1. Pharmacological strategies to reduce periprocedural bleeding
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Pharmacological strategies to reduce periprocedural bleeding
Jonathan Byrne
King’s College Hospital

3. Delicate balancing act
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Delicate balancing act
Benefit
Risk
Bleeding
Patient factors
Procedural factors
Pharmacology
Ischaemic compications
Increasing thrombotic risk usually parallels increased bleeding risk
Increasing risk of ischemic complications
Increasing risk of bleeding complcations

4. Pharmacological strategies to reduce bleeding during PCI
Outpatient PCI Lounge
Pharmacological strategies to reduce bleeding during PCI
Reduced dose/no heparin
LMW versus unfractionated heparin
Newer synthetic anticoaculants
Bivalirudin versus heparin/GPI
Reduced dose GPI
Increasing risk of bleeding complcations
Stable
ACS
High Risk ACS/PPCI

5. Low dose or ‘no’ dose heparin?
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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?

6. Outpatient PCI Lounge
CIAO Study
700 stable, elective patients. Type A/B lesions. No adjunctive GPI use
3.7
Event rate (%)
Higher procedural CK release in the heparin group (3.1 vs 1.7%)
MACE
Major Bleeding
Stabile JACC 2008

7. Low fixed dose or weight adjusted?
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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 .
Similar levels of TnI release
Kidambi Cardiovasc Ther 2010

8. Outpatient PCI Lounge
FUTURA/ OASIS 8
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
FUTURA/OASIS 8 JAMA 2010

9. No benefit with low dose heparin
5.8
Low use of GPI (20%)
~40% radial access
Small reduction in minor bleeds
4.8
4.7
Event rate (%)
3.9
Peri-PCI bleeding/vascular access complications
Peri-PCI bleeding/death/MI/TVR
FUTURA/OASIS 8 JAMA 2010

10. STEEPLE- LMWH in elective PCI
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STEEPLE- LMWH in elective PCI
P=0.01
P=0.05
6.5
trend towards higher mortality in the low dose LMWH group
40% GPI use
5.9
5.9
Event rate (%)
5.3
4.8
2.8
1.2
1.2
Major or minor bleeding
Major Bleeding
Minor bleeding
Monatalescot NEJM 2006

11. Meta-analysis of 13 RCTs
Dumaine Arch Intern Med 2007

12. Avoid crossover from one to the other..
>2000 patients undergoing PCI in the SYNERGY study
P=0.047
5.4
P=0.03
Event rate (%)
3.7
2.8
White Am Heart J 2006

13. Synthetic Xa inhibitors in ACS…
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Synthetic Xa inhibitors in ACS…
Death, MI, refractory ischaemia
Major bleeding
Primary efficacy endpoint: 5.8% (fondaparinux) vs 5.7% (enoxaparin)
Major bleeding: 2.2% (fondaparinux) vs 4.1% (enoxaparin) 1 2 3 4 5 6 7 8 9
0.00
0.01
0.02
0.03
0.04
0.05
0.06
Days
Cumulative hazard
Enoxaparin
Fondaparinux
HR 1.01
95% CI 0.90, 1.13 1 2 3 4 5 6 7 8 9
0.00
0.01
0.02
0.03
0.04
Days
Cumulative hazard
Enoxaparin
HR 0.52
95% CI 0.44, 0.61
p<0.001
Fondaparinux
OASIS 5 N Engl J Med 2006

14. Mortality at 6 months Enoxaparin Fondaparinux HR 0.89
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Mortality at 6 months
Days
Cumulative hazard
0.0
0.02
0.04
0.06 20 40 60 80
100
120
140
160
180
Enoxaparin
Fondaparinux
HR 0.89
95% CI 0.80, 1.00 p=0.05
OASIS 5 N Engl J Med 2006

15. Bivalirudin in ACS/STEMI
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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

16. Outpatient PCI Lounge
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

17. BCIS Autumn Meeting 2008, Stoke on Trent, UK

18. BCIS Autumn Meeting 2008, Stoke on Trent, UK

19. 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)

20. BCIS Autumn Meeting 2008, Stoke on Trent, UK
**Almost identical to those seen with bivalirudin in previous study ** **
BCIS Autumn Meeting 2008, Stoke on Trent, UK
Kastrati ESC 2010

21. STEMI- HORIZONS AMI P=0.029 2.9% Death (%) 1.8%
Time 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

22. HORIZONS-AMI 30 day outcomes
Stone NEJM 2008

23. 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

24. Lower major bleeding rates
21.2
17.6
~40% ACS
97% femoral access
Event Rate (%)
P=0.02
4.2 1
Major Bleeding
Minor Bleeding
Fung JACC 2009

25. 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)