Transcript OASIS 5 Results - Hamilton Health Sciences

THE MICHELANGELO OASIS 5 PROGRAM
MichelAngelo : The Creation of Man (Fragment of the Sistine Chapel ceiling- Detail) (1511-12)
Key Steps in Coagulation Pathway
Intrinsic pathway
Extrinsic pathway
IXa
1
VIIIa
Xa
PL
Ca2+
X
Inhibition of one molecule
of factor Xa can inhibit the
generation of 50 molecules
of thrombin2
Xa
Va
Ca2+
II
PL
IIa
50
Fibrin
Fibrinogen
Clot
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.
Overall Efficacy of Fondaparinux vs
Enoxaparin in VTE Prevention: Metaanalysis
Fondaparinux better
Ephesus
N = 1817
Enoxaparin better
58.5%
Pentathlon 2000
N = 1584
28.1%
Penthifra
N = 1250
61.6%
Pentamaks
N = 724
63.1%
Overall Odds
Reduction
P = 0.000000000000000001
55.3%
% odds reduction
-100 -80
-60
-40
-20
0
20
40
60
80
100
Overall odds reduction for proximal DVT = 57.4%
[CI: 72.3 - 35.6]; p = 10-6
Turpie et. al. Arch Intern Med 2002: 162: 1833-40
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)
Hospital Discharge rec’d
30 day rec’d
Lost to Follow--Up at 9d
Coordinating Center:
100%
99.98%
12 patients (< 0.1%)
Population Health Research Institute,
McMaster University
Hamilton, Canada
Baseline Characteristics
Outcome
Enox (%)
Fonda (%)
No. Rand.
10021
10057
Troponin or CKMB > ULN
70.5
70.3
ECG with ischemia
ST depression > 1mm
79.8
80.6
50.3
51.7
25.1
24.6
Male
61.4
62.0
Suspected MI w/o ST elevation
54.9
54.4
Prior Heart Failure
13.8
13.9
Prior MI
25.7
25.7
Hypertension
67.1
67.4
Diabetic
25.0
25.6
Current or Former Smoker
54.6
54.1
T wave inversion (>3 mm)
Therapies During Initial
Hospitalization
Enox (%)
Fonda (%)
10021
10057
ASA
97.5
97.5
GPIIb/IIIa Inhib
17.6
18.6
During PCI
41.0
41.7
Clopididogrel/Ticlopidine
67.2
67.6
Beta-blockers
87.7
87.2
Calcium Channel Blockers
26.8
26.9
ACE Inhibitors/ARB
76.1
74.9
Statins
77.5
78.5
No. Rand.
70% of patients recruited from centers with cath labs
Days of Study Treatment
Compliance and Duration
Enox
Fonda
% who received
> 1 dose of drug
99.4%
99.2%
Mean No. of days
of therapy (SD)
5.2 (2.3)
5.4 (2.4)
RESULTS
Primary Efficacy Outcome
Death/MI/RI at Day 9
Non-inferiority
Margin=1.185
1.01
0.90
1.13
P-Value for Non-Inferiority=0.007
0.8
1
Fonda Better
1.2
Enox Better
Hazard Ratio
Efficacy Outcomes at Day 9
Enox
Fonda
Death/MI/RI
5.7%
5.8%
Death/MI
4.1%
4.1%
Death
1.9%
1.8%
MI
2.7%
2.6%
Refract
Isch
1.9%
1.9%
Non-inferiority
Margin=1.185
0.8
Fonda Better
1
1.2
Enox Better
Hazard Ratio
0.01 0.02 0.03 0.04 0.05 0.06
HR 1.01
95% CI 0.90-1.13
Enoxaparin
Fondaparinux
0.0
Cumulative Hazard
Death/MI/RI: Day 9
0
1
2
3
4
5
Days
6
7
8
9
Enoxaparin
0.02
0.03
HR 0.52
95% CI 0.44-0.61
P<0.001
0.01
Fondaparinux
0.0
Cumulative Hazard
0.04
Major Bleeding: 9 Days
0
1
2
3
4
5
Days
6
7
8
9
Categories of Major Bleeds
at 9 Days
Enox
(No. Pts)
Fonda
(No. Pts)
10021
10057
412 (4.1%)
217 (2.2%)
Intracranial
7
7
Surgery req’d to stop bleed
73
40
Retroperitoneal
Hb  3 g/dL
36
9
315
152
Transfusion  2 units
282
164
No. Rand.
Total Bleeding
P
<0.001
No. of Patients
Receiving Transfusions
No. Randomized
1 Unit
2 Units
3 Units
4+ Units
Any transfusion
Enox
No. (%)
10021
24 (0.2%)
183 (1.9%)
56 (0.6%)
166 (1.7%)
433 (4.3%)
Fonda
No. (%)
10057
14 (0.1%)
133 (1.3%)
57 (0.6%)
134 (1.3%)
338 (3.4%)
Efficacy-Safety Balance
Death/MI/RI/Maj Bleed: Day 9
0.06
0.04
Fondaparinux
0.02
HR 0.81
0.82
95% CI 0.73
0.74-0.89
0.90
P<0.001
0.0
Cumulative Hazard
0.08
Enoxaparin
0
1
2
3
4
5
Days
6
7
8
9
Efficacy Outcomes at Day 30
Enox
Fonda
Death/MI/RI
8.6%
8.0%
Death/MI
6.8%
6.2%
P=0.07
Death
3.5%
2.9%
P=0.02
MI
4.1%
3.9%
RI
2.2%
2.2%
Strokes
P=0.002
Death/MI/Stroke
0.8
1
1.2
Mortality: Day 30
0.02
Fondaparinux
0.01
HR 0.83
95% CI 0.71-0.97
P=0.02
0.0
Cumulative Hazard
0.03
Enoxaparin
0
3
6
9
12
15
Days
18
21
24
27
30
0.05
Major Bleeding: Day 30
0.03
0.02
Fondaparinux
0.01
HR 0.62
0.63
95% CI 0.54
0.55-0.72
0.73
P<0.001
0.0
Cumulative Hazard
0.04
Enoxaparin
0
3
6
9
12
15
Days
18
21
24
27
30
0.08
0.10
Enoxaparin
0.06
Fondaparinux
0.02
0.04
HR 0.82
0.83
95% CI 0.75
0.76-0.89
0.90
P<0.001
0.0
Cumulative Hazard
0.12
Death/MI/RI/Major Bleeds:
Day 30
0
3
6
9
12
15
Days
18
21
24
27
30
Efficacy at 6 Months
Enox
Fonda
P value
Death/MI/RI
13.2%
12.3%
0.06
Death/MI
11.4%
10.5%
0.05
Death
6.5%
5.8%
0.05
MI
6.6%
6.3%
Strokes
1.7%
1.3%
0.04
Death/MI/Stroke 12.5%
11.1%
0.007
0.8
1
1.2
0.12
Death or MI: 6 Months
0.06
0.08
Fondaparinux
0.02
0.04
HR 0.92
0.91
95% CI 0.84-1.00
P=0.05
0.0
Cumulative Hazard
0.10
Enoxaparin
0
20
40
60
80
100
Days
120
140
160
180
Mortality at 6 Months
0.04
Fondaparinux
0.02
HR 0.89
95% CI 0.80
0.79- 1.00
P=0.05
0.0
Cumulative Hazard
0.06
Enoxaparin
0
20
40
60
80
100
Days
120
140
160
180
0.06
Major Bleeding: 6 Months
0.04
0.03
Fondaparinux
0.01
0.02
HR 0.72
95% CI 0.64 -0.82
P<0.001
0.0
Cumulative Hazard
0.05
Enoxaparin
0
20
40
60
80 Days100
120
140
160
180
Death, MI, RI, Major Bleeding
at 6 Months
0.15
0.10
Fondaparinux
0.05
HR 0.86
0.87
95% CI 0.81-0.93
P<0.001
0.0
Cumulative Hazard
Enoxaparin
0
20
40
60
80
100
Days
120
140
160
180
Subgroup Analysis of Efficacy
Subgroup Analysis of Safety
Patients
Undergoing
PCI
within
Patients Undergoing
PCI
within
the
First88Days
Daysofof
Randomization
the First
Randomization
Enoxaparin
(n=3104)
Concomitant antithrombotic drugs
Fondaparinux
(n=3135)
No. of events (% of patients)
Unfractionated heparin
1724 (55.5%)
651 (20.8%)
GP Iib/IIIa inhibitor
1273 (41.0%)
1308 (41.7%)
Thienopyridines
2317 (74.6%)
2348 (74.9%)
Patients
Undergoing
PCI
within
Patients Undergoing
PCI
within
the
First88Days
Daysofof
Randomization
the First
Randomization
Enoxaparin
(n=3104)
Complications involving
the vascular access site
Fondaparinux
(n=3135)
Relative Risk
(95% CI)
P
Value
<0.001
No. of events (% of patients)
Any complication
251 (8.1%)
103 (3.3%)
0.41 (0.33-0.51)
Pseudoaneurysm
49 (1.6%)
31 (1.0%)
0.63 (0.40-0.98)
Large hematoma
138 (4.4%)
50 (1.6%)
0.36 (0.26-0.49)
Any complication
268 (8.6%)
299 (9.5%)
1.11 (0.94-1.29)
Abrupt closure, new thrombus
with reduced flow, dissection,
or no reflow
161 (5.2%)
188 (6.0%)
1.16 (0.94-1.42)
Catheter-related thrombus not
resulting in clinical
complications
3 (0.1%)
9 (0.3%)
2.99 (0.81-11.04)
0.08
All catheter-related thrombi
8 (0.4%)
29 (0.9%)
3.59 (1.64-7.84)
0.001
PCI-related coronary
complication
0.21
Patients
Undergoing
PCI
within
Patients Undergoing
PCI
within
the
First88Days
Daysofof
Randomization
the First
Randomization
Enoxaparin
(n=3104)
Clinical Events at 9 days
Fondaparinux
(n=3135)
Relative Risk
(95% CI)
P
Value
No. of events (% of patients)
Death
38 (1.2%)
37 (1.2%)
0.96 (0.62-1.51)
MI
154 (5.0%)
161 (5.1%)
1.04 (0.84-1.28)
Stroke
13 (0.4%)
13 (0.4%)
0.99 (0.46-2.13)
Major Bleeding
158 (5.1%)
72 (2.3%)
0.45 (0.34-0.59)
Death, MI or stroke
190 (6.1%)
198 (6.3%)
1.03 (0.87-1.25)
Death, MI, stroke or major
bleeding
321 (10.3%)
255 (8.2%)
0.79 (0.67-0.92)
0.003
Any procedural complication,
major bleeding, death, MI or
stroke
638 (20.6%)
521 (16.6%)
0.81 (0.73-0.90)
<0.001
Patients
Undergoing
PCI
within
Patients Undergoing
PCI
within
the
First88Days
Daysofof
Randomization
the First
Randomization
Enoxaparin
(n=3104)
Clinical Events at 30 days
Fondaparinux
(n=3135)
Relative Risk
(95% CI)
P
Value
No. of events (% of patients)
Death
65 (2.1%)
62 (2.0%)
0.94 (0.67-1.33)
MI
169 (5.4%)
179 (5.7%)
1.05 (0.86-1.29)
Stroke
22 (0.7%)
18 (0.6%)
0.81 (0.44-1.51)
Major Bleeding
169 (5.4%)
87 (2.8%)
0.51 (0.40-0.66)
Death, MI or stroke
228 (7.3%)
231 (7.4%)
1.00 (0.84-1.20)
Death, MI, stroke or major
bleeding
364 (11.7%)
297 (9.5%)
0.81 (0.70-0.93)
0.004
Conclusions
1.
Fondaparinux is non-inferior compared with enoxaparin
at 9 days, with substantially lower rates of important
bleeds. The net benefit-risk balance clearly favors
fondaparinux.
2.
Bleeding increases the risk of death significantly.
3.
At one month and at 6 months there is a significant
reduction in mortality with fondaparinux.
4.
Strokes are also significantly reduced, so that there is a
clear reduction in death, MI, and strokes with
fondaparinux
5.
Consistent results are observed in those undergoing
PCI (including early PCI) and in every other subgroup
examined.
Clinical Implications
THE OASIS 5 TRIAL CLEARLY DEMONSTRATES
THAT FONDAPARINUX IS THE PREFERRED
ANTICOAGULANT FOR TREATMENT OF ACS