baseline characteristics 54.154.6current or former smoker 25.625.0diabetic 67.467.1hypertension 25.7...

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