michelangelo: organization to assess strategies in ischemic syndromes (oasis) 6 trial
DESCRIPTION
MICHELANGELO: Organization to Assess Strategies in Ischemic Syndromes (OASIS) 6 Trial. Disclosure Funded by Organon, Sanofi-Aventis & GSK Mehta & Yusuf have rec’d grants and honoraria from above companies plus several others. Fondaparinux A Synthetic Factor Xa Inhibitor. - PowerPoint PPT PresentationTRANSCRIPT
MICHELANGELO: MICHELANGELO: Organization to Assess Strategies Organization to Assess Strategies
in Ischemic Syndromes in Ischemic Syndromes (OASIS) 6 Trial(OASIS) 6 Trial
Disclosure
Funded by Organon, Sanofi-Aventis & GSK
Mehta & Yusuf have rec’d grants and honoraria from above companies plus
several others.
Fondaparinux Fondaparinux A Synthetic Factor Xa InhibitorA Synthetic Factor Xa Inhibitor
Fondaparinux is an effective factor Xa inhibitor that is given in a once daily fixed dose (2.5 mg) without monitoring
For prevention of VTE it is twice as effective as enoxaparin
In UA/NSTEMI it halves the risk of severe and fatal bleeds compared to enoxaparin, resulting in lower mortality, MI and strokes over long term follow-up
The role of current antithrombotics in STEMI is unclear and there are concerns about increased bleeding and ICH
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
12,000 Patients with STEMI < 12 h of symptom onsetInclusion: ST 2 mm prec leads or 1 mm limb leads
Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo.
12,000 Patients with STEMI < 12 h of symptom onsetInclusion: ST 2 mm prec leads or 1 mm limb leads
Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo.
UFH UFH notnot indicated indicatedUFH UFH notnot indicated indicated
Study Design: Randomized, Double Study Design: Randomized, Double Blind, Double DummyBlind, Double Dummy
Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)
StratificationStratificationStratificationStratification
UFH indicatedUFH indicatedUFH indicatedUFH indicated
Randomization Randomization
Fondaparinux2.5 mg Placebo
Fondaparinux2.5 mg UFH
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
ObjectivesObjectivesPrimary
To determine whether fondaparinux is superior to usual care (UFH/placebo) in patients with STEMI:
Primary Efficacy Outcome: Death or MI at 30 days
Primary Safety Outcome: Severe bleeding (TIMI Major) Balance of Efficacy and Safety: Death, MI, severe bleeds
SecondarySame outcomes and individual components at 9 days and at the end of follow-up (90-180) days.
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Data Management and Follow-upData Management and Follow-up
12,092 patients from 447 centers in 41 countries recruited from Sept 2003 to Sept 2005.
Data were managed independently by the Population Health Research Institute, McMaster University, Hamilton, Canada
Trial was designed and overseen by an international steering committee
Final follow-up in Jan 2006.
Complete follow-up in 99.9%
Clean data in 99.99%
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
Baseline Characteristics and Baseline Characteristics and Medications in HospitalMedications in Hospital
Control (%) n = 6056
Fonda (%)n = 6036
Age 61.5 61.6
Hrs from pain to entry (median ) 4.8 4.8
No reperfusion therapy 23.3 24.3
Thrombolytic therapy 45.3 44.3
Primary PCI 31.4 31.2
ASA 96.4 96.8
Clopidogrel/Ticlopidine 58.5 57.7
ACE-Inhibitor/ARB 80.0 79.4
Beta Blockers 83.8 84.4
Lipid Lowering Agents 74.8 74.5This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology.
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OASIS 6OASIS 6
Results
Primary Efficacy OutcomePrimary Efficacy OutcomeDeath/MI at 30 Days Death/MI at 30 Days
No. of Events (%)
Control Fonda HR 95% CI P
No. of Patients 6056 6036
Death or Re-MI 11.2 9.7 0.86 0.77-0.96 0.008
Death 8.9 7.8 0.87 0.77-0.98 0.026
Reinfarction 3.0 2.5 0.81 0.65-1.01 0.057
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
Primary Efficacy OutcomePrimary Efficacy OutcomeDeath/MI at 30 Days Death/MI at 30 Days
Days
Cum
ulat
ive
Haz
ard
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
UFH/Placebo
Fondaparinux
HR 0.86 95% CI 0.77-0.96
P=0.008
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
Death/MI at 9 Days Death/MI at 9 Days (end of treatment)(end of treatment) No. of Events (%)
Control Fonda HR 95% CI P
No. of Patients 6056 6036
Death or Re-MI 8.9 7.4 0.83 0.73-0.94 0.003
Death 7.0 6.1 0.87 0.75-1.00 0.043
Reinfarction 2.3 1.6 0.67 0.52-0.88 0.004
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
Death/MI at Study EndDeath/MI at Study End(3 or 6 months) (3 or 6 months)
No. of Events (%)
Control Fonda HR 95% CI P
No. of Patients 6056 6036
Death or Re-MI 14.8 13.4 0.88 0.79-0.97 0.008
Death 11.6 10.5 0.88 0.79-0.99 0.029
Reinfarction 4.6 3.8 0.81 0.67-0.97 0.026
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
Death at Study End Death at Study End (3 or 6 months)(3 or 6 months)
Days
Cum
ulat
ive
Haz
ard
0.0
0.02
0.04
0.06
0.08
0.10
0.12
0 18 36 54 72 90 108 126 144 162 180
UFH/Placebo
Fondaparinux
HR 0.88 95% CI 0.79-0.99
P=0.029
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology.
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Efficacy of Fondaparinux by StrataEfficacy of Fondaparinux by Strataon Death/MI at Study End on Death/MI at Study End
No. of Events (%)
Control Fonda HR 95% CI
Stratum I (n = 5658)
(Fonda vs. Placebo)
17.3 15.9 0.87 0.76-0.99
Stratum II (n = 6434)
(Fonda vs. UFH)
12.7 11.2 0.88 0.76-1.02
Interaction P=0.88This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology.
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Death/ReMI in Stratum II at Study EndDeath/ReMI in Stratum II at Study EndPrimary PCI vs. no Primary PCIPrimary PCI vs. no Primary PCI
No. of Events (%)
UFH Fonda HR 95% CI P Interactn
Death or Reinfarction
No 1o PCI (n = 2666) 19.0 14.9 0.77 0.64-0.93 0.008
1o PCI (n = 3772) 8.2 8.5 1.06 0.84-1.33 0.614 0.037
Death
No 1o PCI 15.1 11.9 0.79 0.64-0.97 0.026
1o PCI 5.9 6.1 1.04 0.79-1.36 0.787 0.113
Reinfarction
No 1o PCI 6.5 4.0 0.61 0.43-0.88 0.009
1o PCI 3.2 3.2 1.01 0.69-1.48 0.951 0.061
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
Bleeding Outcomes Bleeding Outcomes Severe Hemorrhage at 9 Days Severe Hemorrhage at 9 Days
No. of Events
Control Fonda HR 95% CI P
Severe Hemorrhage 79 61 0.77 0.55-1.08 0.13
Fatal 49 35 0.72 0.47-1.10 0.13
ICH 10 11 1.10 0.47-2.60 0.82
Retroperitoneal 2 0 - - -
Cardiac Tamponade 48 28 0.59 0.37-0.93 0.02
Hg drop ≥ 5 g/dL 17 19 1.12 0.58-2.15 0.74
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
Severe Hemorrhage by type of Severe Hemorrhage by type of reperfusion therapy at 180 Days reperfusion therapy at 180 Days
No. of Events
Control Fonda HR 95% CI P
None 1.8% 1.6% 0.84 0.47-1.50 0.55
Thrombolytics 2.3% 1.6% 0.66 0.44-0.98 0.04
Primary PCI 1.0% 1.2% 1.18 0.63-2.22 0.60
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
Days
Cum
ulat
ive
Haz
ard
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
UFH/Placebo
Fondaparinux
Death/MI/Severe Hemorrhage at Day 30
HR 0.86
95% CI 0.77-0.95
P=0.005
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
Pre-Specified Subgroup AnalysesPre-Specified Subgroup Analyses
0.5 0.7 0.8 1.0 1.2 1.4 1.6 2.0
UFH/Plac better Hazard Ratio
Overall
None
Thrombolytic
Primary PCI
< 112
>=112
12092
2867
5436
3789
5958
6134
11.2%
15.1
13.6
4.9
4.3
18.0
9.7%
12.2
10.9
6.0
4.6
14.5
0.04
0.03
Initial Reperfusion Rx
GRACE Risk Score
N UFH/Placebo
Death or MI at 30 days
FondaInteraction
P value
Fonda better This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
Death and Net Clinical Benefit at Death and Net Clinical Benefit at Study EndStudy End
Death Death/MI/Stroke/Severe Hemorrhage
HR(95% CI)
P HR(95% CI)
P
No Reperfusion
0.84(0.69-1.01)
0.06 0.81(0.69-0.96)
0.016
Thrombolytic 0.85(0.73-0.99)
0.04 0.83(0.73-0.95)
0.007
1o PCI 1.09(0.83-1.44)
0.52 1.12(0.90-1.39)
0.29
Overall 0.88(0.79-0.99)
0.029 0.88(0.80-0.97)
0.009
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
OASIS 6 Conclusions:OASIS 6 Conclusions:
1. Fondaparinux significantly reduces mortality and re-MI in STEMI without increasing bleeding compared to placebo or UFH.
2. Benefits emerge at 9 days and are sustained to 180 days.
3. In primary PCI, there was no benefit with fondaparinux.
4. The benefits are marked in those receiving no reperfusion therapy and those receiving thrombolytics (21% RRR at 30 days), with lower severe bleeding.
5. Mortality is significantly reduced
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
Number of Events Prevented byNumber of Events Prevented by Treating 1000 patients with Treating 1000 patients with Fondaparinux vs Usual CareFondaparinux vs Usual Care
Type of Event Overall No reperfusion therapy
Thrombolytic therapy
Death 11 25 15
MI 8 17 9
Strokes 2 6 1
Death/MI/Strokes 16 38 20
Severe bleeds 3 2 7
Death/MI/Strokes/ Severe Bleeds
16 39 21
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OASIS 5 (NSTE ACS)OASIS 5 (NSTE ACS)Mortality Day 30Mortality 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=0.022P=0.022
Enoxaparin
Fondaparinux
Published on-line in N Engl J Med March 14, 2006
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
OASIS-6: Committees/Project OfficeOASIS-6: Committees/Project Office
Operations Committee: J.P Bassand, A. Budaj, S. Chrolavicius (Proj Manager), K.A.A. Fox (Co-Chair), C. Granger,
C. Joyner (Chair, Adj Comm), S.R. Mehta (Proj Director), R.J. Peters, L. Wallentin, S. Yusuf (Chair & PI)
Steering Committee: National Coordinators + Sponsors
Sponsors: I. Bobbink, T.Lensing (Organon)A. Moryusef, R. Cariou, A. Denys (Sanofi-Aventis) S. Laing, L.Macartney S. Okada, N. Zariffa (GSK)
Statisticians: R. Afzal, J. Pogue
Project Office: N. Barr, S. Boccalon, K. Chrysler*, B. Cracknell, A. Djuric*, C. Easton, T. Gracie, C. Horsman*, T. Hoskin, B. Jedrzejowski,
M. Lawrence, B. Meeks, R. Napoleoni*, M. Smiley, C. Stevens, J. Willcox** former
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
OASIS-6 slides are available at www.phri.ca/oasis6
OASIS 6OASIS 6
For Discussion
OASIS-6 Study Drug RegimenOASIS-6 Study Drug RegimenStratum I and II (no Primary PCI)Stratum I and II (no Primary PCI)
Indication for UFH
Fondaparinux
Regimen
Control
Regimen NO
(Stratum I)
2.5 mg sc od
x 8 days (1st dose IV)
Placebo sc od
x 8 days (1st dose IV)
YES
(Stratum II)2.5 mg sc od
x 8 days (1st dose IV)
UFH bolus 60 IU/kg
(max 4000 IU) + IV
Infusion 12 IU/kg/hr x 48 hrs
For Primary PCI, doses of fondaparinux and UFH were adjusted for use of GP IIb/IIIa antagonists and pre-randomization UFH
For PCI after the index event, UFH was used for PCIThis presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology.
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Effect of Using UFH Prior to PCI on Catheter Effect of Using UFH Prior to PCI on Catheter Thrombus, Death/MI and BleedingThrombus, Death/MI and Bleeding
Primary PCI PCI After Rand*
No UFH Prior UFH Prior UFH by Protocol
# of Events UFH
N=1652
Fonda
N=1641
UFH
N=251
Fonda
N=245
UFH
N=226
Fonda
N=231
Catheter Thrombus
0 19 0 2 0 0(1)**
Death/MI 30 d 84 106 9 8 33 31
Major Bleed 31 41 4 5 11 10
*includes rescue PCI, routine PCI, and PCI for recurrent ischemia
Only ONE case of catheter thrombus was associated a clinical event
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
Primary PCI Results:Primary PCI Results:Death/MI in 1-3 days and 4-9 daysDeath/MI in 1-3 days and 4-9 days
2.22
2.8
1.4
0
0.5
1
1.5
2
2.5
3
Day 1-3 Day 4-9
UFHFonda
HR 0.6895% CI 0.41-1.13
HR 1.3095% CI 0.87-1.96
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.
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
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 0.53 95% CI 0.45-0.62
P<<0.00001
Enoxaparin
Fondaparinux
OASIS 5: Efficacy and Major Bleeding at Day 9
Death/MI/Ref Ischemia Major Bleeding
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.