Edinburgh, Scotland - 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, a new analysis of OASIS-5 shows [1]. The authors suggest that a more systematic dose adjustment of enoxaparin may be required in ACS patients with renal dysfunction.

The OASIS-5 trial compared the factor Xa inhibitor fondaparinux with enoxaparin in 20 078 patients with non-ST-segment elevation ACS. The main results showed a similar rate of ischemic events with the two agents at day 9, but major bleeding was substantially reduced with fondaparinux, and there were significantly fewer deaths and strokes in the fondaparinux group during long-term follow-up. The current analysis, published in the September 4, 2007 issue of the Annals of Internal Medicine, focuses on how the two drugs compare over the spectrum of renal dysfunction observed in the OASIS-5 trial.

The authors, led by Dr Keith Fox (University of Edinburgh, Scotland), explain that enoxaparin is primarily metabolized by the liver, but that renal clearance of active and nonactive fragments represents about 40% of the administered dose, and a reduced dose is recommended for patients with severe renal impairment. Fondaparinux is excreted by the kidney without previous metabolism.

The current analysis involved 19 979 patients in the OASIS-5 trial in whom creatinine was measured at baseline. Death, MI, refractory ischemia, and major bleeding were evaluated separately and as a composite end point at nine, 30, and 180 days, and the effect of renal dysfunction on these end points with both agents was recorded.

Results showed that the rates of the composite end point were lower with fondaparinux than with enoxaparin in all quartiles of glomerular filtration rate (GFR), but the differences were statistically significant only among patients with the most renal dysfunction (a GFR of <58 mL/min per 1.73 m²). This was true for all times points measured.

The largest difference between fondaparinux and enoxaparin was in bleeding events, which had occurred in 2.8% of fondaparinux and 6.4% of enoxaparin patients with the most marked renal dysfunction at nine days. Statistically significant differences in major bleeding associated with fondaparinux and enoxaparin persisted in this group of patients at 30 and 180 days.

Fox et al note that only one quarter of the ACS patients in this study had well-preserved renal function, and half had a GFR of less than 71 mL/min per 1.73 m². They report that renal function was a powerful and independent determinant of adverse outcome, including the risks for death and major and minor bleeding. Overall, the risk for death was approximately fivefold higher in patients in the lowest quartile of renal dysfunction than in those with well-preserved renal function, and the risk for major bleeding was fourfold higher among those in the lowest vs the highest quartiles of GFR.

They point out that not only are bleeding risks amplified as renal dysfunction deteriorates, but the difference between fondaparinux and enoxaparin in this regard progressively widens, which they suggest may be due to differences in the way the compounds are cleared.

They note that in the EXTRACT trial, in ST-segment elevation MI, the dose of enoxaparin was reduced in elderly patients (to 75% of the standard dose) and it was also reduced in those with severe renal dysfunction, but despite this dose reduction, there was significant excess bleeding with enoxaparin compared with unfractionated heparin. "These findings, together with those of OASIS-5, suggest that a more systematic dose adjustment of enoxaparin may be required across the spectrum of renal dysfunction in patients with ACS," they write.

"The association between bleeding and deaths suggests that every effort is needed in future studies to minimize the risks for major bleeding. In the absence of dose adjustment, fondaparinux is associated with lower risk for bleeding at all levels of renal function," they add.

"The powerful association between renal dysfunction and the adverse outcomes of death and bleeding suggests that results from patients with well-preserved renal function should not be extrapolated to the full spectrum of patients presenting with non-ST-segment elevation ACS," they conclude.