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Pharmacological strategies to reduce
periprocedural bleeding
Jonathan Byrne
King’s College Hospital
Delicate balancing act
Benefit Risk
Patient factors Bleeding
Ischaemic
compications Procedural factors
Pharmacology
Increasing risk of ischemic complications
Increasing risk of bleeding complcations
Increasing thrombotic risk usually parallels
increased bleeding risk
Pharmacological strategies to reduce
bleeding during PCI
1. Reduced dose/no heparin
Stable
Increasing risk of bleeding complcations
2. LMW versus unfractionated heparin
3. Newer synthetic anticoaculants ACS
1. Bivalirudin versus heparin/GPI
High Risk
2. Reduced dose GPI 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 Study
700 stable, elective patients. Type A/B lesions. No adjunctive GPI
use
3.7 Heparin
4
No Heparin
3
Event rate
Higher procedural
2 1.7 CK release in the
1.5
(%)
heparin group (3.1
vs 1.7%)
1
0
0
MACE Major Bleeding
Stabile JACC 2008
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
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
No benefit with low dose heparin
7
Standard dose UFH
6 5.8 Low dose UFH
Low use of GPI
Event rate (%)
5 4.7 4.8
(20%)
3.9
4
~40% radial
3 access
2 Small reduction in
minor bleeds
1
0
Peri-PCI bleeding/vascular Peri-PCI
access complications bleeding/death/MI/TVR
FUTURA/OASIS 8 JAMA 2010
STEEPLE- LMWH in elective PCI
P=0.01
10 P=0.05
0.5ug/kg enox 0.75ug/kg enox
8.5 UFH
8
6.5
Event rate (%)
trend towards
5.9 5.9
6 5.3 higher mortality
4.8 in the low dose
4
LMWH group
2.8
40% GPI use
2 1.2 1.2
0
Major or minor Major Bleeding Minor bleeding
bleeding
Monatalescot NEJM 2006
Meta-analysis of 13 RCTs
Dumaine Arch Intern Med 2007
Avoid crossover from one to the other..
>2000 patients undergoing PCI in
the SYNERGY study
P=0.047
8
6.8
Enoxaparin UFH
6 5.4
P=0.03
Event rate 3.7
(%) 4
2.8
2
0
TIMI major Bleeding Transfusion
White Am Heart J 2006
Synthetic Xa inhibitors in ACS…
Death, MI, refractory ischaemia Major bleeding
0.06 0.04 Enoxaparin
Fondaparinux
0.05 HR 0.52
Cumulative hazard
Cumulative hazard
Enoxaparin 0.03 95% CI 0.44, 0.61
0.04 p<0.001
HR 1.01
0.03 0.02
95% CI 0.90, 1.13
0.02
0.01 Fondaparinux
0.01
0.00 0.00
0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9
Days Days
Primary efficacy endpoint: 5.8% (fondaparinux) vs 5.7% (enoxaparin)
Major bleeding: 2.2% (fondaparinux) vs 4.1% (enoxaparin)
OASIS 5 N Engl J Med 2006
Mortality at 6 months
Enoxaparin
0.06
Cumulative hazard
Fondaparinux
0.04
HR 0.89
0.02
95% CI 0.80, 1.00
p=0.05
0.0
0 20 40 60 80 100 120 140 160 180
Days
OASIS 5 N Engl J Med 2006
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)
**Almost identical to those seen with
** bivalirudin in previous study
**
BCIS Autumn Meeting 2008,
Stoke on Trent, UK
Kastrati ESC 2010
STEMI- HORIZONS AMI
Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)
HR [95%CI] =
0.62 [0.40, 0.96]
Death (%)
P=0.029 2.9%
Cardiac
1.8%
Non cardiac
0.3%
0.2%
Time in Days
Stone NEJM 2008
HORIZONS-AMI 30 day outcomes
Heparin + GPIIb/IIIa inhibitor (N=1802) Bivalirudin monotherapy (N=1800)
30 day event rates (%)
20
15
12.1
10 9.2
8.3
5.5 5.4
4.9
5
0
Net adverse clinical Major bleeding (non MACE
events CABG)
Stone NEJM 2008
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
25
Lower major bleeding rates
2 hour infusion
epitfibatide 21.2
20 Standard infusion
Event Rate (%)
17.6
15 ~40% ACS
97% femoral
10 access
P=0.02
5 4.2
1
0
Major Bleeding Minor Bleeding
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)
