VBWG OASIS-5 The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes trial.

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OASIS-5OASIS-5

The Fifth The Fifth OOrganization to rganization to AAssess ssess SStrategies trategies in Acute in Acute IIschemic schemic SSyndromes trial yndromes trial

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US hospital discharges in ACS

AHA. Heart Disease and Stroke Statistics–2005 Update.

1.67 million hospital discharges/year

STEMI

1.17 million 500,000

Acute coronary syndromes

UA/NSTEMI

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OASIS-5: Background

• The combined use of anticoagulants, antiplatelet agents, and invasive coronary procedures in a routine early invasive strategy reduces ischemic coronary events but also increases bleeding in selected patients with ACS

• OASIS-5 was conducted to assess whether fondaparinux, a selective inhibitor of factor Xa, would preserve the anti-ischemic benefits of enoxaparin and further reduce bleeding

MICHELANGELO OASIS 5 Steering Committee. Am Heart J. 2005;150:1107-14.

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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OASIS-5: Hypotheses

In the acute treatment of patients with UA/NSTEMIfondaparinux is:

• Noninferior to enoxaparin in preventing death, MI, or refractory ischemia through day 9

• Superior to enoxaparin as determined by lower major bleeding events through day 9

• Superior to enoxaparin in benefit/risk balance as determined by lower rate of death, MI, refractory ischemia, and major bleeding

MICHELANGELO OASIS 5 Steering Committee. Am Heart J. 2005;150:1107-14.

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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OASIS-5: Study design

Patients with NSTE ACS, chest discomfort <24 hours,2: Age >60 y, ST segment, cardiac biomarkers

Outcomes

Primary: Efficacy Death, MI, refractory ischemia at 9 dSafety Major bleeding at 9 dBenefit/risk Death, MI, refractory ischemia, major bleeding at 9 d

Secondary: Primary outcomes plus each component at 30 d and 6 mo

MICHELANGELO OASIS 5 Steering Committee. Am Heart J. 2005;150:1107-14.

ASA, clopidogrel, GP IIb/IIIa,planned cath/PCI per local practice

Randomize

N = 20,078Fondaparinux2.5 mg sc qd

Enoxaparin1 mg/kg sc bid

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OASIS-5: Baseline characteristics

Enoxaparin(n = 10,021)

Fondaparinux(n = 10,057)

Age (years) 66.6 66.6

Male (%) 61.4 62.0

Time from pain onset (hours) 12.7 12.7

Heart rate (bpm) 73.0 73.0

Systolic BP (mm Hg) 136.3 136.6

Diagnosis at study entry (%) UA Suspected MI

45.154.9

45.654.4

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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OASIS-5: Medical history

Enoxaparin(n = 10,021)

Fondaparinux(n = 10,057)

MI 25.7 25.7

PCI/CABG 19.5 20.1

Stroke 6.5 5.9

Heart failure 13.8 13.9

Hypertension 67.1 67.4

Diabetes 25.0 25.6

Current/former smoker 54.6 54.1

Any ECG abnormality 79.8 80.6

ST ≥1 mm 50.3 51.7

%

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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OASIS-5: Concomitant in-hospital medications following randomization

Enoxaparin(n = 10,021)

Fondaparinux(n = 10,057)

ASA 97.5 97.5

Clopidogrel/ticlopidine 67.2 67.6

UFH 31.2 22.0

ACEI/ARB 76.1 74.9

β-blocker 87.7 87.2

Lipid-lowering agent 78.4 79.4

%

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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OASIS-5: Treatment effect on primary efficacy outcome at 9 days

Death, MI, refractory ischemia

0 10

0.01

0.02

0.03

0.04

0.05

0.06

2 3

Enoxaparin

Cumulativeevent rate

Time (days)

Fondaparinux

4 5 6 7 8 9

HR 1.01 (0.90-1.13)

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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OASIS-5: Treatment effect on primary safety outcome at 9 days

0.04

0.03

0.02

0.01

00 1 2 3 4 5 6 7 8 9

HR 0.52 (0.44-0.61)P < 0.001

Enoxaparin

Fondaparinux

Time (days)

0.06

Major bleeding

Cumulativeevent rate

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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OASIS-5: Net clinical benefit at 9 days

Death, MI, refractory ischemia, major bleeding

0 1

0

0.02

0.04

0.06

0.08

2 3

Enoxaparin

Time (days)

Fondaparinux

4 5 6 7 8 9

HR 0.81 (0.73-0.89) P < 0.001

Cumulativeevent rate

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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OASIS-5: Primary and secondary efficacy outcomes at 9 days

Prespecifiednoninferiority margin = 1.185

P = 0.007

RI = refractory ischemia

0.6 0.8 1 1.2

Hazard ratio (95% CI)

Fondaparinuxbetter

Enoxaparin better

Death/MI/RI

Death/MI

Death

MI

RI

5.8

4.1

1.8

2.6

1.9

Fondaparinux(n = 10,057)

5.7

4.1

1.9

2.7

1.9

Enoxaparin(n = 10,021)

%

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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0.6 0.8 1 1.2

OASIS-5: Primary and secondary efficacy outcomes at 30 days

*P = 0.13†P = 0.02

Death/MI/RI*

Death/MI

Death†

MI

RI

Hazard ratio

8.0

6.2

2.9

3.9

2.2

Fondaparinux(n = 10,057)

8.6

6.8

3.5

4.1

2.2

Enoxaparin(n = 10,021)

%

Fondaparinuxbetter

Enoxaparin better

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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OASIS-5: Death, MI, refractory ischemia at 6 months

0 20

0

0.02

0.04

0.06

0.08

0.10

0.12

0.14

40 60

Enoxaparin

Fondaparinux

80 100 120 140 160 180

HR 0.93(0.86-1.00) P = 0.06

Time (days)

Cumulativeevent rate

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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OASIS-5: Net clinical benefit at 6 months

0 20

0

0.10

0.05

0.15

40 60

Enoxaparin

Time (days)

Fondaparinux

80 100 120 140 160 180

Death, MI, refractory ischemia, major bleeding

HR 0.86(0.81-0.93)P < 0.001

Cumulativeevent rate

0.20

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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0.6 0.8 1 1.2

OASIS-5: Primary and secondary efficacy outcomes at 6 months

Death/MI/RI*

Death/MI†

Death†

MI

RI

Hazard ratio (95% CI)

13.2

11.4

6.5

6.6

2.4

Enoxaparin(n = 10,021)

%

Fondaparinuxbetter

Enoxaparin better

12.3

10.5

5.8

6.3

2.3

Fondaparinux(n = 10,057)

*P = 0.06†P = 0.05 OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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OASIS-5: Summary

• Primary outcome (death, MI, refractory ischemia)Fondaparinux was similar to enoxaparin in reducing the risk of ischemic events

• Primary safety outcomeRate of major bleeding was significantly lower for fondaparinux vs enoxaparin

• Benefit/risk assessmentRate of combined death, MI, refractory ischemia, and major bleeding was significantly lower for fondaparinux vs enoxaparin

At 9 days

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

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OASIS-5: Summary, cont’d

• Overall, durable long-term results were observed with fondaparinux vs enoxaparin; results occurred early and remained consistent through study end

– Strong trend toward lower rate of death, MI, or refractory ischemia at 30 days (P = 0.13) through 6 months (P = 0.06)

• Net clinical benefit in favor of fondaparinux at 6 months was demonstrated by significantly lower rate of combined death, MI, refractory ischemia, major bleeding (P < 0.001)

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.