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Balancing safety and efficacy: dose selection
Fondaparinux in patients with impaired renal function: the right choice?
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Keith A A Fox, MB ChB, FREP, FESC University of Edinburgh
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k.a.a.fox{at}ed.ac.uk Keith A A Fox
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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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Giuseppe Famularo, MD PhD San Camillo Hospital, Rome, Italy, Giovanni Minisola
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gfamularo{at}scamilloforlanini.rm.it Giuseppe Famularo, et al.
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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 |
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