Dr Robert F. Storey Senior Lecturer and Honorary Consultant in Cardiology, University of Sheffield, Sheffield UK Managing bleeding post PCI.

Dr Robert F. Storey

Senior Lecturer and Honorary Consultant in Cardiology, University of Sheffield,

Sheffield UK

Managing bleeding post PCI

MY CONFLICTSOF INTEREST ARE

Research grants: AstraZeneca, Eli Lilly, Daiichi Sankyo

Consultancy/honoraria/travel: AstraZeneca, Eli Lilly, Daiichi

Sankyo, The Medicines Company, Schering-Plough, Shire

Moscucci, M. et al. Eur Heart J 2003 24:1815-1823

Major bleeding in ACS GRACE registry

3.9

2.3

4.7 4.85.5

3.2

0

2

4

6

8

10

Allpatients

UA NSTEMI STEMI PCI No PCI

% M

ajo

r b

lee

din

g

Adjusted OR for mortality associated with major bleeding = 1.64 (CI 1.18-2.28)

Adjusted OR associated with PCI = 1.63 (CI 1.36-1.94)

REPLACE-2 trialIncreased mortality associated with

major bleeding

Feit F et al. Am J Cardiol. 2007; 100:1364-9

Sites of action of antithrombotic drugs

Storey RF. Current Pharmaceutical Design 2006

Thrombin

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR1

PAR4

Densegranule

Thrombingeneration

Shapechange

IIb3

IIb3

FibrinogenIIb3

Aggregation

AmplificationAmplificationAlpha

granule

Coagulation factorsInflammatory mediators

TP

Coagulation

GPVI

Collagen

ATPATP

P2X1

ASPIRIN

xCLOPIDOGRELPRASUGREL

ACTIVE METABOLITE

x AZD6140 CANGRELOR

GPIIB/IIIA ANTAGONISTS

x

UFHLMWHBIVALIRUDINFONDAPARINUX

xSCH530348E5555

x

Antidotes for bleeding• UFH and LMWH – protamine• Warfarin – FFP, vitamin K• Aspirin, clopidogrel – platelet transfusion• Abciximab – platelet transfusion• Eptifibatide, tirofiban - haemodialysis

Unproven, nonselective agents with safety concerns in CAD patients:

– Recombinant factor VIIa– Desmopressin– Norepinephrine/epinephrine

Risks of reversing antithrombotic drugs

• Stent occlusion and myocardial infarction/death

• Transfusion reaction to platelet transfusion e.g. acute lung injury

• Drug allergy

• Overdose of protamine has an anticoagulant effect

Bivalirudin Angioplasty Trial (BAT)

0

2

4

6

8

10

12

Transfusion Major bleed

%

UFH Bivalirudin

Bittl J et al. N Engl J Med 1995;333:764-9

P < 0.001 P < 0.001

Dumaine R et al. Arch Intern Med 2007; 167:2423-2430.

LMWH vs UFH in PCI meta-analysis

End point HR for LMWH vs UFH (95% CI)

P

Major bleeding 0.57 (0.40–0.82) 0.002

Minor bleeding 0.75 (0.47–1.20) ns

Death/MI 0.99 (0.79–1.24) ns

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

TRITON Efficacy and Safety ResultsTRITON Efficacy and Safety Results

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

Healthy volunteer crossover study of prasugrel and clopidogrel

IPA (20 M ADP) at 24 hours

Brandt JT et al. Brandt JT et al. Am Heart JAm Heart J 2007 2007

––2020

00

2020

4040

6060

8080

100100

Inh

ibit

ion

of

pla

tele

t ag

gre

gat

ion

(%

)In

hib

itio

n o

f p

late

let

agg

reg

atio

n (

%)

Response to Response to prasugrel 60 mgprasugrel 60 mg

Response to Response to clopidogrel 300 mgclopidogrel 300 mg

N=64N=64

Effect of cangrelor on ADP-induced platelet aggregation in patients with NSTE ACS

Whole blood impedance aggregometry

0

20

40

60

80

100

0.5 1.5 2.5 3.5 5 24 20 mpost

1 h post

Mea

n %

inhi

bitio

n of

pla

tele

t agg

rega

tion

Time after onset of infusion (h) Time after termination of infusion

0.05 g/kg/min

0.2 g/kg/min

0.5 g/kg/min

2g/kg/min

Infusion dose

Storey RF et al. Thromb Haemost. 2001; 85:401-7.

Conclusions

• Major bleeding in PCI patients is associated with increased mortality risk

• Strategies that reduce the risk of major bleeding should be developed

• Safer alternatives to high doses of unfractionated heparin are currently available and should be adopted

• New agents with improved reversibility may allow safer management of bleeding associated with PCI