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

4 September 2007 | Volume 147 Issue 5 | Pages 304-310

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.

Editors' Notes Context These researchers hypothesized that the benefit of fondaparinux versus enoxaparin for patients with non–ST-segment acute coronary syndromes would be greatest among patients whose risk for bleeding was greater because of renal dysfunction. Contribution Among patients with a glomerular filtration rate (GFR) less than 58 mL/min per 1.73 m2, fondaparinux had lower rates of combined death, major bleeding, myocardial infarction, or refractory angina compared with enoxaparin: 8.8% vs. 12.5% (hazard ratio, 0.69 [95% CI, 0.58 to 0.82]) at 9 days, 12.9% vs 17.6% (hazard ratio, 0.71 95% [CI, 0.62 to 0.82]) at 30 days, and 21.3% vs 24.7% (hazard ratio, 0.83 [CI, 0.74 to 0.93]) at 180 days. The differences were not statistically significant among patients with a GFR greater than 58 mL/min per 1.73 m2. Implication In non–ST-segment elevation acute coronary syndromes, the net benefits of fondaparinux compared with enoxaparin are most marked among patients with a GFR less than 58 mL/min per 1.73 m2. —The Editors

 

Author and Article 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{at}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.

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