, MD, The Netherlands; Trial Form Support Manel Sabate’, MD, PhD, Spain; FLS-Research Support Elmir Omerovic, MD, PhD, Sweden; Gothia Forum

Data Mng

E. Frigoli, Eustrategy

Project Leader

Executive Committee

Steering Committee

Committee Members

Marco Valgimigl, (PI and Chair), Andrea Gagnor; Paolo Calabrò, Paolo Rubartelli, Stefano Garducci, Giuseppe Andò, Andrea Santarelli, Mario Galli; Roberto Garbo; Ezio Bramucci; Salvatore Ierna, Carlo Briguori, Bernardo Cortese; Ugo Limbruno, Roberto Violini; Patrizia Presbitero; Nicoletta de Cesare; Paolo Sganzerla; Arturo Ausiello; Paolo Tosi; Gennaro Sardella; Manel Sabate’; Salvatore Brugaletta, Peter Jüni

Giovanni Saccone; Pietro Vandoni, Antonio Zingarelli; Armando Liso; Stefano Rigattieri, Emilio Di Lorenzo, Carlo Vigna; Cataldo Palmieri; Camillo Falcone, Raffaele De Caterina, Marcello Caputo; Giovanni Esposito; Alessandro Lupi; Pietro Mazzarotto, Fernando Varbella; Tiziana Zaro; Marco Nazzaro; Sunil V. Rao, Arnoud WJ van‘t Hof; Elmir Omerovic.

Patient Eligibility

UA/NSTEMI

New or worsening ischaemia, occurring at rest or with minimal activity within 7 days

AND

At least 2 high-risk criteria:

Age > 60High Tp T I or

CK-MBECG changes

suggesting ischemia

STEMI

Chest pain for >20 min with ST-segment elevation ≥1 mm in two or more contiguous leads, or with a new left LBBB or true posterior myocardial infarction

AND

Admission <12 hs

OR

Between 12 and 24 hs with evidence of continuing

ischemia or lysis

Of note: Cardiogenic shock, severe PVD and prior CABG were eligible

Do not randomise

for anti-thrombin

Primary Endpoints cohort for Acces Site Comparison

Anti-Thrombin Type/Duration Randomization *

PCI No PCI

*: stratified by presenting syndrome and type of P2Y12i

Primary endpoints Cohort for Anti-thrombin Comparison

Access Site Randomization *

PCI Planned

Diagnostic Catheterisation

STEMI

Medical tx or CABG planned

UA/NSTEMI

MATRIX Recruiting timelines: Anti-thrombin program

7,213Cumulative enrollment by month

First Recruited patient: 11th Oct 2011Last Recruited patient: 7th Nov 2014

Complete follow-up information at 30 days available in all but 13 patients per group

3603 allocated to

UFH

MATRIX Patient Flow Chart: Treatment Duration program

7213 pts included in the Anti-thrombin program

3610 pts included in the Treatment Duration Study

1799 Post-PCI Bivalirudin93.3% received allocated

Intervention

1811 No post-PCI Bivalirudin96.8% received allocated

intervention

13 No post-discharge FUP

1790 (99.4%) Complete 30-day information

1807 (99.8%)Complete 30-day information

Post-PCI Bivalirudin Rx

Bivalirudin could be administered at*:

the full PCI dose (1.75mg/kg/h) for up to 4 hours or

the reduced dose of 0.25 mg/Kg/h for at least 6 hours

Regimens and temporal distribution

*: with the choice between those two regimens made at the discretion of the treating physicians

Full PCI regimen

Reduced regimen

34.4%Infusion duration: 264’

59%Infusion duration: 433’

N=119 (6.6%) receiving no post-PCI bivalirudin in the post-PCI bivalirudin arm

Baseline Characteristics Post-PCI No post-PCI

Bivalirudin (N=1,799) Bivalirudin (N=1,811)

Age (years) 65.4±12.1 65.5±11.7

Age ≥ 75 ys (%) 25.7 24.5

Male (%) 75.1 76.2

Previous CVA (%) 5.8 4.3

PAD (%) 9.3 7.1

Cardiac Arrest (%) 2.0 2.4

Killip > 1 (%) 8.8 9.8

STEMI (%) 55.9 55.5

NSTEMI (%) 40.1 39.3

UA (%) 4.0% 5.1%

Pre-LAB P2Y12i (%) 83.1 83.8 Clopidogrel 46.4 47.7

Ticagrelor/prasugrel 36.7 36.1

Enoxaparin (%) 14.3 15.6

Fondaparinux (%) 9.6 9.2

UFH (%) 32.9 31.8

Procedural Characteristics Post-PCI No post-PCI

Bivalirudin (N=1,799) Bivalirudin (N=1,811)

PCI attempted (%) 94.0 94.3

CABG (%) 0.6 0.7

Medical Tx (%) 4.4 3.7

Medications in the Lab (%) Clopidogrel 7.5 5.8

Ticagrelor/prasugrel 18.6 20.9

Gp IIb/IIIa inhibitors* 3.6 5.5§

LMCA treated (%) 4.5 4.9

Multi-vessel PCI (%) 15 14.9

Total stent length (mm) 32±20 32±21

At least 1 implanted DES (%) 66.3 67.9

At least 1 Complex lesion (%) 52 52

Post dilatation (%) 43.1 46.3

Success in all Tx lesion (%) 93.3 92.0

index procedure

§: p<0.05*: restricted to bailout conditions

Primary EP: NACE

11.0%

No post-PCI bivalirudinPost-PCI bivalirudin

RR: 0.91; 95% CI: 0.74-1.11; P=0.34

11.9%

Treatment Duration Study

1 EP ComponentsDeath, MI, Stroke, urg. TVR, ST and BARC 3 or 5

P=0.03

%

0.53 0.30–0.96

P=0.09

1.78 0.90–3.53

P=0.16

1.49 0.85–2.60

P=0.79

0.86 0.29–2.56

P=0.99

P=0.53

0.85 0.51–1.42

Stent ThrombosisDefinite and Definite or Probable

P=0.14

%

1.89 0.80–4.46

P=0.99

1.01 0.43–2.33

P=0.29

1.38 0.76–2.50

P=0.01

4.37 1.24–15.35

P=0.99

P=0.99

1.01 0.42–2.43

BleedingBARC, TIMI and GUSTO definitions

P=0.01

%

0.39 0.18–0.85

P=0.23

0.65 0.32–1.31

P=0.001

0.25 0.10–0.61

P=0.48

1.38 0.56–3.45

P=0.99 P=0.02

1.46 1.05–2.03

Bleeding Location BARC 3 or 5 in Patients on Bivalirudin According to Post-PCI Treatment Duration

No

. o

f B

leed

ing

Exploratory Analysis*Ischemic and Bleeding EPs according to bivalirudin regimen in the post-PCI bivalirudin arm

%

* The choice of post-PCI bivalirudin regimen was at discretion of the investigator

14.7

Favours Post-PCI Bivalirudin Favours NO Post-PCI Bivalirudin

RATE RATIO (95% CI)

P-VALUES

Superiority Interaction

0.77Intermediate (548-991)0.99 (0.72-1.36)0.75 (0.51-1.10) 1.14

0.95Centre’s annual volume of PCI

Low (247-544)

NSTE-ACS (tp–)ACS type

STEMI

<75Age≥75 0.750.95 (0.69-1.31)

0.86 (0.66-1.12) 0.26 0.65

Composite Outcome: Subgroup Analysis

High (1000-1950)

NSTE-ACS (tp+)

MenSex

Women

<25BMI

≥25

NoTicagrelor or prasugrel

Yes

NoDiabetes

Yes

<60GFR

≥60

NoHistory of PVD

Yes

210.50

0.94 (0.65-1.36) 0.75

0.10

0.96 (0.69-1.33)2.10 (0.86-5.11) 0.09

0.79

0.80 (0.60-1.05) 0.11

0.741.06 (0.74-1.53)

0.84 (0.66-1.07) 0.15 0.28

0.610.94 (0.72-1.21)

0.87 (0.62-1.21) 0.40 0.72

0.150.80 (0.59-1.08)

1.00 (0.76-1.32) 0.97 0.27

0.941.01 (0.70-1.46)

0.87 (0.68-1.11) 0.25 0.48

0.240.85 (0.64-1.12)

0.90 (0.65-1.24) 0.51 0.79

0.751.09 (0.63-1.89)

0.86 (0.69-1.07) 0.170.42

RadialAccess site

Femoral 0.070.77 (0.58-1.02)

1.08 (0.80-1.45) 0.620.11

4

Summary

The post-PCI infusion of bivalirudin for at least 4hours after the intervention did not decrease the composite outcome of ischemic and bleeding events, including stent thrombosis.

This finding was consistent across subgroups, including access site.

Post-PCI bivalirudin infusion was safe and associated to lower risk of major bleeding according to BARC 3/5 or GUSTO scales.

Summary

At exploratory analysis, the post-PCI 0.25 mg/kg/h bivalirudin regimen was associated to higher, whereas the 1.75 mg/kg/h full regimen to lower ischemic and bleeding risks compared to no post-PCI bivalirudin.