pharmacological strategies to reduce periprocedural bleeding jonathan byrne king’s college...
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Pharmacological strategies to reduce periprocedural bleeding
Jonathan Byrne
King’s College Hospital
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Delicate balancing act
Ischaemic compications
BleedingPatient factors
Procedural factors
Pharmacology
Increasing thrombotic risk usually parallels increased bleeding risk
Incr
easi
ng r
isk
of is
chem
ic c
ompl
icat
ions
Incr
easi
ng r
isk
of b
leed
ing
com
plca
tions
Benefit Risk
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Pharmacological strategies to reduce bleeding during PCI
1. Reduced dose/no heparin
2. LMW versus unfractionated heparin
3. Newer synthetic anticoaculants
1. Bivalirudin versus heparin/GPI
2. Reduced dose GPI
Incr
easi
ng r
isk
of b
leed
ing
com
plca
tions
Stable
ACS
High Risk ACS/PPCI
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Low dose or ‘no’ dose heparin?
Current heparin dosages used in PCI are not based on randomised data
Current strategies include weight adjusted/ACT adjusted or fixed dose
Is it safe to use no heparin in selected ‘low risk’ patients?
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CIAO Study700 stable, elective patients. Type A/B lesions. No adjunctive GPI
use
3.7
Eve
nt r
ate
(%
)
Higher procedural CK release in the heparin group (3.1 vs 1.7%)
Stabile JACC 2008
MACE Major Bleeding
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Low fixed dose or weight adjusted?
.Retrospective analysis of 698 patients
Elective PCI
Weight adjusted vs fixed dose UFH (3000 units)
More complex angiographic lesions than CIAO
Kidambi Cardiovasc Ther 2010Similar levels of TnI release
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FUTURA/ OASIS 8
FUTURA/OASIS 8 JAMA 2010
2026 high risk ACS patients within a larger cohort treated with fondaparinux
Fixed low dose heparin (50u/kg) compared with ACT guided weight adjusted (85u/kg), regardless of GPI use
Major outcome composite of major bleeding at 48 hours
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5.8
4.7
Eve
nt r
ate
(%
)
3.9
4.8
Peri-PCI bleeding/vascular access complications
Peri-PCI bleeding/death/MI/TVR
FUTURA/OASIS 8 JAMA 2010
No benefit with low dose heparin
Low use of GPI (20%)
~40% radial access
Small reduction in minor bleeds
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STEEPLE- LMWH in elective PCI
Major or minor bleeding
Major Bleeding Minor bleeding
5.9
6.5
1.2 1.2
2.8
4.85.3
5.9
P=0.01
P=0.05
Monatalescot NEJM 2006
trend towards higher mortality in the low dose LMWH group
40% GPI use
Eve
nt r
ate
(%
)
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Meta-analysis of 13 RCTs
Dumaine Arch Intern Med 2007
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Avoid crossover from one to the other..
White Am Heart J 2006
>2000 patients undergoing PCI in the SYNERGY study
Event rate (%)
3.7
2.8
5.4P=0.03
P=0.047
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Synthetic Xa inhibitors in ACS…
Primary efficacy endpoint: 5.8% (fondaparinux) vs 5.7% (enoxaparin)Primary efficacy endpoint: 5.8% (fondaparinux) vs 5.7% (enoxaparin) Major bleeding: 2.2% (fondaparinux) vs 4.1% (enoxaparin)Major bleeding: 2.2% (fondaparinux) vs 4.1% (enoxaparin)
0 1 2 3 4 5 6 7 8 90.00
0.01
0.02
0.03
0.04
Days
Cu
mu
lati
ve h
azar
d
Death, MI, refractory ischaemia Major bleeding
Enoxaparin
Fondaparinux
HR 0.5295% CI 0.44, 0.61
p<0.001
0 1 2 3 4 5 6 7 8 90.00
0.01
0.02
0.03
0.04
0.05
0.06
Days
Cu
mu
lati
ve h
azar
d
Enoxaparin
Fondaparinux
HR 1.0195% CI 0.90, 1.13
OASIS 5 N Engl J Med 2006
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Mortality at 6 months
OASIS 5 N Engl J Med 2006
Days
Cu
mu
lati
ve h
aza
rd0.
00.
020.
040.
06
0 20 40 60 80 100 120 140 160 180
Enoxaparin
Fondaparinux
HR 0.8995% CI 0.80, 1.00
p=0.05
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Bivalirudin in ACS/STEMI
Paucity of data comparing heparin directly with bivalirudin (without GPI)
Doses of heparin used in most of the studies are higher than standard UK/European practice
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ISAR REACT 3
4570 patients with stable/unstable angina (with no biomarker rise
Preloaded with 600mg clopidogrel
140υg/kg UFH compared with bivalirudin
Triple end-point; net clinical benefit (MACE + bleeding)
Kastrati N Engl J Med 2008
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BCIS Autumn Meeting 2008, Stoke on Trent, UK
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BCIS Autumn Meeting 2008, Stoke on Trent, UK
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ISAR REACT 3a
• Lower dose (100units/kg) heparin in patients preloaded with clopidogrel
• ISAR react 3 heparin group used as historical control
• Same eligibility/exclusion criteria (biomarker negative ACS)
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BCIS Autumn Meeting 2008, Stoke on Trent, UK
**Almost identical to those seen with bivalirudin in previous study
Kastrati ESC 2010
**
**
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STEMI- HORIZONS AMID
eath
(%
)D
eath
(%
)
Time in DaysTime in Days
2.9%
1.8%
Heparin + GPIIb/IIIa inhibitor (n=1802)Bivalirudin monotherapy (n=1800)
0.3%0.2%
Cardiac
Non cardiac
HR [95%CI] =0.62 [0.40, 0.96]
P=0.029
Stone NEJM 2008
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HORIZONS-AMI 30 day outcomes
Stone NEJM 2008
12.1
8.3
5.5
9.2
4.9 5.4
0
5
10
15
20
Net adverse clinical events
Major bleeding (non CABG)
MACE
30 d
ay e
ven
t ra
tes (
%)
Heparin + GPIIb/IIIa inhibitor (N=1802) Bivalirudin monotherapy (N=1800)
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Reduced dose GPI?
• Early data (EPIC) suggested reduced bleeding but higher ischaemic complications with bolus abciximab
• EASY PCI (transradial) - clopidogrel loading. no difference between bolus/infusion of abciximab. Bleeding rates 0.5% (TRI)
• BRIEF PCI – ~700 patients (stable/ACS). Transfemoral. Clopidogrel preloaded. 2 hour versus 18 hour eptifibatide infusion
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Major Bleeding Minor Bleeding
Even
t Rate
(%)
1
4.2
17.6
21.2
P=0.02
Lower major bleeding rates
~40% ACS 97% femoral access
Fung JACC 2009
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Conclusions
• Tailored treatment for individual patients to balance thrombotic/bleeding risk.
• Stepwise approach to antithrombotics with increasing bleeding risk
• Avoid switching between antithrombins (except UFH from fondaparinux)
• Pharmacology should be coupled with other bleeding avoidance strategies (TRI in particular)