Download - Fondapa Mon
Factor Xa Inhibition Across the Spectrum of ACS:
A New Standard of Care
Dr. Ihab Suliman
Meta-analysis of UFH and LMWH vs Placebo in UA/NSTEMI
Eikelboom J. Lancet 2000;355:1936–42
Petersen, J. L. et al. JAMA 2004;292:89-96.
Intention-to-Treat Population: Efficacy End Points at 30 DaysEnoxaparin vs UFH in UA/NSTEMI
Petersen, J. L. et al. JAMA 2004;292:89-96.
Intention-to-Treat Population: Efficacy End Points at 30 DaysEnoxaparin vs UFH in UA/NSTEMI
C o p y r i g h t r e s t r i c t i o n s m a y a p p l y .
P e t e r s e n , J . L . e t a l . J A M A 2 0 0 4 ; 2 9 2 : 8 9 - 9 6 .
S a f e t y A n a l y s i s : M a j o r B l e e d i n g U p t o 7 D a y s A f t e r R a n d o m i z a t i o n
Summary of Evidence for UFH and LMWH in UA/NSTEMI
UFH or LMWH reduce death or MI compared with no anticoagulant
Enoxaparin is marginally superior to UFH for efficacy
Enoxaparin is associated with a non-significant trend toward increased bleeding vs UFH but is more convenient to use than UFH
Herbert JM et alHerbert JM et al. Cardiovasc Drug Rev. Cardiovasc Drug Rev. 1997;15:1. . 1997;15:1. van Boeckel CAA et alvan Boeckel CAA et al. Angew Chem, Int Ed. Angew Chem, Int Ed EngEngll. 1993;32:1671. . 1993;32:1671.
Once daily administration Highly selective for its target No risk of pathogen contamination Rapid onset (Cmax/2=25 min) Effects reversible with
administration of activated Factor VII (Novoseven®)
No liver metabolism No protein binding (other than AT) No reported cases of HIT No dose adjustment necessary in
elderly
Fondaparinux: A Synthetic Inhibitor of Factor Xa
IIa IIa IIII
FibrinogenFibrinogen Fibrin clotFibrin clot
Extrinsic Extrinsic pathwaypathway
IntrinsicIntrinsicpathwaypathway
AT XaXaAT AT
Fondaparinux Fondaparinux
XaXa
Antithrombin
Fondaparinux:Mechanism of Action
Turpie AGG Turpie AGG et al. Net al. N EnEngl J Med. 2001;344gl J Med. 2001;344:619.:619.
THROMBIN
Recycled
EphesusN = 1817
Pentathlon 2000N = 1584
PenthifraN = 1250
PentamaksN = 724
Overall Odds Reduction
% odds reduction
Fondaparinux better Enoxaparin better
-100 -80 -60 -40 -20 200 40 60 80 100
58.5%
28.1%
61.6%
63.1%
55.3%P = 0.000000000000000001
Overall odds reduction for proximal DVT = 57.4% [CI: 72.3 - 35.6]; p = 10-6
Overall Efficacy of Fondaparinux vs Overall Efficacy of Fondaparinux vs Enoxaparin in VTE Prevention: Meta-Enoxaparin in VTE Prevention: Meta-analysisanalysis
Turpie et. al. Arch Intern Med 2002: 162: 1833-40
Patients with NSTE ACS, Chest discomfort < 24 hoursPatients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment 2 of 3: Age>60, ST Segment ΔΔ, , cardiac markers cardiac markers
Patients with NSTE ACS, Chest discomfort < 24 hoursPatients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment 2 of 3: Age>60, ST Segment ΔΔ, , cardiac markers cardiac markers
FondaparinuxFondaparinux2.5 mg sc once daily2.5 mg sc once daily
FondaparinuxFondaparinux2.5 mg sc once daily2.5 mg sc once daily
Study Design: Randomized, Double Blind
ASA, Clop, GP IIb/IIIa, ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per planned Cath/PCI as per
local practicelocal practice
ASA, Clop, GP IIb/IIIa, ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per planned Cath/PCI as per
local practicelocal practice
RandomizeRandomize
EnoxaparinEnoxaparin1 mg/kg sc twice daily1 mg/kg sc twice daily
EnoxaparinEnoxaparin1 mg/kg sc twice daily1 mg/kg sc twice daily
Primary:Primary: EfficacyEfficacy:: Death, MI, refractory ischemiaDeath, MI, refractory ischemia at 9 days at 9 days
SafetySafety:: Major bleeding at 9 daysMajor bleeding at 9 daysRisk benefitRisk benefit:: Death, MI, refractory ischemia, major bleeds 9 days Death, MI, refractory ischemia, major bleeds 9 days
SecondarySecondary:: Above & each component Above & each component separatelyseparately at day 30 & 6 months at day 30 & 6 monthsHypothesisHypothesis:: First test non-inferiority, then test superiority First test non-inferiority, then test superiority
Primary:Primary: EfficacyEfficacy:: Death, MI, refractory ischemiaDeath, MI, refractory ischemia at 9 days at 9 days
SafetySafety:: Major bleeding at 9 daysMajor bleeding at 9 daysRisk benefitRisk benefit:: Death, MI, refractory ischemia, major bleeds 9 days Death, MI, refractory ischemia, major bleeds 9 days
SecondarySecondary:: Above & each component Above & each component separatelyseparately at day 30 & 6 months at day 30 & 6 monthsHypothesisHypothesis:: First test non-inferiority, then test superiority First test non-inferiority, then test superiority
Outcomes
PCI< 6 hPCI< 6 h,, No additional UFH No additional UFHPCI >6 hPCI >6 h,, IV UFH IV UFHWith IIb/IIIa 65 U/kgWith IIb/IIIa 65 U/kgWithout IIb/IIIa 100 U/kgWithout IIb/IIIa 100 U/kg
PCI <6 hPCI <6 h:: IV Fonda 2.5 mg IV Fonda 2.5 mgwithout IIb/IIIa, 0 with IIb/IIIawithout IIb/IIIa, 0 with IIb/IIIaPCI> 6 hPCI> 6 h:: IV Fonda 2.5 mg with IV Fonda 2.5 mg withand 5.0 mg without IIb/IIIa and 5.0 mg without IIb/IIIa
ExcludeAge < 21Any contra-ind to EnoxHem stroke< 12 mo.Creat> 3 mg/dL/265 umol/L
N=20,000
OASIS 5 Investigators. N Engl J Med 2006
Bleeding Definition – OASIS 5
Major bleeding - defined as clinically overt bleeding with at least one of the following:– fatal, – symptomatic intracranial haemorrhage, – retroperitoneal haemorrhage, – intraocular haemorrhage leading to significant vision loss – a decrease in haemoglobin of 3.0 g/dL (with each
blood transfusion unit counting for 1.0 g/dL of Hb) – requiring transfusion of two or more units of red blood
cells or equivalent of whole blood.
Minor bleeding - any clinically significant bleeding not meeting the definition of major and leading to interruption of study drug, surgical intervention or transfusion of 1 unit blood
OASIS 5 Investigators. N Engl J Med 2006
Procedures by 9 Days in Centers With or Without Cath Labs in OASIS-5
Cath Lab+ Cath Lab-
No. Centers 420 (73%) 156 (27%)
No. Patients 14,028 (70%) 6050 (30%)
Angiography 73.2% 27.7%
PCI 39.6% 12.5%
CABG 6.8% 1.8%
Revasc. 46.1% 14.1%
OASIS 5 Investigators. N Engl J Med 2006
Time from Rand to Cath
44.22
17.42
38.4
05
101520253035404550
<24 hrs 24-48 hrs >48
% o
f p
atie
nts
Death/MI/RI: Day 9
Days
Cu
mu
lativ
e H
aza
rd
0.0
0.0
10
.02
0.0
30
.04
0.0
50
.06
0 1 2 3 4 5 6 7 8 9
Enoxaparin
Fondaparinux
HR 1.01 95% CI 0.90-1.13
P for non-inf=0.007
OASIS 5 Investigators. N Engl J Med 2006
Major Bleeding: 9 Days
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0 1 2 3 4 5 6 7 8 9
HR 0.52 95% CI 0.44-0.61
P<<0.00001
Enoxaparin
Fondaparinux
OASIS 5 Investigators. N Engl J Med 2006
Categories of Major Bleeds at 9 Days
Enox(No. Pts)
Fonda(No. Pts)
P
No. Rand. 10021 10057
Major Bleeding 404 (4.1%) 215 (2.2%) <<0.0001
Fatal Bleeding 22 7 0.005
Intracranial 5 6
Surgery req’d to stop bleed 74 41 0.0001
Retroperitoneal 37 9 0.0001
Hb 3 g/dL 312 150 0.0001
Transfusion 2 units 275 162 0.0001
OASIS 5 Investigators. N Engl J Med 2006
Mortality: Day 30
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 HR 0.83 95% CI 0.71-0.9795% CI 0.71-0.97
P=0.02P=0.02
Enoxaparin
Fondaparinux
OASIS 5 Investigators. N Engl J Med 2006
Efficacy at 6 Months
0.8 1 1.2
Enox Fonda
Death/MI/RI 13.2% 12.3%
Death/MI 11.4% 10.5%
Death 6.5% 5.8%
MI 6.6% 6.3%
Strokes 1.7% 1.3%
Death/MI/Stroke 12.5% 11.3%
0.055
0.05
0.05
0.33
0.04
0.007
P value
OASIS 5 Investigators. N Engl J Med 2006
Mortality at 6 Months
Days
Cu
mu
lati
ve H
azar
d0.
00.
020.
040.
06
0 20 40 60 80 100 120 140 160 180
HR 0.89HR 0.8995% CI 0.80-1.00 95% CI 0.80-1.00
P=0.05P=0.05
Enoxaparin
Fondaparinux
OASIS 5 Investigators. N Engl J Med 2006
Relative Impact of MI, Refractory Ischemia or Bleeding on Mortality
Crude Odds Ratio for Death
(95% CI)
30 Days 30 to 180 Days
180 Days
Nonfatal MI 9.6 (7.7-12.0) 2.2 (1.5-3.3) 5.6 (4.6-6.7)
Refractory Ischemia
4.0 (2.9-5.6) 1.4 (0.8-2.3) 2.6 (2.0-3.5)
Major Bleeds 6.5 (5.1-8.2) 2.1 (1.4-3.0) 4.1 (3.3-5.0)
Minor Bleeds 3.0 (2.1-4.3) 1.5 (0.9-2.4) 2.2 (1.6-2.9)
OASIS 5 Investigators. N Engl J Med 2006
Relation Between Bleeding Reduction at
9 Days and Long Term Mortality
No. Deaths at 6 months
Patients with Enox Fonda Difference
No. Bleeds 528 518 -10
Minor Bleeds 31 13 -18
Major Bleeds 76 35 -41
Total: 635 566 -69
-59 (85.5%)
85.5% of difference in death at 6 months is explained by bleeding within the first 9 days
Clinical Events after PCI: Day 30
2.1
5.5 5.4
11.3
2
5.8
2.8
9.4
0
2
4
6
8
10
12
Death MI Major Bleeds Death, MI orMajor Bleed
Eve
nt
Rat
e (%
)
Enox (n=3089) Fonda (n=3118)
P<0.0001
P=0.01
P=0.68
P=0.60
OASIS 5 Investigators. N Engl J Med 2006
Coronary and Vascular Access Site Complications
Events at 30 days Enox(%)
Fonda(%)
HR (95% CI) P value
No. Rand. 3089 3118
Coronary--Any Complicatn 8.6 9.6 1.11 (0.95-1.30) 0.18
Abrupt Closure 1.1 1.5 1.33 (0.86-2.06) 0.20
Threatened Abrupt Closure
4.7 5.2 1.12 (0.90-1.39) 0.31
Vascular Access Site 8.1 3.3 0.40 (0.32-0.50) <<0.0001
Pseudo-aneurysm 1.6 1.0 0.63 (0.40-0.98) 0.039
Large Hematoma 4.4 1.6 0.35 (0.26-0.49) <<0.0001
OASIS 5 Investigators. N Engl J Med 2006
Catheter-Related Thrombus with Enoxaparin and Fondaparinux
Enoxaparin 8 cases total: 6 when PCI performed within 6 h of last enox
dose where no UFH was given Rate is 6/1431=0.42% In Enoxaparin patients receiving study UFH, there was 1
case. 1 case time of PCI not ascertainedFondaparinux 29 cases (UFH was not routinely given to fonda group) Rate is 29/3135=0.9% When open label UFH was used prior to PCI (5000 U
mean), only 1 case of catheter thrombus was reported
Mehta SR et al. ACC 2006
PCI Using Blinded Study Drug: Effect of UFH Before PCI
on Major Bleeding
23
1.82.4
0
2
4
6
8
10
Major Bleeds Major Bleeds
Po
st P
CI
even
ts u
p t
o 4
8 h
rs (
%)
Enox Fonda
No UFH Prior With UFH Prior
UFH Prior
Mehta SR et al. ACC 2006
Major Bleeding 48 hours after PCI According to Time From Last Enox Dose
3.5 3.5
1.4 1.3
0
0.5
1
1.5
2
2.5
3
3.5
4
<6 hours >6 hours
Eve
nt
Rat
e (%
)
Enox Fonda
RR 0.39P<0.00001
RR 0.36P<0.00001
Study Protocol
< 6 hours No UFH given in Enox group
>6 hours UFH given in Enox group
N=1431 N=1460 N=1425 N=1411
Mehta SR et al. ACC 2006
Effect of UFH on Enox PCI complications
Time of PCI from Last Enox Dose
Outcome < 6 hours
Enox alone
>6 hours
UFH Given
No. Rand. 1431 1427
Abrupt Closure 1.4 1.0
Threatened Abrupt Closure
6.4 3.2
No Reflow 1.5 0.8
Angio thrombus 2.5 1.1
Major Bleeding 3.6 3.6
Prior PCI 16.1 16.9
Mehta SR et al. ACC 2006
Vascular Access Site Complications, Large Hematomas and Pseudo-aneurysms
8.1
1.6
4.4
3.3
11.6
0123456789
Vasc Access SiteComplication
Pseudo-aneurysm Large Hematoma
Enox
Fonda
HR 0.41P<<0.0001
HR 0.63P=0.033
HR 0.36P<<0.0001
Mehta SR et al. ACC 2006
PCI-Related Complications and MACE (death, MI or stroke)
16
20.618.1
12.6
16.613.7
0
5
10
15
20
25
Any PCIComplication
Any PCIComplication or
MACE
Any PCIcomplication or
Major Bleed
Enox
FondaHR 0.79
P<<0.0001
HR 0.81P<0.0001 HR 0.75
P<<0.0001
Mehta SR et al. ACC 2006
Conclusions1.1. Fondaparinux is non-inferior compared with enoxaparin at Fondaparinux is non-inferior compared with enoxaparin at
9 days, with 9 days, with substantiallysubstantially lower rates of important bleeds. lower rates of important bleeds. The net benefit-risk balance clearly favors fondaparinux.The net benefit-risk balance clearly favors fondaparinux.
2.2. Bleeding increases the risk of death significantly. Bleeding increases the risk of death significantly.
3.3. At one month and at 6 months there is At one month and at 6 months there is a significant a significant reduction in mortality with fondaparinux.reduction in mortality with fondaparinux.
4.4. Strokes are also significantly reduced, so that there is Strokes are also significantly reduced, so that there is a a clear reduction in death, MI, and strokes with fondaparinuxclear reduction in death, MI, and strokes with fondaparinux
5.5. Consistent results are observed in those undergoing PCI Consistent results are observed in those undergoing PCI (including early PCI)(including early PCI) and in every other subgroup and in every other subgroup examined.examined.
Incidence of Major Bleeds with Enoxaparin in OASIS-5 is Consistent with Previous Trials
Enoxaparin Enox Fond Enox Fond
SYNERGY1
Day 9
ESSENCE2
Day 30
A to Z3
Day 30
Meta-analysis4
Day 7
OASIS 5
Day 9
OASIS 5
Day 9
OASIS 5
Day 30
OASIS 5
Day 30
TIMI major bleed
9.1% 3.0% 1.3% 0.7% 1.5% 1.0%
Major bleed 6.5% 4.7% 4.0% 2.1% 4.9% 3.1%
1. SYNERGY investigators JAMA 2004;2. Cohen JAMA 2004; 3. Blazing JAMA 2004; 4. Petersen JAMA 2004