do we need individualized anticoagulation during percutaneous … · 2016-10-12 · adjunct...

Julinda Mehilli, MD, FESC

Deutsches Herzzentrum,

Technische Universität, München

Do We Need Individualized Anticoagulation during Percutaneous Coronary

Interventions?

Aggregation Activation

Prothrombin

Factor Xa

Thrombus stabilisation

Antithrombin

Modified from Kulkarni et al., JCI 2000

Pathophysiology of Arteriel Thrombosis

Coagulation

Adesion Tethering

Fibrinbildung

Clopidogrel

Abciximab

Heparin

Direct

Thrombin-Inhibitor

Thrombocyte Recruitment

Thrombin

Adjunct Antithrombotic Therapy

15%

16%

24%

45%SAP

STEMI

NSTEMI

IAP ISAR-REACT Kastrati et al.,

N Engl J Med 2004

ISAR-REACT 3 Kastrati et al.,

N Engl J Med 2008

BRAVE 3 Mehilli et al.,

Circulation 2009

HORIZONS AMI Stone et al., N Engl J Med 2008

ISAR-REACT 2 Kastrati et al., JAMA 2006

ISAR-REACT 4 Kastrati et al., N Engl J Med 2011

ACUITY Stone et al., N Engl J Med 2006

Spectrum of Clinical Presentation

at Cath Lab of Patients with CAD

10-Year Experience in Deutsches Herzzentrum and RdI

- ~20,000 patients with CAD and PCI -

Stable AP

STEMI

NSTEMI

Unstable AP

Ndrepepa et al, Cardiology 2009

0

5

10

15

20

0 1 2 3 4 5 6 7 8 9 10 11 12

Mortality

Months after PCI

OR = 3.00 [2.56-3.51], P<0.001 for STEMI vs. IAP

OR = 2.58 [2.20-3.04], P<0.001 for NSTEMI vs. IAP %

Ndrepepa et al.,Cardiology 2009

Clinical Presentation and Mortality after PCI

STEMI

NSTEMI

IAP

%

Clinical Presentation and Peri-PCI Events

REACT 3A EHJ 2009

ACUITY NEJM 2006

HORIZONS AMI NEJM 2008

Ndrepepa et al.,Cardiology 2009

n=5.384

Ndrepepa et al.,JACC 2008

ISAR-REACT, ISAR-SWEET, ISAR-SMART-2 und ISAR-REACT-2 Trials

% HR 2.96 (1.96-4.48), p<0.001

% HR 2.29 (1.52-3.46), p<0.001

Balance Between Antiischemic and Pro-bleeding Effects

Mortality Mortality


15%

16%

24%

45%SAP

STEMI

NSTEMI

IAP ISAR-REACT Kastrati et al.,

N Engl J Med 2004

ISAR-REACT 3 Kastrati et al.,

N Engl J Med 2008

ISAR-REACT 3A Schulz et al.,

Eur Heart J 2010

ISAR-REACT 2 Kastrati et al., JAMA 2006

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization

%

75.3%

74.6%

UFH+Abciximab vs. UFH+Placebo

RR = 1.01[ 95% CI, 0.85 -1.20]

Death, MI, TVR, %

ISAR-REACT, EHJ 2005 ISAR-REACT, NEJM 2004

Patients with Stable Angina

Heparin alone or with GPI ISAR-REACT n = 2951

ISAR-REACT, NEJM 2004

Patients with Unstable Angina

Heparin alone or with GPI


0

5

10

15

20

0 5 10 15 20 25 30 Days after randomization

Death/MI/urg. TVR, %

Troponin-Negative: RR=0.99 [0.56-1.76]

ISAR-REACT 2

ISAR-REACT-2, JAMA 2006 ISAR-REACT 2, JAMA 2006

0

2

4

6

8

10


5.0%

5.9%

RR = 1.16 [95% CI, 0.91-1.49]

Death/MI/urgTVR

%

Bivalirudin vs. UFH


Patients with Stable/Unstable Angina

Heparin alone or Bivalirudin

ISAR-REACT 3 n= 4570

ISAR-REACT 3, NEJM 2008

Incid

ence (

%)

P=0.008 P=0.0001 P=0.15

UFH 140 IU/kg



Heparin alone or Bivalirudin

ISAR-REACT 3, NEJM 2008

Days After Inclusion

Qua

dru

ple

en

dp

oin

t (%

)

0

5

10

15

20

0 5 10 15 20 25 30

HR 0.81 [0.67-1.00]; P=0.045

Adjusted HR 0.75 [0.60-0.92]; P=0.007

140 U/kg UFH: 8.7%

100 U/kg UFH: 7.3%

ISAR-REACT 3A, Eur Heart J 2010


High or Low Dose Heparin

Death,MI,urgTVR,major Bleeding ISAR-REACT 3A n= 4786


UFH 100 U/kg

UFH 140 U/kg

6.2

3.6

9.9

4.6

0

2

4

6

8

10

12

Major Bleeding Minor Bleeding

HR 0.79 [0.59-1.05]; P=0.11

Adjusted HR 0.71 [0.53-0.97]; P=0.03

Incid

en

ce

(%

)

Incid

ence (

%) 4.4

5.0

0

1

2

3

4

5

6

7

Secondary (Triple) Endpoint:

Death, MI or uTVR

HR 0.87 [0.67-1.13]; P=0.29

Adjusted HR 0.82 [0.62-1.08]; P=0.15



High or Low Dose Heparin



15%

16%

24%

45%SAP

STEMI

NSTEMI

IAP ISAR-REACT 2 Kastrati et al., JAMA 2006

ISAR-REACT 4 Kastrati et al., N Engl J Med 2011

ACUITY Stone et al., N Engl J Med 2006

Patients with NSTEMI



0

5

10

15

20


Death/MI/urg. TVR, %

Troponin-Positive: RR=0.71 [0.54-0.95]

ISAR-REACT 2, JAMA 2006

ISAR-REACT 2

n= 1049


%

P=0.29 P=0.46 P=0.008 P>0.99

Heparin+Abciximab Heparin+Placebo




PNI <0.0001

PSup = 0.015

PNI = 0.011

PSup = 0.32

PNI <0.0001

PSup <0.0001


Heparin with GPI or Bivalirudin?

ACUITY, NEJM 2006 ACUITY, NEJM 2006

ISAR-REACT 4 Trial flow-chart

Bivalirudin Abciximab

1,721 Pts with NSTEMI Pre-treated with 600 mg of clopidogrel

Double-blind

(double-dummy drug)

Bolus of 0.25 mg/kg

Infusion of 0.125 μg/kg/min for 12h

Unfractionated heparin Bolus of 70 U/kg

Bolus of 0.75 mg/kg

Infusion of 1.75 mg/kg/hr

for duration of PCI

No PCI: 2 patients 2 patients

861 pts 860 pts

Primary endpoint Death, large MI, uTVR, major bleeding

Days since Randomization

0

5

10

15

20

0 5 10 15 20 25 30

Cu

mu

lative

In

cid

en

ce

(%

)

Relative risk, 0.99 (95% CI, 0.74–1.32)

P=0.94

Bivalirudin

Abciximab 10.9%

11.0%

ISAR-REACT 4, N Engl J Med 2011

Primary endpoint analysis in various subsets Death, large MI, uTVR, major bleeding

Age

>68.3 yr

≤68.3 yr

SexWomenMen

Troponin T>0.12 μg/l≤0.12 μg/l

Relative Risk (95% CI)

0 1 2

Diabetes

YesNo

Abciximab better Bivalirudin better

Body Mass Index

>27.3 kg/m2

≤27.3 kg/m2

48/450 (10.7) 49/443 (11.1)

Abciximab Bivalirudin

46/411 (11.2) 46/417 (11.0)

31/200 (15.5) 25/199 (12.6)

63/661 (9.5) 70/661 (10.6)

27/257 (10.5) 24/243 (9.9)

67/604 (11.1) 71/617 (11.5)

42/435 (9.7) 46/426 (10.8)

52/426 (12.2) 49/434 (11.3)

56/424 (13.2) 66/425 (15.5)

38/437 (8.7) 29/435 (6.7)

P Value for

Interaction

0.94

0.27

0.71

0.51

0.15

no. of events/total no. (%)Subgroup

Glomerular filtration rate

≤83 ml/min 47/440 (10.7) 51/420 (12.1)

0.41>83 ml/min 47/421 (11.2) 44/440 (10.0)

Secondary efficacy endpoint - Death, any MI, uTVR

Bivalirudin

Abciximab

Relative risk, 0.96 (95% CI, 0.74–1.25)

P=0.76

0

5

10

15

20

0 5 10 15 20 25 30

Cu

mu

lative

In

cid

en

ce

(%

)


Abciximab Bivalirudin

Death, % 1.4 1.6

Any MI, % 12.0 11.4

uTVR, % 0.8 1.3

12.8%

13.4%


Secondary safety endpoint - Major bleeding

0

5

10

15

20

0 5 10 15 20 25 30

Cu

mu

lative

In

cid

en

ce

(%

)


Relative risk, 1.84 (95% CI, 1.10–3.07)

P=0.02

Bivalirudin

Abciximab 4.6%

2.6%



15%

16%

24%

45%SAP

STEMI

NSTEMI

IAP

BRAVE 3 Mehilli et al.,

Circulation 2009

HORIZONS AMI Stone et al., N Engl J Med 2008

Patients with STEMI


Placebo

399 pts

Abciximab

401 pts

PCI

800 Patients with STEMI Pretreatment with 600 mg of clopidogrel

Primary endpoint: Scintigraphic final infarct size

Double-blind

Final infarct size Mean

15.7 16.6

0

10

20

30

40

% LV P = .47

Abciximab Placebo

BRAVE 3, Circulation 2009 BRAVE 3, Circulation 2009

%

P = .48 P = .46 P = .39

Patients with STEMI


BRAVE 3, Circulation 2009

Heparin+Abciximab Heparin+Placebo

BRAVE 3, Circulation 2009

HORIZONS AMI, NEJM 2008

RR = 0.99 [0.76, 1.30]

Psup = 0.95 RR = 0.60 [0.46, 0.77]

PNI ≤ 0.0001

Psup ≤ 0.0001

RR = 0.76 [0.63, 0.92]

PNI ≤ 0.0001

Psup = 0.005

Patients with STEMI

Heparin and GPI or Bivalirudin

HORIZONS AMI, N Engl J Med 2008

Stone, Lancet 2010

HORIZONS AMI, NEJM 2008

HORIZONS AMI, NEJM 2008 & Lancet 2011

Patients with STEMI

Heparin and GPI or Bivalirudin


15%

16%

24%

45%SAP

STEMI

NSTEMI

IAP

Heparin bolus 70-100 U/Kg

ACT Monitoring for long

procedures

Bivalirudin as effective as

UFH + Abciximab

regarding ischemic events

superior to

UFH + Abciximab

regarding bleeding events

do we need individualized anticoagulation during percutaneous … · 2016-10-12 · adjunct...

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