Author + information
- Raffaele De Caterina, MD, PhD⁎ (, )
- Steen Husted, MD, DSc,
- Lars Wallentin, MD, PhD,
- ESC Working Group on Thrombosis Task Force on Anticoagulants in Heart Disease
- ↵⁎Institute of Cardiology, “G. d'Annunzio” University—Chieti, Ospedale SS. Annunziata, Via dei Vestini, 66013 Chieti, Italy
We thank Dr. Kaluski and colleagues for their thoughts on the possibility of individualizing dosing strategies for the new oral anticoagulants. From a theoretical perspective, the one-size-fits-all strategy seems not to be ideal, because of the potential pharmacokinetic interactions, the variability in drug metabolism during lifelong administration, and the inherent risks of thrombosis in the case of underdosing or of bleeding in the case of overdosing. For this reason, we favored the European Medicinal Agency position in allowing both doses of dabigatran etexilate studied in RE-LY (150 mg twice daily and 110 mg twice daily), and also the U.S. Food and Drugs Administration policy of recommending the even lower 75 mg twice daily dose in selected conditions of poor renal function (1). Also for the factor (F)Xa-inhibitors rivaroxaban and apixaban, a lower dose has been used in the trials in selected conditions of poor renal function and is recommended in the current or forthcoming labels. In the phase III trial of the FXa inhibitor edoxaban in nonvalvular atrial fibrillation, 2 exposure strategies and 3 dosing regimens were tested to obtain a more personalized treatment approach. Such trial design leads to the need for a very large patient sample size in the pivotal phase III trial, which has not always been possible because it is forbiddingly expensive. A more feasible approach may be to test alternative dosing regimens after regulatory approval, that is, in the context of simple trials in a registry-like environment. This will allow a firmer documentation of the best regimens and a considerably more valid background than basing the choice of alternative regimens only on pharmacokinetic considerations. Still, there is no evidence that an individualized regimen with frequent monitoring and dose changes is either safer or more effective than a standard dose regimen, especially when using medications with a wider therapeutic window than vitamin K antagonists.
We very much warn against the proposal in the letter to extend the clinical use of these new treatments to patients with mechanical valves or hypercoagulable states based only on pharmacokinetic considerations, other than in the design of real efficacy trials. Patients with these diseases may well require drug dosing regimens different from those evaluated so far in clinical trials. Specific efficacy trials in these new settings are needed, and actually already have begun.
We certainly agree with a plea for prudence in the use of these new drugs, for which simplicity of use—undoubtedly much higher than for vitamin K antagonists—may create the illusion of absence of problems, which is certainly not the case.
- American College of Cardiology Foundation