high risk acs: pci & real life data eurovision registry martial hamon, md, fesc university...

High Risk ACS: PCI & Real LIFE data EUROVISION registry

Martial HAMON, MD, FESCUniversity Hospital of Caen

INSERM 744, IPL

EURO-VISION EUROpean biValIrudin utiliSatION in practice

Disclosure Statement of Financial Interest

● Grant/Research Support:

GlaxoSmithKline, Lilly, The Medicines Company.

● Consulting Fees/Honoraria:

Terumo, The Medicines Company, Biotronik, Cordis, Medtronic.

Affiliation/Financial Relationship

www.angiosoft.netwww.angiosoft.net


Real World Studies

Premier Perspective Database

EUROVISION

Diversity across PCIpatients

BATACUITY-PCI

REPLACE-2

HORIZONSAMI

Meta-analyses

Time

Clinical data across randomized trials and real world use in PCI

Bivalirudin: direct thrombin inhibitor


Central Role of Thrombin in Thrombosis

Rupture, Erosion, Fissuration

Hoffman et al Thromb Haemost. 2001 Becker R. Am Heart J. 2005

1.Initiation: Tissue factor

2.Amplification: Platelets

Thrombin platelet activation

3.Propagation

Massive thrombin production

Adapted from Mann K et al. Arterioscler Thromb Vasc Biol. 2003Coughlin S et al. Thromb Haem. 2001

Thrombin Generation in Thrombosis

0 2 4 6 8 10 12 14 16 18 20

Clot Time 4.7 ± 0.2

Initiation

Threshold of Amplification

Propagation

>96% of thrombin produced afterthe clot is seen

Time (min)

Thro

mbi

n-an

tithr

ombi

n co

mpl

ex (

nM)

0

200

400

600

800

1,000

Whole blood from 35 healthy volunteers,tissue factor and phospholipid added to induce clotting


ADP+

TXA2

NeutrophilsMonocytes

Activated platelets

Endothelial cells

Activated platelets

Resting platelets

Monocyte

Resting platelets

IITenasecomplex

Thrombin

Prothrombin

Prothrombinasecomplex

TF

Activatedplatelets

Fibrin

THROMBIN

Croce K et al. Curr Opin Hematol. 2007Coughlin SR. Nature. 200

Mann KG. Chest. 2003Monroe DM et al. ATVBiol. 2002

The critical roles of thrombin


2

1

AntithrombinThrombin

Antithrombin

Heparin

Pentasaccharide sequence

AntithrombinFactor

Xa

LMWH

Pentasaccharide sequence

Heparin chains with pentasaccharide sequence

(~30%) bind to AT causing a conformational change

Thrombin inhibition requires “bridging” by heparin chain

(at least 18 units)

LMWH has greater activity against Xa than thrombin

Heparin/LMWH: mechanism of action

Hirsh J et al. Chest. 2001; 119:64S–94S

Heparin concentration (units/mL)

Inh

ibiti

on

(%

)

0

50

100

0.1 0.2 0.4 1.0

Soluble thrombin Clot-bound thrombin

Weitz JI et al. J Clin Invest. 1990

Unpredictable anticoagulant responseNarrow therapeutic windowLimited activity in the presence of platelet-rich clotProcoagulant effect (Heparin-induced platelet activation)Heparin-induced thrombocytopenia (Heparin-PF4 Ab)

Heparin Limitations

Hirsh J et al. Chest. 1995; Weitz JI et al. Circulation. 2002; Hirsh J et al. Chest. 1998;Sobel M et al. J Vasc Surg. 2001; Anand SX et al. Am J Cardiol. 2007.


1.00 2.00 3.00 4.00 5.0040

0

30

20

10

Time (min:sec)

1.00 2.00 3.00 5.00 7.00

Time (min:sec)

4.00 6.00 8.00

70

0

50

30

10

60

40

20

60

0

50

30

10

40

20

2.00 3.00 4.00 5.00

Time (min:sec)

Plat

elet

agg

rega

tion

(%)

Plat

elet

agg

rega

tion

(%)

Gra

nule

secr

etion

2 µM ADP

+3 µM/mlFond.

ADP 2 µM NaClLMWH 0.2U/ml

LMWH+ ADP

ADP

UFH+ ADP

ADP

UFH+ ADP

ADP

Heparin or NaClADP 2 µM

These agents bind directly to and activate the GP IIb/IIIa receptor

Platelet activation increasedWith UFH, LMWH, Fondaparinux

Ex vivo data based on human platelet -rich plasma; concentrations of heparin used were 0.1 to 1 U/mL, to simulate therapeutic range;

similar concentrations of LMWH and fondaparinux used.

Adapted from Gao C. et al and supplemental data Blood 2011; 117(18):4946-52.


Bivalirudin mechanism of action

(Gly)4

D-Phe-Pro-Arg-Pro(active-site-binding portion)

C-terminal dodecapeptide(Substrate recognition:Exosite 1-binding portion)

Bivalirudin binds to active siteand substrate recognition site

of thrombin

Bivalirudin slowly cleavedallowing thrombin to resume

its hemostatic function

Maraganore J et al Biochemistry 1990;30:7095-101

Direct and reversible binding to thrombin

Thrombin

PCIDose

InitialDose

0

1

2

3

4

5

6

7

8

9

-1 -0 .5 0 0 .5 1 1 .5 2 2 .5 3 3 .5

Mea

n Pl

asm

a Co

nc. (

mcg

/mL)

Elapsed Time From Start of Bivalirudin Bolus (Hours)

BB B III

0.75 mg/kg bolus B + 1.75 mg/kg/h infusion I*2

Initial 0.1 mg/kg B + 0.25 mg/kg/h I;

At the time of PCI 0.5 mg/kg B + 1.75 mg/kg/h I†3

Shown to provide adequate anticoagulation in PCI (6.5 mcg/mL) 4

= 25-minutes half-life

† Dose used in the ACUITY trial. PCI dose derived from phase 2 dose ranging study used in REPLACE-1 & 2.2Lincoff AM et al. JAMA 2003; 289: 853-863. 3Stone G et al. Am Heart J. 2004;148:764-75. 4Topol E, et al. Circulation 1993; 87:1622.

Bivalirudin: predictable pharmacology


110%

0.01 0.1 1 10 100 1000Bivalirudin concentration (mcg/mL)

% a

ggre

gatio

n re

spon

se

Thrombin (0.5 U/mL)

therapeutic plasma level

range90

70

50

30

10

Bivalirudin: Platelet inhibition via thrombinThrombin is the most potent platelet agonist known

Coughlin SR, Nature 2000Weitz J, et al. Am J Cardiol 2001.

Anand SX et al. Am J Cardiol. 2007

Control platelets Platelets treated with UFH

Platelets treated with Bivalirudin

Platelets from healthy volunteers treated with 30 min bivalirudin (12μg/mL) or 0.1 to 1.0 U/mL of heparin

Schneider et al Cor Ar Dis 2006

UFH 1.2 U/mL UFH 2 U/mL UFH + EptifibatideBivalirudin%

of p

late

lets

exp

ress

ing

p-se

lect

in

% of Activated Platelets

% o

f pla

tele

ts b

indi

ng P

AC

-1

Thrombin U/mL


*Ischemic endpoints: death, MI, and revascularization

REPLACE-21

N=6,002UFH +GP IIb/IIIa vsBivalirudin(Urgent/elective PCI)

ACUITY2

N=9,215UFH + GPIIb/IIIa vsBivalirudin(ACS)

HORIZONS-AMI3

N=3,602UFH ± GP IIb/IIIa vsBivalirudin (primary PCI)

Heparin + GP IIb/IIIa Bivalirudin

Ischemia Bleeding Ischemia Bleeding Ischemia Bleeding

7.3%

5.7%

3.0%

7.8%

0%

2%

4%

6%

8%

10%P=.32

P<.0016.2%

4.2%

2.4%

7.0%

0%

2%

4%

6%

8%

10%P=.23

P<.001 5.5%

8.3%

4.9%5.4%

0%

2%

4%

6%

8%

10%

P=.95

P<.001

30 d

ay e

vent

s (%

)Bivalirudin Trials Ischemic and Bleeding Outcomes

Lincoff AM et al. JAMA. 2003;289:853-863. 2 Stone GW et al. NEJM. 2006;355:2203-2216. 3 Stone GW. NEJM 2008;358:2218-30


Cardiac mortality30 days to 3 years

Bivalirudin (n=1800)Bivalirudin (n=1800)Heparin + GPIIb/IIIa (n=1802)Heparin + GPIIb/IIIa (n=1802)

Card

iac

Mor

talit

y (%

)

P=0.001

3-yr† HR [95%CI]=0.56 [0.40, 0.80]

2.9%

5.1%

P=0.005

1-yr† HR [95%CI]=0.57 [0.38, 0.84]

0 12 15 18 21 24 27 30 33 36

Months3 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%

In hospital and 30 day outcomes in all-comer PCI with BivalirudinInitial report of the prospective EUROVISION Registry.

Hamon M1, Nienaber C2, Galli S3, Huber K4, Gulba D5, Hill J6, Lafont A7, Cequier A8, Bernstein D9, Deliargyris E9 on Behalf of the Eurovision Investigators

1. Centre Hospitalier Universitaire de Caen, France. 2. Department of Cardiology and Angiology, University Hospital Rostock, Rostock School of Medicine, Rostock, Germany. 3. Department of Cardiovascular Sciences, University of Milan, Centro

Cardiologico Monzino, IRCCS, Milan, Italy. 4. Third Department of Medicine, Cardiology and Emergency Medicine, Wilhelminen hospital, Vienna, Austria. 5. Department of Cardiology, Krankenhaus Düren, Düren, Germany. 6. King's College Hospital, King's

College, London, UK. 7. Cardiology Department, University Paris-Descartes; AP-HP; European Georges Pompidou Hospital, Paris, France. 8. Hospital de Bellvitge, Barcelona, Spain. 9. The Medicines Company, Parsippany NJ, USA.


13

● Purpose: The EUROVISION Registry was designed to capture patterns of bivalirudin utilization and short term outcomes associated with the use of bivalirudin (BIV) during PCI procedures in Europe.

● Methods: consecutive BIV-treated patients included from 58 sites in 5 countries (Germany, Italy, France, Austria, United Kingdom).

● Outcomes: In-hospital and 30-day assessments

- Death, MI, stroke and urgent revascularization

- major bleeding according to ACUITY definition

- and minor bleeding any bleeding not included in the definition of major bleeding

Objectives and Methods

● In the ImproveR registry bolus only dosing was observed in EU clinical practice.

● Bolus only dosing was associated with increased in-hospital ischaemic events (MACE)

● The safety and efficacy of a bolus only dose of ANGIOX has not been evaluated and is not recommended even if a short PCI procedure is planned.


0 1 2 3 4 5 6 7 8 9Ischaemic events less

frequentIschaemic events more

frequent

Odds ratio [95% CI]

UFH/LMWH <24h after PCI (n=1069)

Age >65 years (n=2230)

Angiox double bolus (n=268)

STEMI (n=407)

PCI >45 minutes (n=1074)

Coumarins (n=99)

GP IIb/IIIa inhibitors (n=179)

ImproveR Registry

Madsen JK et al. EuroIntervention 2008:3:610-6

● An observational study of Angiox use in 4552 patients undergoing PCI.

– 26.3% of patients received a single bolus dose – no subsequent infusion

– 7.1% of patients received a double bolus dose – no subsequent infusion

– Bolus only dosing associated with in-hospital ischaemic events (MACE)


Study Population

2018 PCI-patients from 58 sitesin 5 European countries

French Investigators, Top 12:- Dr Lipiecki (n=96)- Dr Elhadad (n=88)- Pr Paganelli (n=87)- Pr Lafont (n=60)- Dr Hassani (n=36)- Pr Schiele (n=30)- Pr Carrié (n=25)- Dr Caussin (n=21)- Dr Loubeyre (n=18)- Dr Vilarem (n=15)- Dr Dibon (n=15)- Pr Steg (n=9)

Top Investigators (n>100):Pr Galli, Dr Goldman, Pr Huber,Dr Helmreich.


Distribution of PCI-patients: Indication

Overall, 58% of patients were cardiac marker -positive

N=523 N=315 N=499 N=678

- Overall, P2Y12 inhibitor preloading occurred in 95% of patients

- 91% clopidogrel (65% with 600 mg, 33% with 300 mg) and 9% prasugrel

- 45% of patients received other antithrombin therapy prior to PCI and were then switched to bivalirudin

- Activated clotting time was checked in only 2.8%


n/N Bivalirudin (N=2018)

Age (yrs), mean ± SD 65.5 ± 11.9

Age >65 yr 1122 /2018 55.6%

Female 499 /2018 24.7%

Weight (kg) mean ± SD - 79.8 ± 14.9

Prior MI 486 /2018 24.1%

Dyslipidemia 1215 /2018 60.2%

Prior PCI 636 /2018 31.5%

Hypertension 1385 /2018 68.6%

Previous CABG 145 /2018 7.2%

Congestive Heart Failure 130 /2018 6.4%

Current Smoker 588 /2018 29.1%

Family history of PVD 405 /2018 20.1%

Diabetes 482 /2018 23.9%

Baseline characteristics


n/N Bivalirudin (N=2018)

# diseased vessels >1 1086 /2018 53.8%

Actual treatment PCI 1933 /2018 95.8%

Actual treatment CABG 13 /2018 0.6%

Medical management 70 /2018 3.5%

Femoral access 1353 /1936 69.9%

Radial access 580 /1936 30.0%

Intervention Type:

Balloon Angioplasty 883 /2018 43.8%

Drug-Eluting Stent 1219 /2018 60.4%

Non drug-Eluting Stent 626 /2018 31.0%

Procedure duration, mean ±SD 36.0 ± 43.6

GP IIb/IIIa use 85 /2017 4.2%

Procedural characteristics


EUROVISION: 30-day Efficacy outcomes%

of E

vent

s

All patients n=2018


EUROVISION: 30-day Safety outcomes

All patients n=2018

% o

f Eve

nts


Overall rate of stent thrombosis 0.3% (6/2018)

Stent thrombosis by diagnosis


Deaths at 1 yearsubsequent to an event

UFH + GP IIb/IIIa inhibitorBivalirudin

Acute ST (<24 H)

Sub-acute ST (24 H to 30 d)

Late ST (30 days to 1 y)

Protocol Major Bleeding (1 y)

Re-infarction (1 y)

Stroke (1 y)

Mortality rate at 1 Year % (n/N)* Event

*In this post-hoc analysis, the mortality rate, n/N, is defined as the number of patients, n, who died after 1 year out of the number of patients, N, who had the event per treatment group


Outcomes by post-PCI infusion

Bivalirudin post-PCI infusion

n=916

Bivalirudin no post-PCI infusion

n=1017

Death/ MI/ Stroke/ Revasc 2.4% 3.3%

Death/ MI/ Revasc/ Stroke/ Major Bleed

3.4% 5.1%

Death 0.9% 1.2%

Stent thrombosis 0.4% 0.2%

Acute 0.1% 0.1%

Sub-acute 0.3% 0.1%

Major bleed 1.1% 2.0%

Among STEMI patients, 62% received a post-procedural bivalirudin infusion for a median duration of 122 minutes


EUROVISION: 30-day Diabetes - Efficacy

No Diabetes n=1514 Diabetes n=482

% o

f Eve

nts


EUROVISION: 30-day Diabetes - Safety


% o

f Eve

nts


EUROVISION: 30-day Diabetes - Summary



Country

Bivalirudin Femoral(N=1353)

Bivalirudin Radial

(N=580)

France 14.6% 62.9%

Italy 16.0% 28.3%

Austria 21.4% 0.7%

United Kingdom 4.4% 3.6%

Germany 43.5% 4.5%

Diagnosis

Stable Angina 29.3% 15.5%

Unstable Angina 14.7% 18.1%

NSTEMI 20.8% 33.8%

STEMI 35.1% 32.6%

Access route by country and diagnosis


Baseline Characteristics

Bivalirudin Femoral(n=1353)

Bivalirudin Radial

(n=580)p-value

Age (yrs), mean ± SD 65.7 ± 11.6 65.4 ± 12.2 NS

Female 23.7% 24.3% NS

Weight (kg) mean ± SD 80.0 ± 14.9 79.3 ± 14.9 NS

Prior MI 26.5% 19.8% 0.003

Dyslipidemia 63.3% 54.1% <0.0001

Prior PCI 35.3% 24.7% <0.0001

Hypertension 72.7% 59.5% <0.0001

Previous CABG 8.2% 5.0% 0.0436

Congestive Heart Failure 8.0% 3.4% <0.0001

Current Smoker 29.2% 28.8% <0.0001

Family history of PVD 21.5% 16.4% <0.0001

Diabetes 24.4% 20.9% NS


30 day Ischemic Outcomes (unadjusted)

Femoral(n=1353)

Radial(n=580) P-value

Death/ MI/ Stroke/ Revasc 3.2% 2.2% 0.2605

Death/MI/ Revasc/ Stroke/ Major Bleed 4.7% 3.3% 0.1483

Death 1.1% 0.9% 0.6234

MI 1.6% 0.2% 0.0088

Unplanned revasc 0.7% 1.4% 0.1233

Stroke 0.3% 0% 0.1899

Stent thrombosis 0.2% 0.5% 0.2844

Acute 0.1% 0.2% 0.5370

Sub-acute 0.1% 0.3% 0.3824

There were no differences noted in ischemic events at 30 daysbetween the two groups


Bleeding Outcomes (unadjusted)

Femoral(n=1353)

Radial(n=580) P-value

Major Bleeding 1.7% 1.2% 0.4216

Minor Bleeding 4.8% 1.9% 0.0026

Thrombocytopenia 0% 0% -

Access Site Bleed 3.6% 1.0% 0.0017

Non-Access Site Bleed 1.6% 0.9% 0.1897


Odds Ratio (95% CI)

P-value

Ischemic events(D/MI/UR/Stroke)Congestive heart failure

2.37 [1.22-4.61] 0.011

Major bleeding (ACUITY)Renal impairment 3.99 [1.93-8.26] <0.001

Independent predictors ofischemic events and major bleeding


Odds Ratio (95% CI)

P-value

Age ≥ 65 1.96 [1.15 - 3.33] 0.013

Hypertension 2.86 [1.40 - 5.87] 0.004

Prior PCI 0.58 [0.34 - 0.98] 0.044

Radial access 0.40 [0.21 - 0.79] 0.007

Independent predictors of minor bleeding


CONCLUSION (1)

● Adoption of BIV as the foundation for all-comer PCI including high percentage of STEMI and NSTEMI patients is :

- associated with excellent ischemic protection

- and unsurpassed safety.

● The use of Bivalirudin negated the risk associated with diabetes

● In the context of bivalirudin monotherapy during PCI, both ischemic and major bleeding complication rates at 30 days were similar irrespective of a femoral versus radial access site choice.

● The choice of radial access, however, was associated with lower rates of both minor and access site bleeding.

● Outcomes at 30 day observed in EUROVISION compare favorably to other large existing registry datasets


ESC/ EACTS 2010 Guidelines for Myocardial Revascularization

Wijns et al Eur Heart J. 2010 Oct;31(20):2501-55

STEMIClass Level

I B Bivalirudin (monotherapy)I C UFHIII B Fondaparinux

NSTE-ACS

Class Level

Very high-risk of ischaemia

I B Bivalirudin (monotherapy) or

I C UFH (+GPIIb-IIIa antagonists)

Medium-to-high-risk of ischaemia

I B Bivalirudin

I C UFH

I B Fondaparinux


High Risk PCI: 1 year mortality /Risk factorsREPLACE-2, ACUITY & HORIZONS-AMI (n= 14,258 DAPT)

Risk Factors included in the stratification model:1) Age>65, 2) Diabetes, 3) Hypertension, 4) Creatinine clearance<60mg/mL, 5) LVEF<35%, 6)NSTEMI, 7)STEMI, 8)Previous MI and 9) hematocrit<36.


One year mortality and risk factors

Pooled analysis: REPLACE-2, ACUITY & HORIZONS-AMI (n= 14,258 DAPT)

† fixed model ‡random effects model

RR (95% CI) P-value

REPLACE-2 0.76 (0.52,1.09) 0.14

ACUITY 0.92 (0.70,1.20) 0.53

HORIZONS 0.67 (0.48, 0.94) 0.018

Pooled analysis† 0.80 (0.66, 0.96) 0.015

Pooled analysis‡ 0.79 (0.66, 0.96) 0.018

Bivalirudin betterBivalirudin better UFH/GPIIbIIIa betterUFH/GPIIbIIIa better

Pooled analysis, 1-year mortalityRisk factor (n / N) RR (95% Cl)

P-value

Age >65 (314 / 5797) 0.79 (0.64, 0.98) 0.036

Diabetes (159 / 3598) 0.77 (0.57, 1.05) 0.097

Hypertension (313 / 9130) 0.84 (0.68, 1.05) 0.121

CrCl<60 mg/mL (171 / 2370) 0.75 (0.56, 1.00) 0.049

LVEF <35 (82 / 682) 0.47 (0.30, 0.72) 0.0004

biomarkers (NSTEMI) (139 / 3494) 0.91 (0.66, 1.26) 0.573

STEMI (135 / 3490) 0.67 (0.48, 0.94) 0.019

Previous MI (144 / 4088) 0.89 (0.64, 1.22) 0.463

Hematocrit <36% (102 /1684) 0.86 (0.59, 1.25) 0.418


1-year mortality and subgroup analysis

20% RR Death reduction with Bivalirudin Consistent results among subgroups


One year mortality and risk factors

REPLACE-2, ACUITY & HORIZONS-AMI (n= 14,258 DAPT)

RR (95% CI) P-value

30- day death

0, 1 or 2 risk factors 0.87 (0.45, 1.67) 0.67

3 or more risk factors 0.71 (0.51, 1.00) 0.047

1-year death

0, 1 or 2 risk factors 0.94 (0.66, 1.35) 0.75

3 or more risk factors 0.76 (0.61, 0.94) 0.01

30-day and 1-year Mortality Low Risk = 8082High Risk = 6176


1-ye

ar d

eath

(%)

Log Rank P-Value: Estimate:

Overall: 0.0083 Biv: 4.9%

Biv* vs Hep: 0.0083 Hep: 7.1%

1-year mortality, ≥ 3 risk factors (n=6,176)

Bivalirudin better in high risk PCI


1-year mortality, LVEF <35%● (n=682, overall 1 year mortality rate of 12%)

Patients at Risk:

Biv 351 342 335 334 329 328 328 323 323 322 319 314 247

Hep 331 305 300 296 295 291 289 286 279 278 273 269 209

16.9%

7.8%

p=0.0003

RR (95% Cl) P-value

REPLACE-2 LVEF <35 (N=214) 0.46 (0.19, 1.12) 0.078

ACUITY LVEF <35 (N=253) 0.51 (0.26, 0.99) 0.044

HORIZONS LVEF <35 (N=215) 0.43 (0.20, 0.91) 0.022

Pooled LVEF <35 (N=682) 0.47 (0.30, 0.72) 0.0004

REPLACE-2 LVEF ≥35 (N=3703) 0.85 (0.53, 1.37) 0.499

ACUITY LVEF ≥35 (N=3499) 1.06 (0.74, 1.53) 0.739

HORIZONS LVEF ≥35 (N=2744) 0.80 (0.51, 1.24) 0.311

Pooled LVEF ≥35 (N=9946) 0.92 (0.72, 1.17) 0.496


Consistent effectREPLACE-2, ACUITY, HORIZONS

1-year mortality by LVEF

Bivalirudin better in high risk PCI


Risk of Death, MI, Revasc. up to 7-days

Pooled meta-analysisCleveland Clinic F (n=16,519)

GPIIb-IIIawith heparin(n=7,629)

≥14,000 Uheparin(n=2,151)

7-10,000 Uheparin(n=4,578)

Angiomax(n=2,161)R

isk

of

TIM

I m

ajo

r B

leed

ing

in

Ho

spti

al

02

2Indirect and unpredictable thrombin

inhibition by UFH provides inadequate ischemic protection in high risk ACS

Addition of GPI’s improves ischemic protection at the cost of increased bleeding – modest if any mortality benefit

Bivalirudin trials have consistently demonstrated equivalent efficacy to GPI+UFH with reduced bleeding

Progress in High Risk ACS/PCIConclusion (2)


ESC/ EACTS 2010 Guidelines for Myocardial Revascularization

Wijns et al Eur Heart J. 2010 Oct;31(20):2501-55

STEMIClass Level

I B Bivalirudin (monotherapy)I C UFHIII B Fondaparinux

NSTE-ACS

Class Level

Very high-risk of ischaemia

I B Bivalirudin (monotherapy) or

I C UFH (+GPIIb-IIIa antagonists)

Medium-to-high-risk of ischaemia

I B Bivalirudin

I C UFH

I B Fondaparinux


THANK YOU FOR YOUR ATTENTION


0 1 2 3 4 5 6 7

Bleeding Risk: Access and non-access bleeding

Jolly S et al Lancet 2011;377:1409-20

RIVAL TrialPCI-patients randomized to radial

or femoral access, N=7021

2.1

0.8

0.8

1.6

0

1

2

3

4

5

6

TIMI Major + Minor%

of

pa

tie

nts

Access Site Only Both Non-Access Site Only No Location

Sources and incidence of bleedingPooled analysis REPLACE-2, ACUITY-PCI, HORIZONS-AMI: N=17,393

5.3% (n=925)

Non- access site

61.4% (n=568)

Access site only

38.6% (n=375)

Verheugt JACC Cardio Interv 2011;4:191-7

3.3%

2.1%

Hazard ratio

Access site 1.82 (1.17–2.83) 0.008

Non-access site 3.94 (3.07–5.15) <0.0001

No Bleed TIMI Major + Minor Bleed

1-year (adjusted) mortality hazardbleeding vs no bleeding

1-year mortality risk non-access site vs access site bleedingHR 2.27 (95%CI 1.42-3.64), p=0.0007


Bleeding Risk / Pharmacotherapy strategy

0 0.5 1 1.5 2

TIMI Major + Minor Bleeding Relative Risk P-Value

Access only 0.45 (0.35-0.58) <0.0001

All non-access 0.62 (0.51-0.75) <0.0001

Both 0.31 (0.19-0.49) <0.0001

Non-access only 0.70 (0.47-1.04) 0.08

Indeterminate 0.75 (0.58-0.96) 0.02

Bivalirudin better Hep + GPI better

Verheugt JACC Cardio Interv 2011;4:191-7

Relative risk of bleeding by treatmentPooled analysis REPLACE-2, ACUITY-PCI, HORIZONS-AMI, N=17,393

Bleeding Risk Access/PharmacotherapyBy bleeding risk category (n=982,077)

Marso et al. ACC/i2 Scientific Sessions 2010; abstract 2505-458

Low*(<1%)

Intermediate*(1-3%)

High*(>3%)

Overall*

MC BV R BR MC BV R BR MC BV R BR MC BV R BR

*P<0.001, 4-way comparison

MC = Manual compressionBV = Bivalirudin R = Radial PCIBR = Bivalirudin + radial

P=0.05 P=0.06

Records from NCDR 2004-2008

Synergistic effect of radial and bivalirudin for reducing major bleedingAnd subsequent potential deleterious outcomes


Risk of Death, MI, Revasc. up to 7-days

Summary resultsRR (95% CI)

GPIIb-IIIa inh.+UFH/LMWH

HeparinLMWH

Bivalirudin

Ris

k o

f T

IMI

maj

or

Ble

edin

g i

n H

osp

tial

0 2

2Indirect and unpredictable thrombin

inhibition by UFH provides inadequate ischemic protection in high risk ACS

Addition of GPI’s improves ischemic protection at the cost of increased bleeding – modest if any mortality benefit

Bivalirudin trials have consistently demonstrated equivalent efficacy to GPI+UFH with reduced bleeding

Progress in High Risk ACS/PCIConclusion (2)

high risk acs: pci & real life data eurovision registry martial hamon, md, fesc university...

Documents

j vasc

j clin

j cardiol

mechanism of action

presence of platelet

thrombin generation

weitz ji

supplemental data blood