michelangelo: organization to assess strategies in ischemic syndromes (oasis) 6 trial

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


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.


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%


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.

Content Distributed by Cardiosource.

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


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


Death/MI at 9 Days Death/MI at 9 Days (end of treatment)(end of treatment) No. of Events (%)



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


Death/MI at Study EndDeath/MI at Study End(3 or 6 months) (3 or 6 months)

No. of Events (%)



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


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.


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.


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


Bleeding Outcomes Bleeding Outcomes Severe Hemorrhage at 9 Days Severe Hemorrhage at 9 Days

No. of Events


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


Severe Hemorrhage by type of Severe Hemorrhage by type of reperfusion therapy at 180 Days reperfusion therapy at 180 Days

No. of Events


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


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


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


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


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


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


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


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


YES

(Stratum II)2.5 mg sc od


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.


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


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


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


michelangelo: organization to assess strategies in ischemic syndromes (oasis) 6 trial

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