1. An update with the MATRIX study
Bivalirudin in 2015-
An update with the MATRIX study
Bernardo Cortese
Intv’ Cardiology, A.O. Fatebenefratelli
bernardocortese.com

2. 30 Day and 1-Year All-Cause Mortality
HORIZONS AMI
30 Day and 1-Year All-Cause Mortality '
Cardiac Mortality (%)
2.9%
5.1% 12 15 18 21 24 27 30 33 36
Months 3 6 9 1 5 4 2
3.8%
2.1%
Bivalirudin (n=1,800)
Heparin + GP IIb/IIIa (n=1,802)
1-yr† HR [95%CI]=
0.57 [0.38, 0.84]
P = 0.005
30-d† HR [95% CI]= 0.62; [0.40,0.96]
P = 0.03
2.9%
3-yr† HR [95%CI]=
0.56 [0.40, 0.80]
P = 0.001
NNT=45
Stone
Mehran
Stone
1.8%
*3-year all cause mortality was also lower with bivalirudin (5·9% vs 7·7%), HR 0·75 [0·58–0·97]; p=0·03 †These time points were prespecified analyses. NNT=number needed to treat
Stone GW NEJM. 2008;358: Mehran R Lancet. 2009;374: Stone GW Lancet. 2011;377:

3. Three-Year Stent Thrombosis (ARC Definite/Probable)
Bivalirudin alone (n=1611) 6
Heparin + GPIIb/IIIa (n=1591)
5.1% 5
4.5%
3.5% 4
HR [95%CI]=
Stent Thrombosis (%) 3
3.0%
0.89 [0.65, 1.23]
p=0.49 2
HR [95%CI]=
1.16 [0.79, 1.71] 1
p=0.45 3 6 9 12 15 18 21 24 27 30 33 36
Months
Number at risk
Bivalirudin
1611
1509
1478
1453
1432
1398
971
Heparin+GPIIb/IIIa
1591
1484
1456
1401
1373
1335
906

4. HEAT PPCI: Design and enrollment
1917 STEMI pts scheduled for emergency angiography at a single center between Feb 2012–Nov 2013*
29 (1.5%) already randomized in the trial
59 (3.0%) met one or more other exclusion criteria
Exclusion Criteria
Active bleeding at presentation
Factors precluding oral DAPT
Intolerance or contraindication to trial medications
Previous enrolment in this trial
1829 eligible for recruitment were randomized 1:1
All of these patients were randomized – to create an unselected ‘Real-World’ population
Heparin 70 IU/Kg (n=914)
Bivalirudin (n=915)
17 (1%) refused post procedure consent and were withdrawn
Heparin* (n=907)
Assigned to
Bivalirudin (n=905)
Shahzad A et al. Lancet 2014 4

5. HEAT PPCI: MACE Outcomes
Bivalirudin (n=905)
Heparin (n=907)
Any MACE
79 (8.7%)
52 (5.7%)
- Death
46 (5.1%)
39 (4.3%)
- CVA
15 (1.6%)
11 (1.2%)
- Reinfarction
24 (2.7%)
8 (0.9%)
- TLR
6 (0.7%)
-Acute ST
20 (2.9%)
6 (0.9%)
Some patients experience more than one event. This table lists all the observed MACE events.
Heparin advantage is seen in all elements of the composite
I need to draw you attention to the reinfarction and TLR figures
697 pts
Shahzad A et al. Lancet 2014 5

6. HEAT PPCI: Safety Outcomes
Bivalirudin
(n=905)
Heparin
(n=907) P
BARC 2-5
115 (12.7%)
126 (13.9%)
0.54
- BARC 3-5
32 (3.5%)
28 (3.1%)
0.59
- BARC 2
83 (9.2%)
98 (10.8%)
0.25
Thrombocytopenia (moderate/severe)
6 (0.8%)
0.99
Rates of minor bleeding – and rate of combined major or minor bleeding were also similar
Shahzad A et al. Lancet 2014 6

7. BRIGHT: Study flow
2,194 pts with AMI randomized at 82 centers in China
Aspirin and clopidogrel
86.2 % STEMI
13.8% NSTEMI
79% radial
Randomization (1:1:1)
Bivalirudin alone
N=735
Biv 0.75 mg/kg bolus mg /kg/h (0.3 mg/kg bolus if ACT< 225s).
Biv infusion (0.2 mg/kg/h) continued for at least 30 min post PCI (mean 4h).
4.4% bailout tirofiban.
UFH alone
N=729
Heparin 100 U/kg bolus + additional dose if ACT <200 s. ACT goal =
5.6% bailout tirofiban.
UFH + Tirofiban
N=730
Heparin 60U/kg bolus .
Tirofiban 10μg/kg bolus μg/kg/min infusion for h.
ACT goal =
This is the study flowchart.
Bivalirudin, unfractionated Heparin, and Tirofiban were administrated according to the protocol.
Follow-up at 30 days, 6 months and 1 year
Primary endpoint: NACE, including MACCE (all-cause death, reMI, TVR or stroke) and bleeding events at 30 days.
Han Y. JAMA April ‘15

8. BRIGHT: events at 30 Days NACE MACCE Any Bleeding Primary endpoint (%)
Bivalirudin (n=735)
Heparin (n=729)
Heparin + Tirofiban (n=730)
Primary endpoint
Biv vs. Hep, p=0.009
RR (95%CI) 0.67 ( ), NNT=23.1
Biv vs. Hep+Tiro, p<0.001
RR (95%CI) 0.52 ( ), NNT=12.3
Hep vs. Hep+Tiro, p=0.04
RR (95%CI) 0.78 ( ), NNT=26.2 18
17.0
P<0.001 16
13.2 14
12.3 12
P<0.001
(%) 10
8.8
P=0.74
7.5 8
5.8
Primary events occurred in 8.8% of the patients receiving bivalirudin, which acquired 33% and 48% relative risk reductions compared with those of heparin monotherapy and heparin plus tirofiban, respectively, and the number need treatment were 23.1 and 12.3, respectively. The incidences of MACCE were similar among three treatment arms. Bivalirudin treatment was associated with a significantly reduced risk of overall bleeding events compared with heparin monotherapy and heparin plus tirofiban.
5.0 6
4.9
4.1 4 2
NACE
MACCE
Any Bleeding
Han Y. JAMA April ‘15 8

9. BRIGHT: 30-day ST STEMI Only
Bivalirudin (N=629)
Heparin (N=620)
Heparin+Tirofiban (N=609)
P=0.59
1.2
1.0
1.0
P=0.49
1.0
0.8
0.8
0.8
0.8
P=0.71
0.8
0.6
(%)
0.6
0.5
0.5
P=0.81
0.5
P=1.00
0.4
This slide demonstrates the incidence of different types of stent thrombosis for STEMI patients. Again, the incidences of definite or probable stent thrombosis and acute thrombosis were similar among three arms.
0.3
0.3
0.3
0.3
0.2
0.2
0.2
0.2
Def/prob
Definite
Probable
Acute
Subacute
Han Y. JAMA April ‘15 9

10. “Pre-MATRIX” Bivalirudin Trials
Study N
Comparator
Setting
Ischemic Events
Bleeding
REPLACE-2
6002
UFH + GPI
Elective PCI - 
ISAR REACT 3
4570
UFH (140 u/kg)
ACUITY
13800
UFH/LMWH + GPI
NSTEACS
ISAR REACT 4
1721
BRIGHT
2100
UFH or UFH + GPI
STEMI & NSTEMI
HORIZONS
3602
STEMI
(-) MACE
Death
 Stent thromb
EUROMAX
2218
UFH ± GPI
HEAT PPCI
1829
UFH
 MACE
courtesy of A Kirtane, 2014

11. 45%↓ Bivalirudin vs UFH Monotherapy Meta-analysis Major Bleeding
16 studies (3 rand, 13 reg), 32,492 pts undergoing PCI:
Study
or subgroup
Events
Bivalirudin
Total
Events
Heparin
Total
Odds Ratio M-H, Random, 95% CI
Odds Ratio M-H, Random, 95% CI
Observational
Wolfram 2003
Rha 2005
Chu 2006
Bonello 2009
Lemesle 2009
Lemesle 2009-b
Delhaye 2010
Lindsey 2010
Lopes 2010
Schultz 2010
Bangalore 2011
Subtotal (95% CI) 4 1 2 23 10 26 5 6
101 12 38
335 54
216
566 79
1207
267
503
1771
2289
1511
8798 35 2 14 20
101 26 89 16 78
1543 60
456
333 92
1559
129
861
1365
2505
1551
10414
0.52 [0.18, 1.47]
0.55 [0.05, 6.12]
0.30 [0.07, 1.31]
0.97 [0.49, 1.90]
0.52 [0.21, 3.17]
0.32 [0.21, 0.49]
1.21 [0.23, 6.33]
0.39 [0.16, 0.95]
0.87 [0.65, 1.16]
0.82 [0.39, 1.74]
0.47 [0.32, 0.70]
0.57 [0.42, 0.78]
Total Events
Test for heterogeneity: Tau2=0.11, Chi2=20.84, df=10 (P=0.02),I2=52%
Test for overall effect: Z=3.55 (P=0.0004)
Randomized
Kastrati 2008
Parodi 2010
Patti 2011
Subtotal (95% CI) 12 3 1
2289
363
198
2850 24 8 2
2281
308
203
2792
0.50 [0.25, 0.99]
0.31 [0.08, 1.19]
0.51 [0.05, 5.67]
0.45 [0.25, 0.82]
Total Events
Test for heterogeneity: Tau2=0.00, Chi2=0.37, df=2 (P=0.83),I2=0%
Test for overall effect: Z=2.60 (P=0.009)
45%↓
Total (95% CI)
11648
13206
0.55 [0.43, 0.72]
Total Events
Test for heterogeneity: Tau2=0.08, Chi2=21.99, df=13 (P=0.06),I2=41%
Test for overall effect: Z=4.38 (P<0.0001)
Test for subgroup differences: Chi2=0.47, df=1 (P=0.49),I2=0%
0.01
0.1 1 10
100
Favors Bivalirudin
Favors Heparin
Bertrand OF et al. Am J Cardiol 2012;110:599–606

12. Anticoagulation Regimens During PCI
N = 458,448 PCI pts at 299 hosps
(Premier Perspective Database, ~1/5th of all US hosp discharges; bival in 41%)
In-hospital events, propensity adjusted
Bleeding + Transfusion
Mortality OR
(95% CI) OR
(95% CI)
Comparator OR
(95% CI)
P Value
Comparator OR
(95% CI)
P Value
Bivalirudin
monotherapy
(n=156,064)
Bivalirudin monotherapy
(n=156,064)
0.51 (0.48, 0.55)
<0.0001
0.59 (0.54, 0.65)
<0.0001
Bivalirudin + GPI
(n=33,566)
Bivalirudin + GPI
(n=33,566)
0.96 (0.87, 1.06)
0.37
0.82 (0.72, 0.94)
0.004
Heparin alone
(n=85,870)
Heparin alone
(n=85,870)
0.71 (0.66, 0.76)
<0.0001
0.88 (0.82, 0.96)
0.003
Comparator Better 1
Heparin + GPI Better
(n=182,948) 2
Comparator Better 1
Heparin + GPI Better
(n=182,948) 2
Wise GR et al. J Interv Cardiol 2012;25:278–88

13. acute stent thrombosis with bivalirudin
in STEMI
NO prolonged infusion
prolonged infusion
prolonged infusion
0.2 mg/Kg/min
NO prolonged infusion
B Cortese, 2015

14. Stent Thrombosis to 30 days*
Landmark Analysis:
Stent Thrombosis to 30 days*
Stent thrombosis adjudicated according to Academic Research Consortium (ARC)
CEC blindly adjudicated ST after review of angiograms (CEC chair : K.Thygesen)
AST = 0 deaths at 30 days. Sub-acute ST = 1 death at 30 days (UFH)
Bivalirudin (n=1089)
UFH ± GPI (n=1109)
The median time to AST was 2.3 hours (IQR )
1.11%
Estimated event rate (%)
Log rank p=0.71
Log rank p=0.007
0.48%
0.37%
0.18%
Time from Randomization (days)
*Based on the ITT population. Data on file, The Medicines Company.

15. Treatment Breakdown and Outcomes by Bivalirudin Post-PCI Infusion Dose
Bolus 0.75 mg/kg mg/kg/hour infusion
Pre-PCI
ASA
P2Y12 Load +
BIVALIRUDIN
1.75 mg/kg/hour infusion
PCI
0.25 mg/kg/hr
(n=670)‡
1.75 mg/kg/hr
(n=244)§
Post-PCI†
Heparins
± GPI
BIV-LOW
BIV-HIGH
AST
2 (0.2%)
11 (1.6%)*
1 (0.4%)
Major Bleeding
57 (6.0%)
16 (2.4%)*
7 (2.9%)
*p < 0.05 vs. heparins ± GPI

16. antithrombotics halflife
minutes

17. “Antithrombotic protection”
antithrombotics “protection”
“Antithrombotic protection”
GPI
Prolonged B
-Plt activation
-Distal embolization
-Small vess closure
B stop end of PCI
-Stent thrombosis
PCI
4 hrs
12 hrs
24 hrs
end of PCI
TIME
B Cortese 2008 & 2011

18. PROBI VIRI study design
178 pts with SA or UA, complex PCI
Cath lab Biv bolus and infusion (1.75 mg/Kg/h)
Randomization (post angio)
Stop infusion (n=90)
4-hrs infusion at 0.25 mg/Kg/h (n=88)
Primary endpoint: periprocedural MI
B Cortese et al., AJC 2009

19. PROBI VIRI Results In-hospital Major Bleedings, %
16,7%
p=0.041
6,8%
CONTROL
GROUP
(n=90)
PROL BIV
(n=88)
p value
In-hospital Major Bleedings, %
1,1
0.87
In-hospital Minor Bleedings, %
3,3
3,4
0.96
B Cortese et al., AJC 2009

20. PATIENT POPULATION AND TREATMENT
PROBI VIRI II study design
ASA i.v mg in ambulance/first aid
clopidogrel 600 mg cath lab
92 pts.
86 pts.
86 pts.
Cath lab UFH (60 IU/Kg bolus and
subseq boluses with target ACT
sec) and abciximab (0.25
mg/Kg bolus and µg/Kg/min)
Cath lab bivalirudin (0.75 mg/Kg
bolus and 1.75 mg/Kg/h infusion)
Cath lab bivalirudin (0.75 mg/Kg
bolus, 1.75 mg/Kg/h infusion)
Primary PCI
bivalirudin infusion at 0.25 mg/Kg/h (4 hours after PCI)
abciximab infusion (12 hours after PCI)
B Cortese et al., AJC 2011

21. RESULTS primary endpoint20 40 60 80
100
STR >70% 90 min
GPI
Prol B B
P between GPI and B = 0.046
P between B and PB = 0.048
P between GPI and PB = 0.98
69,6
69,8
48,8
B Cortese et al., AJC 2011

22. Study Organization and Sites
Sponsor
Gruppo Italiano Studi Emodinamica
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
First Recruited patient: 11th Oct 2011
Last Recruited patient: 7th Nov 2014
Clinical Event Committee
Statistical Committee (CTU)
P. Vranckx, Chair
S. Leonardi Co-Chair
P. Tricoci
P.Jüni, MD, Chair
M. Rothenbühler
Dik Heg

23. Study Organization and Sites
Sponsor
Gruppo Italiano Studi Emodinamica
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
First Recruited patient: 11th Oct 2011
Last Recruited patient: 7th Nov 2014
Clinical Event Committee
Statistical Committee (CTU)
P. Vranckx, Chair
S. Leonardi Co-Chair
P. Tricoci
P.Jüni, MD, Chair
M. Rothenbühler
Dik Heg
BIVA STOP
BIVA PROLONGED

24. Endpoints MACE: composite of death, MI and stroke
The MATRIX Anti-thrombin program had two pre-specified primary superiority endpoints at 30 days:
MACE: composite of death, MI and stroke
NACE: composite of death, MI or stroke and
major bleeding (BARC 3 or 5)
For both the RR was assumed in the range of 0.70 with a background event rate of 6% and 9%, respectively. With an alpha error set at 2.5%, 3,400 patients per group would provide study power greater than 85% and 95% for MACE and NACE, respectively.
Major 2 EPs: each component of the co-primary endpoints, any bleeding according to BARC, TIMI and GUSTO scales and stent thrombosis

25. Baseline Characteristics
Bivalirudin (N=3,610) UFH (N=3,603)
Age (years) ± ±11.9
Age ≥ 75 ys (%)
Male (%)
Previous CVA (%)
PAD (%)
Cardiac Arrest (%)
Killip > 1 (%)
Killip 3 or 4 (%)
STEMI (%)
NSTEMI (%)
UA (%)
Pre-LAB P2Y12i (%)
Clopidogrel
Ticagrelor/prasugrel
Enoxaparin (%)
Fondaparinux (%)
UFH (%)

26. Procedural Characteristics
Bivalirudin (N=3,610)* UFH (N=3,603)
PCI attempted (%)
CABG (%)
Medical Tx (%)
Medications in the Lab (%)
Clopidogrel
Ticagrelor/prasugrel
Gp IIb/IIIa inhibitors
Treated vessel(s)
LMCA (%)
LAD (%)
Multivessel PCI (%)
Total stent length (mm) ± ±20
index procedure
*: 47.7% underwent prolonged infusion post-PCI of which 36% received 1.75 regimen

27. Primary EP: MACE 10.9% 10.3% UFH Bivalirudin
RR: 0.94; 95% CI: ; P=0.45

28. MI and CVA endpoints: Any MI, STEMI, NSTEMI, unclassified
MI and CVA endpoints: Any MI, STEMI, NSTEMI, unclassified*, stroke, TIA
*: LBBB, paced rhythm or unavailability of interpretable ECG %
P=0.92 %
P=0.57
P=0.28

29. Mortality: All-Cause, Cardiac, Vascular and non-CV mortality
RR:0.70
( )
P=0.037
RR: 0.68
( )
P=0.032 %
2.3%
1.7%
UFH
Bivalirudin

30. Bleeding endpoints: BARC 3 or 5
2.5%
1.4%
UFH
Bivalirudin

31. Bleeding endpoints: BARC, TIMI, GUSTO, access vs non-access related
RR: 0.61 %
P=0.002
RR: 0.50
P=0.005
RR: 0.53
P=0.027
RR: 0.61
2.5%
P=0.07
RR: 0.59
P=0.0016
RR: 0.31
1.4%
BARC 3 or 5
Major or minor
Moderate or severe

32. Primary EP: NACE 12.4% 11.2% RR: 0.89; 95% CI: 0.78-1.103; P=0.122 UFH
Bivalirudin

33. Primary EPs components: Focus on the relative contribution of each componentMI
66% MI
77% MI
75% MI
83%
RR:0.71
( )
P=0.042
RR:0.55
( )
P=0.001 B B S D S S D S D D
MACE
NACE
81% of MIs were adjudicated as type 4a (i.e. peripricedural), which
occurred in 247 patients (6.9%) in each treatment group

34. Stent thrombosis: Definite, Probable, Acute and Subacute%
P=0.048
RR: 1.71
P=0.23
RR: 1.53
P=0.10
RR: 1.99
P=0.34
RR: 1.37
P=0.54
RR: 1.21
P=0.27
RR: 1.28
1.4%
Definite Stent Thrombosis
Definite/Probable Stent ST

35. Subgroup Analysis
P-VALUES
HAZARD RATIO (95% CI)
HAZARD RATIO (95% CI)
MACE
Superiority
Interaction
Femoral
0.94 ( )
0.56
0.98
Radial
0.95 ( )
0.62
NACE
Treatment effects were also consistent across other pre-specified subgroups,
including Centre’s PCI volume or %
of TRI, ACS type, age, gender, P2Y12i,
diabetes, renal function and PVD
Femoral
0.87 ( )
0.15
Radial
0.66
0.93 ( )
0.46
Death
Femoral
0.66 ( )
0.07
Radial
0.64
0.77 ( )
0.31
Bleeding
Femoral
0.50 ( )
0.0024
Radial
0.51
0.64 ( )
0.10 2 1
0.25
UFH Better
Bivalirudin Better

37. Summary
In an all-comers, unselected ACS patient population randomly allocated to radial or femoral access, the use of bivalirudin as compared to UFH with provisional GPI did not reduce the composite of death, MI or stroke or the composite of death, MI stroke or major bleeding (BARC 3/5)

38. Summary ii
At individual outcomes analyses, bivalirudin was associated to:
A reduction in all-cause mortality, driven by CV fatalities (NNTB≈ 150)
Reduced bleeding risk across all scales, including fatal events (NNTB ≈ 333), and non -
access site events (NNTB ≈ 125)
We observed an increase in definite ST and not in definite/probable ST. This item can be reduced/attenuated by a prolonged bivalirudin infusion.