La bivalirudina ed il - PowerPoint Presentation

Slide1

La

bivalirudina ed il suo annus horribilis: un update scientifico

Bernardo CorteseIntv’ Cardiology, A.O. Fatebenefratellibcortese@gmail.com

Slide2

HORIZONS AMI

30 Day and 1-Year All-Cause Mortality

Number at risk

Bivalirudin alone

Heparin+GPIIb/IIIa

1800

1705

1684

1669

1520

1802

1678

1663

1646

1486

Mortality (%)

0

1

2

3

4

5

Time in Months

0

1

2

3

4

5

6

7

8

9

10

11

12

Bivalirudin alone (n=1800)

Heparin + GPIIb/IIIa (n=1802)

4.8%

3.4%

HR [95%CI] =

0.69 [0.50, 0.97]

P=0.029

3.1%

2.1%

Δ

= 1.0%

Δ

= 1.4%

Stone GW et al. NEJM 2008;358:2218-30

Mehran R et al. Lancet 2009;374:1149-59.

HR [95%CI] =

0.66 [0.44, 1.00]

P=0.048

Slide3

cardiac mortality30 days to 3 years*

Stone GW NEJM. 2008;358:2218-30. Mehran R Lancet. 2009;374:1149-59. Stone GW Lancet. 2011;377:2193-204.'

Bivalirudin (n=1,800)Heparin + GP IIb/IIIa (n=1,802)

Cardiac

Mortality (%)

2.9%

5.1%

0

12

15

18

21

24

27

30

33

36

Months

3

6

9

0

1

6

5

4

3

2

3.8%

2.1%

30-d

†

HR [

95% CI

]= 0.62; [0.40,0.96]

P =

0.03

1.8%

2.9%

*

3-year a

ll

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

1-yr

†

HR [95%CI]=

0.57 [0.38, 0.84]

P =

0.005

3-yr

†

HR [95%CI]=

0.56

[

0.40, 0.80]

P =

0.001

NNT=45

Slide4

1432

1373

1478

1509

1484

6

1611

Bivalirudin

0

2

3

4

5

0.89 [0.65, 1.23]

1

0

12

15

18

21

24

27

30

33

36

Three-Year Stent Thrombosis

(ARC Definite/Probable)

971

1591

1456

906

p=0.49

HR [

95%CI

]=

4.5%

5.1%

Stent Thrombosis (%)

Months

3

6

9

Bivalirudin alone (n=1611)

Heparin + GPIIb/IIIa (n=1591)

Number at risk

Heparin+GPIIb

/IIIa

1453

1401

1.16 [0.79, 1.71]

p=0.45

HR [95%CI]=

1398

1335

3.5%

3.0%

Slide5

HEAT PPCI: Design and enrollment

29 (1.5%) already randomized in the trial59 (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

1917 STEMI pts scheduled for emergency angiography at a single

center

between Feb 2012–Nov 2013*

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17 (1%) refused post procedure consent and were withdrawn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)

1829 eligible for recruitment were randomized 1:1

Shahzad

A et al. Lancet 2014

Slide6

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

24 (2.7%)

6 (0.7%)

-Acute ST

20 (2.9%)

6 (0.9%)

Shahzad

A et al. Lancet 2014

697

pts

Slide7

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%)

6 (0.8%)

0.99

Shahzad

A et al. Lancet 2014

Slide8

HEAT PPCI: ACT* and GPI bailoutBivalirudin arm (n=915)

N Measure

ACT 5-15 mins after bolus806 (88%)

251 [229, 285] sec

ACT end-procedure

771 (84%)

246 [229, 270] sec

Bivalirudin

rebolus

anytime**

12.7%

GPI bailout

13.5%

*

*By protocol,

rebolus

for ACT <225 seconds

~

25% <229 seconds;

rebolus

rate should have been ~25%

Shahzad

A et al. Lancet 2014

Slide9

 

Bivalirudin aloneN=735Biv 0.75 mg/kg bolus + 1.75 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 aloneN=729

Heparin 100 U/kg bolus + additional dose if ACT <200 s.

ACT goal = 250-300.5.6% bailout tirofiban

.UFH +

TirofibanN=730Heparin 60U

/kg bolus .Tirofiban 10μg/kg bolus + 0.15

μg/kg/min infusion for 18-36 h.ACT goal = 200-250.

BRIGHT: Study flow

Follow-up at 30 days, 6 months and 1 year

Randomization (

1:1:1)

Primary

endpoint:

NACE, including MACCE (all-cause death, reMI, TVR or stroke

) and bleeding events at 30 days.

H

an Y. TCT 2014

86.2 % STEMI13.8% NSTEMI79% radial

Aspirin and clopidogrel2,194

pts with AMI randomized at 82 centers in China

Slide10

BRIGHT: events at 30 Days

P<0.001P<0.001P=0.74

Biv vs. Hep, p=0.009RR (95%CI) 0.67 (0.50-0.90), NNT=23.1Biv

vs. Hep+Tiro

, p<0.001

RR (95%CI) 0.52 (0.39-0.69), NNT=12.3

Hep

vs.

Hep+Tiro

,

p=0.04RR (95%CI) 0.78 (0.61-0.99), NNT=26.2(%)

Primary endpointNACE

8.8

16

12

6

018

14

10

8

2

4

13.2

17.0

5.0

5.8

4.9

4.1

7.5

12.3

MACCE

Any Bleeding

Bivalirudin (n=735

)

Heparin (n=729

)

Heparin + Tirofiban (n=730)

H

an Y. TCT 2014

Slide11

BRIGHT: 30-day ST

STEMI OnlyP=0.59P=0.49P=1.00

P=0.81P=0.71

(%)

0.8

0.4

0

1.2

1.0

0.6

0.2

0.5

1.0

0.8

Bivalirudin (N=629)

Heparin (N=620)

Heparin+Tirofiban

(N=609)

0.5

1.0

0.8

Definite

0.3

0.8

0.8

Probable

0.2

Acute

0.2

0.3

Subacute

0.6

0.5

0.2

0

0.3

0.3

Def/prob

H

an Y. TCT 2014

Slide12

Study

NComparatorSettingIschemic EventsBleedingREPLACE-26002UFH + GPIElective PCI-ISAR REACT 34570UFH (140 u/kg)

Elective PCI-ACUITY13800UFH/LMWH + GPINSTEACS

-



ISAR REACT 4

1721

UFH + GPI

NSTEACS

-



BRIGHT2100UFH or UFH + GPISTEMI & NSTEMI-

HORIZONS3602UFH + GPI

STEMI(-) MACEDeath

 Stent thrombEUROMAX2218

UFH ± GPISTEMI(-) MACE Stent

thrombHEAT PPCI1829

UFHSTEMI MACE-

“Contemporary” Bivalirudin Trials

courtesy of A

Kirtane, 2014

Slide13

Question n°

1:

Bleedingsthe deck was stacked against heparin!(routine GPI use explains bleeding advantage)vascular Closure Devices could mitigate the bleeding advantage of bivalirudin!t

ransradial access could mitigate the bleeding advantage of bivalirudin!

Slide14

16 studies (3 rand, 13 reg), 32,492 pts undergoing PCI:

Bivalirudin vs UFH Monotherapy Meta-analysis

Major Bleeding

Bertrand OF et al.

Am J Cardiol

2012;110:599–606

Study

or subgroup

Events

Odds Ratio M-H,

Random, 95% CI

Odds Ratio M-H,

Random, 95% CI

Total

Bivalirudin

Events

Heparin

0.01

Favors Bivalirudin

0.1

1

10

100

Favors Heparin

Total Events 244 431

Test for heterogeneity: Tau

2

=0.08, Chi

2

=21.99, df=13 (

P=0.06

),I

2

=41%

Test for overall effect: Z=4.38 (

P<0.0001

)

Test for subgroup differences: Chi

2

=0.47, df=1 (

P=0.49

),I

2

=0%

Total (95% CI)

Observational

Randomized

Kastrati 2008

Parodi 2010

Patti 2011

Subtotal (95% CI)

0.55 [0.43, 0.72]

11648

Total Events 16 34

Test for heterogeneity: Tau

2

=0.00, Chi

2

=0.37, df=2 (

P=0.83

),I

2

=0%

Test for overall effect: Z=2.60 (

P=0.009

)

12

3

1

0.50 [0.25, 0.99]

0.31 [0.08, 1.19]

0.51 [0.05, 5.67]

0.45 [0.25, 0.82]

2289

363

198

2850

24

8

2

Total Events 228 397

Test for heterogeneity: Tau

2

=0.11, Chi

2

=20.84, df=10 (

P=0.02

),I

2

=52%

Test for overall effect: Z=3.55 (

P=0.0004

)

4

1

2

23

10

26

5

6

101

12

38

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]

335

54

216

566

79

1207

2675031771228915118798

352141420

101226891678

Wolfram 2003Rha 2005Chu 2006Bonello 2009Lemesle 2009Lemesle 2009-bDelhaye 2010

Lindsey 2010Lopes 2010Schultz 2010Bangalore 2011Subtotal (95% CI)

Total

13206

2281

308

203

2792

1543

60

456

333

92

1559

129

861

1365

2505

1551

10414

45%↓

Slide15

N = 458,448 PCI pts 2004-2008 at 299 hosps

(Premier Perspective Database, ~1/5th of all US hosp discharges; bival in 41%)

Wise GR et al.

J

Interv

Cardiol

2012;25:278–88

Bleeding + Transfusion

In-hospital events, propensity adjusted

Mortality

Comparator Better

Heparin + GPI Better

(n=182,948)

0

2

1

0.71 (0.66, 0.76)

Heparin alone

(n=85,870)

<0.0001

0.96 (0.87, 1.06)

Bivalirudin + GPI

(n=33,566)

0.37

0.51 (0.48, 0.55)

Bivalirudin

monotherapy

(n=156,064)

<0.0001

OR

(95% CI)

Comparator

P

Value

Comparator Better

Heparin + GPI Better

(n=182,948)

0

2

1

0.88 (0.82, 0.96)

Heparin alone

(n=85,870)

0.003

0.82 (0.72, 0.94)

Bivalirudin + GPI

(n=33,566)

0.004

0.59 (0.54, 0.65)

Bivalirudin

monotherapy

(n=156,064)

<0.0001

OR

(95% CI)

Comparator

P

Value

Anticoagulation Regimens During PCI

OR

(95% CI)

OR

(95% CI)

Slide16

NCDR

CathPCI Registry 2004-2008: PCI in 1,522,935 ptsManual compression alone, closure devices, bivalirudin, or both were

used in 35%, 24%, 23%, and 18% of pts, respectively. Propensity-adjusted bleeding

Impact of Bleeding Avoidance Strategies

Marso

SP

et al

. JAMA.

2010;303:2156-64

23%↓

Adj OR (95%CI) =

0.77 (0.73 – 0.80)

NNT

= 148

Adj OR (95%CI) =0.67 (0.63 – 0.70)

NNT = 118 Adj OR (95%CI) =

0.38 (0.35 – 0.42)NNT = 70

33%↓

62%↓

Slide17

Impact of Access and Non-Access Site Bleeding after PCI

17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS568(61.4%)

non accesssite related925 pts (5.3%) had TIMI major or minor bleeding within 30 days

Source of bleeding (absolute rate)

Indeterminate – most likely intraprocedural (catheter exchanges) or baseline anemia with lower transfusion threshold

Verheugt

FWA et al. JACC Int 2011;4;191-197

Slide18

Impact of Access and Non-Access

Site Bleeding after PCI17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS925 pts (5.3%) had TIMI major or minor bleeding within 30 daysTime-updated multivariable risk of death within 1-year

Adjusted risk of 1-year mortality

TIMI Bleed - All

TIMI Bleed – Non Access Site

TIMI Bleed – Access Site Only

0.1

8

1

HR [95%CI] P

3.17 [2.51, 4.00] <0.0001

3.94 [3.07, 5.15] <0.0001

1.82 [1.17, 2.83] 0.008

Verheugt FWA et al. JACC Int 2011;4;191-197

Slide19

Study

NComparatorSettingIschemic EventsBleedingREPLACE-26002UFH + GPIElective PCI-ISAR REACT 34570UFH (140 u/kg)

Elective PCI-ACUITY13800UFH/LMWH + GPINSTEACS

-



ISAR REACT 4

1721

UFH + GPI

NSTEACS

-



BRIGHT2100UFH or UFH + GPISTEMI & NSTEMI-

HORIZONS3602UFH + GPI

STEMI(-) MACEDeath

 Stent thrombEUROMAX2218

UFH ± GPISTEMI(-) MACE Stent

thrombHEAT PPCI1829

UFHSTEMI MACE-

“Contemporary” Bivalirudin Trialsc

ourtesy of A Kirtane, 2014

Slide20

Question n°

2:does bivalirudin increase early thrombotic events???

Slide21

a

cute stent thrombosis with bivalirudin in STEMINO prolonged infusion

NO prolonged infusionprolonged infusion

0.2 mg/Kg/min

prolonged infusion

Slide22

Landmark Analysis:

Stent Thrombosis to 30

days*

Estimated event rate (%)

Time from Randomization (days)

0.48%

0.37%

Bivalirudin (n=1089)

UFH

±

GPI (n=1109)

1.11%

0.18%

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)

*Based

on the

ITT population. Data

on

file

, The Medicines Company

.

Log rank p=0.007

Log rank p=0.71

The median time

to AST

was 2.3 hours (IQR 1.9-2.8)

Slide23

Different drug regimens

Slide24

a

ntithrombotics halflife

minutes

Slide25

In CKMB negative pts (80%) eptifibatide protected from

procedural-related MIs

better than bivalirudin

(any CK MB increase, 16.6 vs. 25.2%, p=0.01).

Protect

TIMI 30

study

CM Gibson, J Am

Coll

Cardiol

2006

Slide26

“Antithrombotic protection”

TIME

PCI

end of PCI

4 hrs

12 hrs

24 hrs

GPI

B stop

end of PCI

Prolonged B

-Plt activation

-Distal embolization

-Small vess closure

-Stent thrombosis

a

ntithrombotics

“protection”

B

Cortese

2008 & 2011

Slide27

PROBI VIRI study

design178 pts with SA or UA, complex PCIRandomization (post angio)

Primary endpoint

Cath lab Biv bolus and infusion (1.75 mg/Kg/h)

4-hrs infusion at 0.25 mg/Kg/h (n=88)

Stop infusion (n=90)

B Cortese et

al

., AJC 2009

Slide28

PROBI VIRI

Results16,7%

6,8%

p=0.041

In-hospital Major Bleedings, %

1,1

1,1

0.87

In-hospital Minor Bleedings, %

3,3

3,4

0.96

CONTROL

GROUP

(n=90)

PROL BIV

(n=88)

p value

B Cortese et

al

., AJC 2009

Slide29

Slide30

PATIENT POPULATION AND TREATMENT

ASA i.v. 250-500 mg in ambulance/first aidclopidogrel 600 mg cath lab

Cath lab UFH (60 IU/Kg bolus and subseq boluses with target ACT 200-250 sec) and abciximab (0.25 mg/Kg bolus and 0.125 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)

abciximab infusion (12 hours after PCI)

bivalirudin

infusion

at 0.25 mg/Kg/h (4 hours

after PCI)

Primary

PCI

92

pts

.

86

pts

.

86

pts

.

PROBI VIRI II

study

design

B Cortese et

al., AJC 2011

Slide31

RESULTSprimary endpoint

0

20

40

60

80

100

STR >70% 90 min

GPI

Prol B

B

69,6

69,8

48,8

P

between

GPI and B = 0.046

P

between

B and PB = 0.048

P

between

GPI and PB = 0.98

B Cortese et

al

., AJC

2011

Slide32

Treatment Breakdown and Outcomes by

Bivalirudin

Post-PCI Infusion Dose

BIVALIRUDIN

1.75 mg/kg/hour infusion

0.25 mg/kg/

hr

(n=670)

‡

1.75 mg/kg/

hr

(n=244)

§

Pre-PCI

PCI

Post-PCI

†

BIVALIRUDIN

Bolus 0.75 mg/kg + 1.75 mg/kg/hour infusion

P2Y

12

Load

ASA

+

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

Slide33

1:1

1:1

NSTEACS or STEMI with invasive management

Aspirin+P2Y12 blocker

Trans-Femoral Access

Heparin

±GPI

Bivalirudin

Mono-

Tx

Stop

Infusion

Prolong≥ 6 hs

infusion

1:1

Trans-Radial Access

MATRIX Trial

NCT01433627

http://matrixstudy.ospfe.it/web/

Slide34

conclusions

b

ivalirudin decreases bleeds independently from its antagonist;this might be associated with improved long term outcome;there is an increased very early thrombotic risk;this risk might be attenuated or eliminated by a prolonged bivalirudin infusion.

Slide35

La

bivalirudina ed il suo annus horribilis: un update scientifico

Bernardo CorteseIntv’ Cardiology, A.O. Fatebenefratellibcortese@gmail.com