VBWG OASIS-6 The Sixth Organization to Assess Strategies in Acute Ischemic Syndromes trial

VBWG

OASIS-6The Sixth The Sixth OOrganization to rganization to AAssess ssess SStrategies trategies in Acute in Acute IIschemic schemic SSyndromes trialyndromes trial

VBWG

OASIS-6: Background and hypothesis

• There is a clear need for safe and effective antithrombotic agents for STEMI patients

• In clinical trials, unfractionated heparin, direct thrombin inhibitors, and enoxaparin have failed to demonstrate significant mortality reductions and lower bleeding rates in STEMI patients

• Compared to standard antithrombotic therapies, does fondaparinux prevent CV events, revascularization, and mortality when initiated early in a broad range of STEMI patients?

OASIS-6 Trial Group. JAMA. 2006;295:1519-30.

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OASIS-6: Study design

Stratum I:UFH not indicated

(receiving thrombolytics)(n = 5658)

Stratum II:UFH indicated

(receiving tPA or scheduled PCI)(n = 6434)

Patients with STEMI randomized <12 h of symptom onsetN = 12,092

Primary outcome: Composite of death or reinfarction at 30 days Main safety outcome: Severe bleeding

Placebo*(n = 2835)

Fondaparinux 2.5 mg qd*(n = 2823)

UFH 60 IU/kg IV bolus/12 IU/kg 24–48 h infusion

+ placebo*(n = 3221)

Fondaparinux 2.5 mg qd + placebo*(n = 3213)

*Up to 8 days (or earlier discharge)

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OASIS-6: Baseline characteristics

Fondaparinux(n = 6036)

Placebo/UFH(n = 6056)

Age (years) 61.6 61.5

Male (%) 72.8 71.9

Time from pain onset (hours) 4.8 4.8

Heart rate (bpm) 76.3 76.0

Systolic BP (mm Hg) 134.0 134.3


Strata 1 and 2 combined

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OASIS-6: Medical history



Current/former smoker 58.8 57.2Hypertension 54.3 54.6Diabetes 18.0 17.6Heart failure 14.0 13.9MI 12.8 12.3Stroke 6.9 6.4PCI/CABG 3.9 3.9

%



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OASIS-6: Concomitant in-hospital medications following randomization




ASA 96.8 96.4Clopidogrel/ticlopidine 57.7 58.5GP IIb/IIIa receptor antagonist 15.8 15.5UFH 10.8 11.2Low-molecular-weight heparin 5.3 6.3β-Blocker 84.4 83.8ACEI/ARB 79.4 80.0Lipid-lowering agents 74.5 74.8Calcium channel blockers 10.6 10.3

%

Other medications <1% each


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OASIS-6: Treatment effect on primary efficacy outcome at 30 daysComposite of death, MI


Cumulative event rate

UFH or placebo FondaparinuxDays

0.14

0.12

0.10

0.08

0.06

0.04

0.02

00 3 6 9 12 16 18 21 24 27 30

HR 0.86(0.77–0.96)P = 0.008

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OASIS-6: Severe bleeding at 30 days


0.016

0.014

0.010

0.008

0.006

0.004

0.002

0

Cumulative event rate

UFH or placebo Fondaparinux

0.012

0 3 6 9 12 16 18 21 24 27 30

Modified TIMI criterion

Days

HR 0.79(0.58–1.09)P = 0.15

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OASIS-6: Net clinical benefit

9.3

11.6

14.7

7.7

10.0

12.9

9 days

30 days

6 months

Death, MI, severe bleeding

FondaparinuxUFH or placebo

Hazard ratio(95% CI)

Favors fondaparinux

Favors UFH or placebo


%

0.8 1.0 1.2

0.003

0.005

0.005

P

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OASIS-6: Treatment effect on primary outcome at 30 days–Subgroup analyses

11.28.3

12.210.96.0

14.08.7

15.113.64.9

StratumUFH not indicatedUFH indicated

Initial reperfusiontherapy

NoneThrombolyticPrimary PCI

Composite of death, MI at 30 days

FondaparinuxUFH or placeboCharacteristic

Hazard ratio(95% CI)

Favors fondaparinux

Favors UFH or placebo

0.5 1 2.0


%

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OASIS-6: Reduction in death and MI at study end


Cumulativeevent rate

0 300

0.02

0.04

0.10

0.08

0.06

0.12

0.14

0.16

60 90 120 150Days

180 0 300

0.02

0.04

0.10

0.08

0.06

0.12

0.14

0.16

60 90 120 150Days

180

HR 0.81(0.67–0.97)P = 0.03

HR 0.88(0.79–0.99)P = 0.03

UFH or placebo Fondaparinux

Death MI

All patients followed for 3 months; n = 6976 followed for 6 months

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OASIS-6: Conclusion

• Primary efficacy outcome at 30 daysFondaparinux significantly reduced death and reinfarction vs UFH/placebo

• Main safety outcomeTrend to lower rate of severe bleeding

• Overall, results occurred early (9 days) and remained consistent through study endSignificant reduction in death (12%, P = 0.03) and MI (19%, P = 0.03)

• Benefit/risk balanceRate of combined death, MI, and severe bleeding was significantly lower for fondaparinux vs UFH/placebo

• Subgroup analysisBenefit shown in 5436 patients who received thrombolytic therapyLittle benefit in 3789 patients who underwent primary PCI


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OASIS-6: Summary

• Fondaparinux demonstrated a moderate reduction in mortality and reinfarction vs UFH/placebo

• Unlike other antithrombotic agents (eg, LMW heparin, direct thrombin inhibitors, intravenous antiplatelet agents), fondaparinux reduced deaths and reinfarction without increased bleeding or hemorrhagic stroke

• There appears to be little advantage in using fondaparinux as the initial treatment in patients undergoing primary PCI


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The OASIS program: Safety and efficacy of fondaparinux in a broad range of patients with ACS

• OASIS-5: N = 20,078 with UA/NSTEMI: Fondaparinux vs enoxaparin– Similar efficacy in reducing risk of death, MI, and refractory ischemia

at 9 days– Significantly lower rate of major bleeding (P < 0.001) at 9 days

• OASIS-6: N = 12,092 with STEMI: Fondaparinux vs UFH/placebo– Significantly lower rate of death and reinfarction at 30 days (P = 0.008)

• Benefit principally in patients who did not undergo primary PCI– Nonsignificant trend towards lower rate of severe bleeding at 30 days

• In both trials, efficacy and net clinical benefit remained consistent through study end

OASIS-5 Investigators. N Engl J Med. 2006; epublished March 14.OASIS-6 Trial Group. JAMA. 2006;295:1519-30.

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VBWG OASIS-6 The Sixth Organization to Assess Strategies in Acute Ischemic Syndromes trial