16th Interventional Cardiology SymposiumMontreal, Quebec / June 14-16, 2007
Adapted from a presentation by:
Shamir R. Mehta, MD, MSc, FRCPC, FACC
“Transitioning ACS Patients to the Cath Lab: Optimizing Outcomes
with Upstream Fondaparinux and Bivalirudin/UFH”
Friday, June 15, 2007
Shamir R. Mehta, MD, MSc, FRCPC, FACCShamir R. Mehta, MD, MSc, FRCPC, FACCDirector, Interventional Cardiology
Hamilton Health SciencesAssociate Professor of Medicine
McMaster UniversityHamilton, Ontario, Canada
Transitioning ACS Patients to the Cath Lab: Optimizing Outcomes with Upstream Fondaparinux and Bivalirudin/UFH
Antithrombotics in UA/NSTEMI Patients in the Last Decade:Increased Efficacy at the Price of Increased Bleeding
16-20% 12-15% 8-12% 6-10% 4-8%Dea
th /
MI
BleedingBleeding
1988ASA
1992ASA+UFH
1998 ASA+UFH+
GPIIb/IIIaInhib
2003ASA+
LMWH +Clopidogrel +
PCI
Coagulation Cascade and New Anticoagulants
Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin
Intrinsic pathway Extrinsic pathway
1
50
X
II
FibrinFibrinogen
Clot
XaVa
PLCa2+
VIIIa
Ca2+
PL
IXa
Bivalirudin
Fondaparinux
Xa
IIa
Rosenberg & Aird. N Engl J Med. 1999;340:1555–64.Wessler & Yin. Thromb Diath Haemorrh. 1974;32:71–8.
OASIS-5: A Randomized, Double-Blind, Double-Dummy Trial
20,078 patients with UA/NSTEMI20,078 patients with UA/NSTEMI
Fondaparinux2.5 mg s.c. od up to 8 days
Aspirin, Clopidogrel, anti-GPIIb/IIIa, planned Cath/PCI as per local practice
Randomization
Enoxaparin1 mg/kg s.c. bid for 2-8 days
1 mg/kg s.c. od if ClCr<30mL/min
Michelangelo OASIS-5 Steering Committee. Am Heart J. 2005;150:1107.e1-.e10.OASIS 5 Investigators. I. 1464-76.
Majority of Patients Undergoing Catheterizationin OASIS-5 Went Early
Mehta et al. JACC 2006; abstract 821-5
44.2%
17.4%
38.4%
05
101520253035404550
<24 hrs 24-48 hrs >48 hrs
Pa
tie
nts
(%
)N = 14,206
Fondaparinux and Enoxaparin Non-inferiorfor Efficacy at 9 Days
OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.
5.8%5.7%Death/MI/RI
1.9%1.9%Refractory Ischemia
2.6%2.7%MI
1.8%1.9%Death
4.1%4.1%Death/MI
FondaparinuxEnoxaparin
0.8 1.0 1.2
Non-inferiorityMargin = 1.185
P=0.002
Hazard Ratio
Fondaparinux better Enoxaparin better
Fondaparinux Substantially Reduces Major BleedingCompared with Enoxaparin
Days
Cu
mu
lati
ve H
azar
d
0 1 2 3 4 5 6 7 8 9
0.0
0.01
0.02
0.03
0.04HR 0.52
95% CI 0.44-0.61 P<<0.00001
Enoxaparin
Fondaparinux
Fondaparinux Reduces 30-Day all-cause Mortality Compared with Enoxaparin
Days
Cu
mu
lati
ve H
azar
d0.
00.
010.
020.
03
0 3 6 9 12 15 18 21 24 27 30
HR 0.83 95% CI 0.71-0.97
P=0.02
Enoxaparin
Fondaparinux
Fondaparinux Superior to Enoxaparin for Efficacy at 6 Months
OASIS 5 Investigators. N Engl J Med. 2006;354:1464-76.
0.8 1.2
11.3%12.5%Death/MI/Stroke
12.3%13.2%Death/MI/RI
1.3%1.7%Stroke
6.3%6.6%MI
5.8%6.5%Death
10.5%11.4%Death/MI
0.06
0.05
0.05
0.04
0.007
P value
Fondaparinux better Enoxaparin better
Enoxaparin Fondaparinux Hazard Ratio
Hazard Ratio1
Net Clinical Benefit Favours Fondaparinux in Patients Undergoing PCI and Early PCI
Outcome Day 9Enox
N = 3072Fonda
N = 3105HR (95% CI) P value
Death, MI or Stroke 6.2 6.3 1.03 0.79
Major Bleeding 5.1 2.4 0.46 <0.00001
Death, MI, stroke, major bleeding
10.4 8.2 0.78 0.004
Mehta et al. JACC. 2006;abstract 821-5.
Death, MI or Stroke 5.4 5.3 0.98 0.89
Major Bleeding 4.9 2.3 0.48 0.0005
Death, MI, stroke, major bleeding
9.5 7.3 0.76 0.035
Early PCI<24 hours
Catheter Thrombus Virtually Eliminated After Protocol Amendment Allowing UFH to be Used for PCI
No UFH Prior to PCI UFH Prior to PCI
Enox(%)
Fonda(%)
HR (95% CI)
Enox(%)
Fonda(%)
HR(95% CI)
No. randomized 810 793 80 75
Death/MI/Stroke 60 (7.4) 57 (7.2) 0.97(0.68-1.40) 5 (6.3) 3 (4.0) 0.62
(0.15-2.61)
Major Bleed 35 (4.3) 26 (3.3) 0.75(0.45-1.25) 5 (6.2) 1 (1.3) 0.21
(0.02-1.79)
Catheter Thrombus 4 (0.5) 9 (1.1) 2.30(0.71-7.4) 0 1 (1.3)* --
Final 1758 patients randomized*represents 1 patient with low dose of UFH 5 IU/kg vs mean dose of 47 IU/kg
Mehta et al. JACC. 2006;abstract 821-5
Adding UFH to Fondaparinux for PCI is Safe and Preserves the Lower Bleeding with Fondaparinux vs Enoxaparin
Enox Fonda HR CI
No UFH post-Randomization
1.2
(n = 1277)
0.5
(n = 1313)
0.45 0.18-1.11
UFH or equivalent placebo mandated by protocol during PCI
1.1
(n = 1229)
0.4
n = 1279)
0.34 0.12-0.95
Open Label UFH 2.7
(n = 598)
1.3
(n = 543)
0.48 0.20-1.17
Overall 1.5
(n = 3104)
0.6
(n = 3135)
0.42 0.24-0.71
Yusuf S. et al. N Engl J Med. 2006; 354:2829.
Mean Dose of UFH for PCI Used in OASIS 5: 47 IU/Kg
OASIS 5: Using UFH for PCI Reduces Angiographic Complications with Enoxaparin without Increasing Bleeding
Mehta et al. Presented at WCC/ESC Hotline Session, Barcelona, 2006
RR 0.4295% CI 0.26-0.65
P <0.0001
RR 0.9695% CI 0.73-1.26
P = 0.78
RR 0.3995% CI 0.22-0.67
P <0.0001
RR 1.4095% CI 1.00-1.97
P = 0.048
Major Bleeding 48 hours after PCI
Abrupt/threatened abrupt closure
N = 1277 N = 1275 N =
1633
N = 1648
N = 1275
RR 0.94 95% CI 0.63-1.33
P=0.62
RR 0.70 95% CI 0.51-0.96
P=0.026
3.83.4
6.2
4.3
1.3
5.9 6
0
2
4
5
6
7
% E
ven
ts
Fonda FondaEnox alone
UFH+
Enox
Fonda FondaEnoxalone
UFH+
Enox1
N= 1633
N = 1648
1.6
3
N = 1277
N = 1633
N = 1648
N = 1277
N = 1275
OASIS 5: Fondaparinux Reduces Major Bleeding with or without Concomittant Use of IV GP IIb/IIIa Inhibitors
HR 0.63P<0.0001
HR 0.60P = 0.0001
N = 16448 N = 3630
Fondaparinux Superior to Enoxaparin Even with Very Short Durations of Treatment
HR 0.69P = 0.001
HR 0.55P <0.0001
HR 0.67P = 0.018
N = 5581 N = 8712 N = 5785
How to Transition Patients Initiated on Fonda to the Cath Lab
• Treat with ASA, Clopidogrel, Statin and Fondaparinux +/- IV nitro in the ER
• Proceed to Cath Lab as usual*
• If PCI needed, give bivalirudin or UFH (dose 50 IU/kg) +/- IIb/IIIa
• Post procedure, follow usual practice for sheath removal. Immediate removal if closure device or radial and 6 hours after last fonda sc dose if no closure device used
*May perform cath>6 hours after last sc dose if this was center’s usual practice with using LMWH
ACUITY Study Design – Patient Flow
UFH/Enox+ GP IIb/IIIa(N = 4,603)
UFH/Enox+ GP IIb/IIIa(N = 4,603)
Bivalirudin+ GP IIb/IIIa(N = 4,604)
Bivalirudin+ GP IIb/IIIa(N = 4,604)
BivalirudinAlone
(N = 4,612)
BivalirudinAlone
(N = 4,612)
Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategyModerate-high risk unstable angina or NSTEMI undergoing an invasive strategy
GPI upstream (N = 2294)
GPI CCL for PCI (N = 2309)
GPI upstream (N = 2311)
GPI CCL for PCI (N = 2293)
Aspirin in allClopidogrel
dosing and timingper local practice
Aspirin in allClopidogrel
dosing and timingper local practice
* Stratified by pre-angiography thienopyridine use or administration* Stratified by pre-angiography thienopyridine use or administration
Moderate-high risk
ACS
Moderate-high risk
ACS
Stone GW, et al. N Engl J Med. 2006 Nov 23;355(21):2203-16.
R*
ACUITY Primary Endpoint: Lower Bleeding with BIV vs Hep+IIb/IIIa
PSup = 0.015 PSup = 0.32 PSup <0.0001
Stone GW, et al. N Engl J Med. 2006;355:2203-16.
Thienopyridine Exposed* Not Thienopyridine Exposed
ACUITY PCI: Influence of Thienopyridine Exposure – PCI pts
RR [95%CI]
0.81 (0.68-0.96)
RR [95%CI]
0.96 (0.77-1.20)
RR [95%CI]
0.50 (0.37-0.67) RR [95%CI]
1.07 (0.83-1.39)
RR [95%CI]
1.37 (1.00-1.88)
RR [95%CI]
0.61 (0.39-0.97)
Interaction P values = 0.17, 0.19 and 0.65 respectivelyInteraction P values = 0.17, 0.19 and 0.65 respectively
*Thienopyridine at any time, any dose, up to time of PCI
RR [95%CI]
1.00 [0.67-1.49]RR [95%CI]
0.53 [0.34-0.83]
RR [95%CI]
0.84 [0.62-0.1.13]
Troponin+ PCI pts, Thienopyridine use prior to PCIGPI started after angiography but before PCI (N=1358)
ACUITY PCI: “ISAR-REACT-2 Like” Patients
• Anticoagulation is recommended for all patients in addition to antiplatelet therapy (I-A)
• Anticoagulation should be selected according to the risk of both ischaemic and bleeding events (I-B)
• Several anticoagulants are available, namely UFH
Evidence-Based Risk Stratification to Target Therapies in UA/NSTEMI
Recurrent Ischemia or high risk stress test
Aspirin, Clopidogrel, Fondaparinux (Class 1A)
β-blocker, Nitrates
Higher Risk +Troponin, ST s, TRS 3, Recurrent Ischemia, CHF,Prior Revascularization
Lower Risk– ECG, – Markers, TRS 0-2
Invasive StrategyConservative
Strategy
PCIBivalirudin or
UFH (+IV GP IIb/IIIa)UFH dose 50 IU/kg
No PCIMedical Rx or CABG
(hold fonda and clopidogrel)
Summary
• Fondaparinux reduces bleeding and mortality in patients with NSTEACS compared with enoxaparin including those undergoing early intervention (<24 hours)
• Bivalirudin with a thienopyridine reduces bleeding compared with UFH/enox + GPI
• Fondaparinux and bivalirudin are likely to be complementary—fondaparinux for initial upstream therapy of ACS and bivalirudin in place of UFH+GP IIb/IIIa in those undergoing PCI
• This strategy has the potential to lead to the lowest rates of bleeding (and enhanced efficacy) we have ever seen in ACS
