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Influence of Renal Function on the Efficacy and Safety of Fondaparinux Relative to Enoxaparin in Non–ST-Segment Elevation Acute Coronary Syndromes

Keith A.A. Fox, MBChB; Jean-Pierre Bassand, MD; Shamir R. Mehta, MD; Lars Wallentin, MD, PhD; Pierre Theroux, MD; Leopoldo Soares Piegas, MD, PhD; Vicent Valentin, MD; Tiziano Moccetti, MD; Susan Chrolavicius, BA; Rizwan Afzal, MSc; Salim Yusuf, MD, DPhil, on behalf of the OASIS 5 Investigators
[+] Article and Author Information

From the University of Edinburgh, Edinburgh, United Kingdom; McMaster Clinic, Hamilton, Ontario, Canada; University Hospital Jean-Minjoz, Besançon, France; Montreal Heart Institute, Montréal, Québec, Canada; Uppsala University Hospital, Uppsala, Sweden; Instituto Dante Pazzanese, São Paulo, Brazil; and Hospital Clinico Universitario, Valencia, Italy.


Potential Financial Conflicts of Interest: Consultancies: K.A.A. Fox, J.P. Bassand, S.R. Mehta (GlaxoSmithKline, Eli Lilly Inc., Sanofi-Aventis), S. Yusuf (GlaxoSmithKline, Sanofi-Aventis). Honoraria: K.A.A. Fox, J.P. Bassand, S. Yusuf (GlaxoSmithKline, Sanofi-Aventis). Grants received: K.A.A. Fox (for OASIS 5), S.R. Mehta (Population Health Research Institute, from Glaxo SmithKline and Sanofi-Aventis), S. Yusuf (GlaxoSmithKline, Sanofi-Aventis). Grants pending: S. Yusuf (Sanofi-Aventis).

Requests for Single Reprints: Keith A.A. Fox, MBChB, Cardiovascular Research, The University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, United Kingdom; e-mail, k.a.a.fox@ed.ac.uk.

Current Author Addresses: Dr. Fox: Cardiovascular Research, The University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, United Kingdom.

Dr. Bassand: Department of Cardiology, Pôle Coeur Poumans, University Hospital Jean-Minjoz, Boulevard Fleming, 25030 Besançon Cedex, France.

Dr. Mehta: Hamilton Health Sciences, General Division, McMaster Clinic, 237 Barton Street East Hamilton, Ontario L8L 2X2, Canada.

Dr. Wallentin: Uppsala University Hospital, UCR, 75185 Uppsala, Sweden.

Dr. Theroux: Montreal Heart Institute, 5000 Belanger East, Montréal, Québec H1T 1C8, Canada.

Dr. Soares Piegas: Instituto Dante Pazzanese de Cardiologia, Avenida Dr. Dante Pazzanese 500-12 andar, CEP 04012-80, São Paulo, Brazil.

Dr. Valentin: Unidad Coronaria, Hospital Universitaria Dr. Peset, Valencia, Spain.

Dr. Moccetti: Cardiocentro Ticino, Lugano, Italy.

Ms. Chrolavicius and Mr. Afzal: Population Health Research Institute, HHSC, Hamilton General Hospital, McMaster Clinic, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Dr. Yusuf: Department of Medicine (Cardiology), HHSC, Hamilton General Hospital, McMaster Clinic, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Author Contributions: Conception and design: K.A.A. Fox, S.R. Mehta, L. Wallentin, P. Theroux, V. Valentin, S. Chrolavicius.

Analysis and interpretation of the data: K.A.A. Fox, S.R. Mehta, L. Wallentin, V. Valentin, S. Chrolavicius, R. Afzal.

Drafting of the article: K.A.A. Fox, J.P. Bassand, L. Wallentin, V. Valentin.

Critical revision of the article for important intellectual content: K.A.A. Fox, J.P. Bassand, S.R. Mehta, L. Wallentin, P. Theroux, V. Valentin, R. Afzal.

Final approval of the article: K.A.A. Fox, J.P. Bassand, L. Wallentin, P. Theroux, V. Valentin.

Provision of study materials or patients: L. Wallentin, V. Valentin.

Statistical expertise: P. Theroux, R. Afzal.

Collection and assembly of data: V. Valentin, S. Chrolavicius.


Ann Intern Med. 2007;147(5):304-310. doi:10.7326/0003-4819-147-5-200709040-00005
Text Size: A A A

Background: A recent randomized, controlled trial, the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS 5) trial, reported that major bleeding was 2-fold less frequent with fondaparinux than with enoxaparin in acute coronary syndromes (ACS). Renal dysfunction increases the risk for major bleeding.

Objective: To compare the efficacy and safety of fondaparinux and enoxaparin over the spectrum of renal dysfunction observed in the OASIS 5 trial.

Design: Subgroup analysis of a randomized, controlled trial.

Setting: Patients presenting to the hospital with non–ST-segment elevation ACS.

Patients: 19 979 of the 20 078 patients in the OASIS 5 trial in whom creatinine was measured at baseline.

Measurements: Death, myocardial infarction, refractory ischemia, and major bleeding were evaluated separately and as a composite end point at 9, 30, and 180 days. Glomerular filtration rate (GFR) was calculated by using the Modification of Diet in Renal Disease formula.

Results: The absolute differences in favor of fondaparinux (efficacy and safety) were most marked in patients with a GFR less than 58 mL/min per 1.73 m2; the largest differences occurred in major bleeding events. At 9 days, death, myocardial infarction, or refractory ischemia occurred in 6.7% of patients receiving fondaparinux and 7.4% of those receiving enoxaparin (hazard ratio, 0.90 [95% CI, 0.73 to 1.11]); major bleeding occurred in 2.8% and 6.4%, respectively (hazard ratio, 0.42 [CI, 0.32 to 0.56]). Statistically significant differences in major bleeding persisted at 30 and 180 days. The rates of the composite end point were lower with fondaparinux than with enoxaparin in all quartiles of GFR, but the differences were statistically significant only among patients with a GFR less than 58 mL/min per 1.73 m2.

Limitations: Subgroup analyses warrant caution; the study was powered to detect noninferiority at 9 days. Fondaparinux is not approved for use in patients with ACS in the United States.

Conclusions: The benefits of fondaparinux over enoxaparin when administered for non–ST-segment elevation ACS are most marked among patients with renal dysfunction and are largely explained by lower rates of major bleeding with fondaparinux.

Figures

Grahic Jump Location
Appendix Figure. ACS = acute coronary syndromes; GFR = glomerular filtration rate.
Study flow diagram.
Grahic Jump Location
Grahic Jump Location
Figure. Lines show smoothed estimates derived from individual data. Tick marks on the curves show the density of patients at each glomerular filtration rate ( ).
Relation between deaths and renal dysfunction by 180 days and between major bleeding events and renal dysfunction by 9 days.GFR
Grahic Jump Location

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Fondaparinux in patients with impaired renal function: the right choice?
Posted on September 9, 2007
Giuseppe Famularo
San Camillo Hospital, Rome, Italy
Conflict of Interest: None Declared

OASIS-5 investigators report an excess of bleeding events with enoxaparin as compared with fondaparinux among NSTEMI patients with reduced glomerular filtration rate (1). However, in view of the pharmacokinetic characteristics of fondaparinux, which has a longer half- life (17 hours) than enoxaparin (< 10 hours) (2,3), we are concerned the trial did fail to demonstrate the opposite. In other words, we would reasonably expect enoxaparin be found more safe than fondaparinux in patients with impaired renal function. We agree with Fox and colleagues that many other features in addition to the glomerular filtration rate, such as for example the direct antithrombin activity or the binding to endothelial cells and plasma proteins, should be accounted for to estimate as exactly as possible the probability of bleeding if treatment with fondaparinux rather than with enoxaparin is planned. However, the severity of renal function impairment remains the most accurate single determinant of the hemorrhagic risk in patients treated with either fondaparinux or enoxaparin. One important point is that OASIS-5 patients were randomized to receive fondaparinux 2.5 mg daily or enoxaparin 1 mg/kg twice daily, even though in this latter group enoxaparin dose was reduced to 1 mg/kg once daily if creatinine clearance decreased to less than 30 ml/min. Fondaparinux at 2.5 mg daily is the currently recommended dose for the prevention of venous thromboembolism rather than for the treatment of acute venous or arterial thrombosis (4) whereas enoxaparin was given at a full dose. It is also noteworthy that OASIS-6 trial, which compared fondaparinux 2.5 mg daily with placebo or unfractionated heparin in patients with acute STEMI, showed only a marginal or no at all reduction in bleeding events among fondaparinux-treated patients (5). Use of this relatively low dose of fondaparinux could explain in our opinion the lower hemorrhagic burden with fondaparinux as compared with enoxaparin in the subgroup of OASIS-5 patients with impaired renal function. We believe the advantages of fondaparinux relative to enoxaparin in terms of a greater antithrombotic efficacy paralleled by a lower bleeding risk remain to be firmly established.

References

1. Fox KA, Bassand JP, Mehta SR et al. Influence of the renal function on the efficacy and safety of fondaparinux relative to enoxaparin in Non-ST-Segment Elevation acute coronary syndromes. Ann Intern Med 2007; 147:304-10.

2. Donat F, Duret JP, Santoni A, et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet 2002; 42 (Suppl 2): 1"“9.

3. Hulot JS, Vantelon C, Urien S, et al. Effect of renal function on the pharmacokinetics of enoxaparin and consequences on dose adjustment. Ther Drug Monitor 2004; 26: 305-10.

4. Francis CW. Prophylaxis for thromboembolism in hospitalized medical patients. N Engl J Med 2007; 356:1438-44.

5. The OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-Segment Elevation myocardial infarction. JAMA 2006; 295:1519-30.

Conflict of Interest:

None declared

Balancing safety and efficacy: dose selection
Posted on October 9, 2007
Keith A A Fox
University of Edinburgh
Conflict of Interest: None Declared

We thank the writers for their comments but it is important to point out that the dose of enoxaparin was the approved dose by regulatory agencies and ACS guideline recommendations. The dose of fondaparinux was chosen following the phase II study in patients with acute coronary syndromes (PENTUA), and other data, in order to optimize both efficacy and safety. The concept of just using the "full dose" of an experimental drug may not be appropriate, in the effort to minimize bleeding risk yet provide appropriate efficacy. The findings of this study suggest that similar considerations need to be applied to the dose selection of enoxaparin, and especially in those with moderate or more severe renal dysfunction, a lower dose may provide a better balance between efficacy and safety, but this is speculative and yet to be proven in randomized trials.. , Not only renal function and patient risk features, but also age and many other factors such as direct antithrombin activity or the binding to endothelial cells and plasma proteins, should be considered in relation to bleeding risk. In the OASIS 6 trial, the lack of an increase in bleeding with fondaparinux vs placebo (in Stratum 1) or unfractionated heparin (in Stratum II) is noteworthy, because there was also a significant reduction in mortality and re-infarction, and a trend towards fewer strokes. The results of both Oasis 5 and Oasis 6 reinforce the concept that efficacy benefits can be achieved without compromising patient safety.

1. Fox KA, Bassand JP, Mehta SR et al. Influence of the renal function on the efficacy and safety of fondaparinux relative to enoxaparin in Non-ST-Segment Elevation acute coronary syndromes. Ann Intern Med 2007; 147:304-10.

2. The OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-Segment Elevation myocardial infarction. JAMA 2006; 295:1519-30.

Conflict of Interest:

Grants from: Sanofi-Aventis, MSD, GSK

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