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THE MICHELANGELO OASIS 5 PROGRAM
MichelAngelo : The Creation of Man (Fragment of the Sistine Chapel ceiling- Detail) (1511-12)
Key Steps in Coagulation Pathway
Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin2
Intrinsic pathway Extrinsic pathway
1. Rosenberg RD, Aird WC. N Engl J Med 1999;340(20):1555–64.2. Wessler S, Yin ET. Thrombo Diath Haemorrh 1974;32(1):71–8.
Intrinsic pathway
1
50
Xa X
II
FibrinFibrinogen
Clot
Xa
Va
PL
Ca2+
IIa
VIIIa
Ca2+
PL
IXa
IIaIIaIIII
FibrinogenFibrinogen Fibrin clotFibrin clot
Extrinsic Extrinsic pathwaypathway
IntrinsicIntrinsicpathwaypathway
AT XaXaAT AT
Fondaparinux Fondaparinux
XaXa
Antithrombin
Fondaparinux: A Synthetic Factor Xa Inhibitor
Adapted with permission from Adapted with permission from TurpieTurpie AGG AGG et al. et al. NN EnEnglgl J Med.J Med. 2001;3442001;344:619.:619.
THROMBIN
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 Overall Efficacy of FondaparinuxFondaparinux vsvsEnoxaparinEnoxaparin in VTE Prevention: Metain VTE Prevention: Meta--analysisanalysis
Turpie et. al. Arch Intern Med 2002: 162: 1833-40
Patients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment Δ, 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 markerscardiac markers
Fondaparinux2.5 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, planned Cath/PCI as per
local practice
ASA, Clop, GP ASA, Clop, GP IIb/IIIaIIb/IIIa, , planned planned CathCath/PCI as per /PCI as per
local practicelocal practice
RandomizeRandomize
Enoxaparin1 mg/kg sc twice daily
EnoxaparinEnoxaparin1 mg/kg sc twice daily1 mg/kg sc twice daily
Primary: Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 daysRisk benefit: Death, MI, refractory ischemia, major bleeds 9 days
Secondary: Above & each component separately at day 30 & 6 monthsHypothesis: 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 daysDeath, MI, refractory ischemia, major bleeds 9 days
SecondarySecondary:: Above & each component Above & each component separatelyseparately at day 30 & 6 monthsat day 30 & 6 monthsHypothesisHypothesis:: First test nonFirst test non--inferiority, then test superiorityinferiority, then test superiority
Outcomes
PCI< 6 hPCI< 6 h,, No additional UFHNo additional UFHPCI >6 hPCI >6 h,, IV UFHIV UFHWith With IIb/IIIaIIb/IIIa 65 U/kg65 U/kgWithout Without IIb/IIIaIIb/IIIa 100 U/kg100 U/kg
PCI <6 hPCI <6 h:: IV Fonda 2.5 mgIV Fonda 2.5 mgwithout without IIb/IIIaIIb/IIIa, 0 with , 0 with IIb/IIIaIIb/IIIaPCI> 6 hPCI> 6 h:: IV Fonda 2.5 mg withIV Fonda 2.5 mg withand 5.0 mg without and 5.0 mg without IIb/IIIaIIb/IIIa
ExcludeAge < 21Any contra-ind to EnoxHem stroke< 12 mo.Creat> 3 mg/dL/265 umol/L
N=20,000
20,078 Patients from 576 Centres in 41 Countries
Argentina
Australia
Austria
Belgium
Brazil
Canada
Chile
China
Croatia
Czech Republic
Denmark
Estonia
Finland
France
Germany
Greece
Hong Kong
Hungary
India
Italy
Latvia
Lithuania
Malaysia
Mexico
Netherlands
Norway
Poland
Portugal
Russia
Singapore
Slovakia
Slovenia
South Africa
South Korea
Spain
Sweden
Switzerland
Taiwan
Ukraine
United Kingdom
United States
Completeness of Follow-up (20,078 patients)
12 patients (< 0.1%)Lost to Follow--Up at 9d
99.98%30 day rec’d
100%Hospital Discharge rec’d
Coordinating Center: Population Health Research Institute, McMaster UniversityHamilton, Canada
Baseline Characteristics
54.154.6Current or Former Smoker
25.625.0Diabetic
67.467.1Hypertension
25.725.7Prior MI
13.913.8Prior Heart Failure
54.454.9Suspected MI w/o ST elevation
62.061.4Male
1005710021No. Rand.
80.679.8ECG with ischemia
24.625.1T wave inversion (>3 mm)
51.750.3ST depression 1mm
70.370.5Troponin or CKMB > ULN
Fonda (%)Enox (%)Outcome
Therapies During Initial Hospitalization
41.741.0During PCI
78.577.5Statins
74.976.1ACE Inhibitors/ARB
26.926.8Calcium Channel Blockers
87.287.7Beta-blockers
67.667.2Clopididogrel/Ticlopidine
18.617.6GPIIb/IIIa Inhib
97.597.5ASA
1005710021No. Rand.
Fonda (%)Enox (%)
70% of patients recruited from centers with cath labs
Days of Study Treatment Compliance and Duration
5.4 (2.4)5.2 (2.3)
FondaEnox
Mean No. of days of therapy (SD)
% who received > 1 dose of drug
99.2%99.4%
RESULTS
Primary Efficacy OutcomeDeath/MI/RI at Day 9
0.8 1 1.2
1.01 1.130.90
P-Value for Non-Inferiority=0.007
Non-inferiorityMargin=1.185
Hazard RatioFonda Better Enox Better
Efficacy Outcomes at Day 9
5.8%5.7%Death/MI/RI
1.9%1.9%Refract Isch
2.6%2.7%MI
1.8%1.9%Death
4.1%4.1%Death/MI
FondaEnox
0.8 1 1.2
Non-inferiorityMargin=1.185
Hazard RatioFonda Better Enox Better
Death/MI/RI: Day 9
Days
Cum
ulat
ive
Haz
ard
0.0
0.01
0.02
0.03
0.04
0.05
0.06
0 1 2 3 4 5 6 7 8 9
Enoxaparin
Fondaparinux
HR 1.01 95% CI 0.90-1.13
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<0.001
Enoxaparin
Fondaparinux
Categories of Major Bleedsat 9 Days
164282Transfusion 2 units
152315Hb 3 g/dL
<0.001
P
217 (2.2%)412 (4.1%)Total Bleeding
936Retroperitoneal
1005710021No. Rand.
4073Surgery req’d to stop bleed
77Intracranial
Fonda(No. Pts)
Enox(No. Pts)
No. of Patients Receiving Transfusions
1005710021No. Randomized
338 (3.4%)
134 (1.3%)
57 (0.6%)
133 (1.3%)
14 (0.1%)
FondaNo. (%)
433 (4.3%)Any transfusion
166 (1.7%)4+ Units
56 (0.6%)3 Units
183 (1.9%)2 Units
24 (0.2%)1 Unit
EnoxNo. (%)
Efficacy-Safety BalanceDeath/MI/RI/Maj Bleed: Day 9
Days
Cu
mu
lati
ve H
azar
d
0.0
0.02
0.04
0.06
0.08
0 1 2 3 4 5 6 7 8 9
HR 0.82 HR 0.81 95% CI 0.7495% CI 0.73 --0.900.89
P<0.001
Enoxaparin
Fondaparinux
Efficacy Outcomes at Day 30
Death/MI/Stroke
Strokes
8.0%8.6%Death/MI/RI
2.2%2.2%RI
3.9%4.1%MI
2.9%3.5%Death
6.2%6.8%Death/MI
FondaEnox
P=0.02
P=0.07
0.8 1 1.2
P=0.002
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 0.7195% CI 0.71--0.970.97
P=0.02
Enoxaparin
Fondaparinux
Major Bleeding: Day 30
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0.05
0 3 6 9 12 15 18 21 24 27 30
HR 0.63 HR 0.62 95% CI 0.5595% CI 0.54 --0.730.72
P<0.001
Enoxaparin
Fondaparinux
Death/MI/RI/Major Bleeds:Day 30
Days
Cu
mu
lati
ve H
azar
d
0.0
0.02
0.04
0.06
0.08
0.10
0.12
0 3 6 9 12 15 18 21 24 27 30
HR 0.83HR 0.8295% CI 0.7695% CI 0.75 --0.900.89
P<0.001
Enoxaparin
Fondaparinux
Efficacy at 6 Months
0.8 1 1.2
11.1%12.5%Death/MI/Stroke
12.3%13.2%Death/MI/RI
1.3%1.7%Strokes
6.3%6.6%MI
5.8%6.5%Death
10.5%11.4%Death/MI
FondaEnox
0.06
0.05
0.05
0.04
0.007
P value
Death or MI: 6 Months
Days
Cu
mu
lati
ve H
azar
d
0.0
0.02
0.04
0.06
0.08
0.10
0.12
0 20 40 60 80 100 120 140 160 180
HR 0.91HR 0.9295% CI 0.8495% CI 0.84--1.00
P=0.05
Enoxaparin
Fondaparinux
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 0.7995% CI 0.80 --1.00
P=0.05
Enoxaparin
Fondaparinux
Major Bleeding: 6 Months
Days
Cum
ulat
ive
Haz
ard
0.0
0.01
0.02
0.03
0.04
0.05
0.06
0 20 40 60 80 100 120 140 160 180
HR 0.72HR 0.7295% CI 0.64 --0.820.82
P<0.001
Enoxaparin
Fondaparinux
Death, MI, RI, Major Bleedingat 6 Months
Days
Cu
mu
lati
ve H
azar
d0.
00.
050.
100.
15
0 20 40 60 80 100 120 140 160 180
Enoxaparin
Fondaparinux
HR 0.87HR 0.8695% CI 0.8195% CI 0.81--0.930.93
P<0.001
S u b g ro u p A n a ly s is o f E ff ic a c yS u b g ro u p A n a ly s is o f E ff ic a c y
S u b g r o u p A n a ly s is o f S a fe tyS u b g r o u p A n a ly s is o f S a fe ty
Patients Undergoing PCI withinPatients Undergoing PCI withinthe First 8 Days of Randomizationthe First 8 Days of Randomization
2348 (74.9%)2317 (74.6%)Thienopyridines
1308 (41.7%)1273 (41.0%)GP Iib/IIIa inhibitor
651 (20.8%)1724 (55.5%)Unfractionated heparin
No. of events (% of patients)Concomitant antithrombotic drugs
Fondaparinux
(n=3135)
Enoxaparin
(n=3104)
Patients Undergoing PCI withinPatients Undergoing PCI withinthe First 8 Days of Randomizationthe First 8 Days of Randomization
0.0013.59 (1.64-7.84)29 (0.9%)8 (0.4%)All catheter-related thrombi
0.082.99 (0.81-11.04)9 (0.3%)3 (0.1%)Catheter-related thrombus not resulting in clinical complications
1.16 (0.94-1.42)188 (6.0%)161 (5.2%)Abrupt closure, new thrombus with reduced flow, dissection, or no reflow
0.211.11 (0.94-1.29)299 (9.5%)268 (8.6%)Any complication
PCI-related coronary complication
0.36 (0.26-0.49)50 (1.6%)138 (4.4%)Large hematoma
0.63 (0.40-0.98)31 (1.0%)49 (1.6%)Pseudoaneurysm
<0.0010.41 (0.33-0.51)103 (3.3%)251 (8.1%)Any complication
No. of events (% of patients)Complications involving the vascular access site
P Value
Relative Risk
(95% CI)Fondaparinux
(n=3135)Enoxaparin
(n=3104)
Patients Undergoing PCI withinPatients Undergoing PCI withinthe First 8 Days of Randomizationthe First 8 Days of Randomization
0.0030.79 (0.67-0.92)255 (8.2%)321 (10.3%)Death, MI, stroke or major bleeding
1.03 (0.87-1.25)198 (6.3%)190 (6.1%)Death, MI or stroke
0.99 (0.46-2.13)13 (0.4%)13 (0.4%)Stroke
0.45 (0.34-0.59)72 (2.3%)158 (5.1%)Major Bleeding
<0.0010.81 (0.73-0.90)521 (16.6%)638 (20.6%)Any procedural complication, major bleeding, death, MI or stroke
1.04 (0.84-1.28)161 (5.1%)154 (5.0%)MI
0.96 (0.62-1.51)37 (1.2%)38 (1.2%)Death
No. of events (% of patients)Clinical Events at 9 days
P Value
Relative Risk
(95% CI)Fondaparinux
(n=3135)Enoxaparin
(n=3104)
Patients Undergoing PCI withinPatients Undergoing PCI withinthe First 8 Days of Randomizationthe First 8 Days of Randomization
0.0040.81 (0.70-0.93)297 (9.5%)364 (11.7%)Death, MI, stroke or major bleeding
1.00 (0.84-1.20)231 (7.4%)228 (7.3%)Death, MI or stroke
0.51 (0.40-0.66)87 (2.8%)169 (5.4%)Major Bleeding
0.81 (0.44-1.51)18 (0.6%)22 (0.7%)Stroke
1.05 (0.86-1.29)179 (5.7%)169 (5.4%)MI
0.94 (0.67-1.33)62 (2.0%)65 (2.1%)Death
No. of events (% of patients)Clinical Events at 30 days
P Value
Relative Risk
(95% CI)Fondaparinux
(n=3135)Enoxaparin
(n=3104)
Conclusions1.1. Fondaparinux is nonFondaparinux is non--inferior compared with enoxaparin inferior compared with enoxaparin
at 9 days, with at 9 days, with substantiallysubstantially lower rates of important lower rates of important bleeds. bleeds. The net benefitThe net benefit--risk balance clearly favors risk balance clearly favors fondaparinuxfondaparinux..
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 reduction in mortality with fondaparinuxfondaparinux..
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 clear reduction in death, MI, and strokes with fondaparinuxfondaparinux
5.5. Consistent results are observed in those undergoing Consistent results are observed in those undergoing PCI (including early PCI)PCI (including early PCI) and in every other subgroup and in every other subgroup examined.examined.
Clinical Implications
THE OASIS 5 TRIAL CLEARLY DEMONSTRATES THAT FONDAPARINUX IS THE PREFERRED ANTICOAGULANT FOR TREATMENT OF ACS