pharmacological strategies to reduce periprocedural bleeding
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Pharmacological strategies to reduce periprocedural bleeding
Jonathan ByrneKing’s College Hospital
Delicate balancing act
Ischaemic compications
BleedingPatient factors
Procedural factors
Pharmacology
Increasing thrombotic risk usually parallels increased bleeding risk
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Benefit Risk
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
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Stable
ACS
High Risk ACS/PPCI
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?
CIAO Study700 stable, elective patients. Type A/B lesions. No adjunctive GPI use
3.7
Eve
nt ra
te
(%)
Higher procedural CK release in the heparin group (3.1 vs 1.7%)
Stabile JACC 2008
MACE Major Bleeding
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
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
5.8
4.7
Eve
nt ra
te (%
)
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
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 ra
te (%
)
Meta-analysis of 13 RCTs
Dumaine Arch Intern Med 2007
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
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
Cum
ulat
ive
haza
rd
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
Cum
ulat
ive
haza
rd Enoxaparin
Fondaparinux
HR 1.0195% CI 0.90, 1.13
OASIS 5 N Engl J Med 2006
Mortality at 6 months
OASIS 5 N Engl J Med 2006
Days
Cum
ulat
ive
haza
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
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
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
BCIS Autumn Meeting 2008, Stoke on Trent, UK
BCIS Autumn Meeting 2008, Stoke on Trent, UK
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)
BCIS Autumn Meeting 2008, Stoke on Trent, UK
**Almost identical to those seen with bivalirudin in previous study
Kastrati ESC 2010
**
**
STEMI- HORIZONS AMID
eath
(%)
Dea
th (%
)
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
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
vent
rat
es (%
)
Heparin + GPIIb/IIIa inhibitor (N=1802) Bivalirudin monotherapy (N=1800)
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
Major Bleeding Minor Bleeding
Event R
ate (%)
1
4.2
17.6
21.2
P=0.02
Lower major bleeding rates
~40% ACS 97% femoral access
Fung JACC 2009
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)
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