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Yusuf S, et al. "Comparison of fondaparinux and enoxaparin in acute coronary syndromes". The New England Journal of Medicine. 2006. 354(14):1464-1476.
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Clinical Question

Among patients with NSTE-ACS, is fondaparinux non-inferior to enoxaparin in preventing death, myocardial infarction, or refractory ischemia?

Bottom Line

Among patients with NSTE-ACS, fondaparinux is non-inferior to enoxaparin in preventing death, myocardial infarction, or refractory ischemia.

Major Points

The benefit of anticoagulant agents in cardiovascular morbidity and mortality in patients with NSTE-ACS was first demonstrated in multiple trials conducted in the 1990s using unfractionated heparin (UFH). Subsequent studies using low molecular weight heparin (LMWH) in NSTE-ACS compared against UFH in mostly medically managed (e.g. TIMI 11B, FRISC) and invasively managed (e.g. SYNERGY, A to Z) populations demonstrated an overall further reduction in 10% in death or MI.[1] Despite the efficacy of both these agents however, major bleeding remained a major concern with treatment.

Fondaparinux is a synthetic pentasaccharide that leads to rapid and predictable inhibition of factor Xa.[2] Published in 2006, the Comparison of Fondaparinux and Enoxaparin in Acute Coronary Syndromes (OASIS-5) trial was conducted to determine whether fondaparinux was non-inferior to enoxaparin in preventing cardiovascular morbidity and mortality in NSTE-ACS. This multi-national, double-blind, double-dummy, placebo-controlled randomized trial randomized 20,078 patients to either fondaparinux 2.5mg SC daily or Enoxaparin 1mg/kg SC BID. The primary composite outcome of death, MI, or refractory ischemia at 9 days (HR 1.01; 95% CI 0.90-1.13; P = 0.007 for non-inferiority) was non-inferior using fondaparinux compared to LMWH. Major bleeding was significantly lower in the fondaparinux arm, which may have contributed to a decreased mortality compared to LMWH at 30 and 180 days.

Subgroup analysis of patients undergoing percutaneous intervention demonstrated a higher rate of catheter-related thrombus formation with the use of fondaparinux, a finding also demonstrated in OASIS-6 which investigated the use of fondaparinux in STE-ACS.[3] Post-hoc analysis showed that patients simultaneously on fondaparinux and UFH compared to fondaparinux alone led to significantly less thrombus formation.[4] The prospective cohort study FUTURA/OASIS-8 subsequently determined that a low dose of UFH was non-inferior to a high dose of UFH in preventing thrombus formation during PCI in high-risk NSTE-ACS patients.[4]


AHA/ACC NSTE-ACS Guidelines (2014, adapted)[5]

  • In patients with NSTE-ACS, fondaparinux 2.5mg SC daily is recommended irrespective of initial treatment strategy for the duration of hospitalization or until PCI is performed (Class 1B).
  • If PCI is to be performed on a patient on fondaparinux, an additional anticoagulant with anti-IIa activity (bivalirudin or UFH) should be administered because of the risk of catheter thrombosis (Class 1B).
  • Fondaparinux should not be used as the sole anticoagulant to support PCI in patients with NSTE-ACS due to an increased risk of catheter thrombosis (Class 1B).


  • Multi-national, randomized, double-blind, double-dummy, placebo-controlled trial
  • N=20,078
    • Fondaparinux arm (n=10,057)
    • Enoxaparin arm (n=10,021)
  • Setting: 576 sites in 41 countries
  • Analysis: Intention-to-treat
  • Primary outcome: Death, myocardial infarction, or refractory ischemia at nine days


Inclusion Criteria

  • Symptoms of UA or MI without persistent ST elevation plus ≥2 of the following:
    • 60 years or olders
    • Elevated troponin or CK-MB
    • ECG changes indicative of ischemia

Exclusion Criteria

  • Contraindications to LMWH
  • Recent hemorrhagic stroke
  • indications for anticoagulation other than ACS
  • Serum creatinine >3mg/dL (365 μmol/L)

Baseline Characteristics

From the fondaparinux treatment arm.

  • Demographics: Age 67 years, 61% male sex
  • Time from pain to randomization: 12.7 hr
  • Vital signs: HR 73 BPM, SBP 136 mmHg
  • Diagnosis at entry: Unstable angina 45%, suspected MI 55%
  • Any ECG abnormality: 79.8%
  • ST depression >=1mm: 50.3%
  • PMH: MI 26%, CABG or PCI 20%, stroke 6%, HF 14%, HTN 67%, DM 25%, current or former smoker 55%
  • Medications at randomization: Aspirin 78%, clopidogrel or ticlopidine 32%, UFH 18%, LMWH 32%, ACE inhibitor or ARB 51%, beta-blocker 60%, CCB 22%, lipid-lowering agent 38%
  • Medications after randomization: Aspirin: 98%, clopidogrel or ticlopidine 67%, UFH 31%, ACE inhibitor or ARB 76%, beta-blocker 88%, lipid-lowering agent 78%
  • Procedures in hospital: Coronary angiography 63%, PCI 34%, CABG 9%
  • Procedures after discharge: Coronary angiography 8%, PCI 5%, CABG 6%


  • Randomly assigned to a study group within 24 hours after the onset of symptoms
    • Fondaparinux arm: Fondaparinux 2.5mg SC daily + Placebo enoxaparin SC BID
    • Enoxaparin arm: Enoxaparin 1mg/kg SC BID + Placebo fondaparinux SC daily
      • Given at 1mg/kg SC once daily if CrCl < 30
  • Fondaparinux was given until hospital discharge or up to eight days, whichever occurred first
  • Enoxaparin was given until clinically stable, or between two to eight days
  • Cardiac catheterization could be performed at any time
  • Other standard treatments given at the investigators' discretion


Comparisons are fondaparinux vs. enoxaparin. Non-inferiority analyses utilized a noninferiority margin (delta) of 1.185. One-sided P<0.025. P values are for superiority when not explicitly stated

Primary Outcomes

Death, MI, or refractory ischemia after 9 days
5.8% vs. 5.7% (HR 1.01; 95% CI 0.90-1.13; P = 0.007, non-inferiority; P=NS, superiority)

Secondary Outcomes

At 9 days.

Death or MI
4.1% vs. 4.1% (HR 0.99; 95% CI 0.86-1.13; P=0.005, non-inferiority; p=NS, superiority)
Major Bleeding
2.2% vs. 4.1% (HR 0.52; 95% CI 0.44-0.61; P<0.001; NNT=53)
Death, MI, refractory ischemia, or major bleeding
7.3% vs. 9.0% (HR 0.81; 95% CI 0.44-0.61; P<0.001; NNT=59)
No difference in rates of death, stroke, MI, refractory ischemia, stroke alone or combined death, MI, and stroke were noted.

At 30 days.

Death, MI, or refractory ischemia
8.0% vs. 8.6% (HR 0.93; 95% CI 0.84-1.02; P=0.13)
Death or MI
6.2% vs. 6.8% (HR 0.90; 95% CI 0.81-1.01; P=0.07)
2.9% vs. 3.5% (HR 0.83; 95% CI 0.71-0.97; P=0.02; NNT=167)
Major Bleeding
3.1% vs. 5.0% (HR 0.62; 95% CI 0.54-0.72; P<0.001; NNT=53)
Death, MI, refractory ischemia, or major bleeding
10.2% vs. 12.4% (HR 0.82; 95% CI 0.75-0.89; P<0.001; NNT=45)
Death, MI, or stroke
6.7% vs. 7.5% (HR 0.89; 95% CI 0.80-0.98; P=0.02; NNT=125)
No difference in rates of death, stroke, MI, refractory ischemia, or stroke alone were noted.

At 180 days.

Death, MI, or refractory ischemia
12.3 vs. 13.2% (HR 0.93; 95% CI 0.86-1.00; P=0.06; NNT=111)
Death or MI
10.5% vs. 11.4% (HR 0.92; 95% CI 0.84-1.00; P=0.05; NNT=111)
5.8% vs. 6.5% (HR 0.89; 95% CI 0.80-1.00; P=0.05; NNT=143)
1.3% vs. 1.7% (HR 0.78; 95% CI 0.62-0.99; P=0.04; NNT=250)
Major bleeding
4.3% vs. 5.8% (HR 0.72; 95% CI 0.64-0.82; P<0.001; NNT=67)
Death, MI, refractory ischemia, or major bleeding
15.0% vs. 17.1% (HR 0.86; 95% CI 0.81-0.93; P<0.001; NNT=48)
Death, MI, or stroke
11.3% vs. 12.5% (HR 0.90; 95% CI 0.82-0.97; P=0.007; NNT=83)
No difference in rates of MI or refractory ischemia alone were noted.

Additional Outcomes

Those undergoing PCI.

Concomitant Antithrombotic Agents
UFH: 20.8% vs. 55.5%
GP IIb/IIIa inhibitor: 41.7% vs. 41.0%
Thienopyridines: 74.9% vs. 74.6%
Any vascular access site complication
3.3% vs. 8.1% (RR 0.41; 95% CI 0.33-0.51; P<0.001)
All catheter-related thrombi
0.9% vs. 0.4% (RR 3.59; 95% CI 1.64-7.84; P=0.001)
Death, MI, stroke, or major bleeding at 9 days
8.2% vs. 10.3% (RR 0.79; 95% CI 0.67-0.92; P=0.003)
Death, MI, stroke, major bleeding, or any procedural complication at 9 days
16.6% vs. 20.6% (RR 0.81; 95% CI 0.73-0.90; P<0.001)

No differences in death, MI, Stroke, or major bleeding alone were noted at 9 days. No difference in combined death, MI, or stroke was noted at 9 days.

Death, MI, stroke, or major bleeding at 30 days
9.5% vs. 11.7% (RR 0.81; 95% CI 0.70-0.39; P=0.004)

No differences in death, MI, stroke, or major bleeding alone were noted at 30 days. No difference in combined death, MI, or stroke was noted at 30 days.

Subgroup Analysis

Primary Outcome at 9 Days
Fondaparinux was non-inferior to enoxaparin regardless of age group, gender, creatinine, use of heparin, use of revascularization, and presence of a catheterization laboratory.
Major Bleeding at 9 Days
Fondaparinux reduced major bleeding regardless of age group, gender, creatinine, use of heparin, use of revascularization, and presence of a catheterization laboratory.


  • Some patients randomized to enoxaparin received an additional bolus of IV UFH prior to catheterization, a combination which was found to increase death, MI, or hemorrhagic events in SYNERGY[6][7]. This may have contributed to increased bleeding in the enoxaparin arm.
  • Only 75 patients in the fondaparinux arm received UFH to prevent catheter thrombus formation under an amended protocol introduced partway through the study where UFH could be added (One case of thrombosis was noted)[8]. There is therefore limited data from this study alone in assessing the safety and efficacy of combination therapy during catheterization.
  • Low use of clopidogrel and other non-aspirin antiplatelets[9]


  • Sanofi-Aventis/Organon (Previous owner of Fondaparinux, Arixtra), and GlaxoSmithKline (current owner)

Further Reading

  1. Petersen JL et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-Segment elevation acute coronary syndromes: a systematic overview. JAMA 2004. 292:89-96.
  2. Blick SK et al. Fondaparinux sodium: a review of its use in the management of acute coronary syndromes. Am J Cardiovasc Drugs 2008. 8:113-25.
  3. Yusuf S et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 2006. 295:1519-30.
  4. 4.0 4.1 Steg PG et al. Fondaparinux with UnfracTionated heparin dUring Revascularization in Acute coronary syndromes (FUTURA/OASIS 8): a randomized trial of intravenous unfractionated heparin during percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux. Am. Heart J. 2010. 160:1029-34, 1034.e1.
  5. Amsterdam EA et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2014. 64:e139-e228.
  6. Cohen M et al. A subgroup analysis of the impact of prerandomization antithrombin therapy on outcomes in the SYNERGY trial: enoxaparin versus unfractionated heparin in non-ST-segment elevation acute coronary syndromes. J. Am. Coll. Cardiol. 2006. 48:1346-54.
  7. Majure DT & Aberegg SK Fondaparinux versus enoxaparin in acute coronary syndromes. N. Engl. J. Med. 2006. 354:2829; author reply 2830.
  8. Schiele F Fondaparinux and acute coronary syndromes: update on the OASIS 5-6 studies. Vasc Health Risk Manag 2010. 6:179-87.
  9. Gibbons RJ & Fuster V Therapy for patients with acute coronary syndromes--new opportunities. N. Engl. J. Med. 2006. 354:1524-7.