Laboratory tests during direct oral anticoagulant treatment? No.

The anticoagulant effect of Dabigatran etexilate, Rivaroxaban, and Apixaban is dose-predictable, steady, and little influenced by diet and drugs [1]. Thus, similar to lowmolecular weight heparin, laboratory tests have been unnecessary to evaluate such direct oral anticoagulant drugs (DOACs) in trials on thromboprophylaxis (Table 1). Nor such testing was needed in patients with atrial fibrillation (AF) receiving Dabigatran etexilate (RE-LY trial), Rivaroxaban (ROCKET AF trial) or Apixaban (ARISTOTLE trial). In the AF setting, vis-à-vis an at least as effective prevention of stroke and systemic embolism, the risk of intracranial hemorrhage was lower with DOACs than with INR-adjusted warfarin. Patients at high risk of bleeding are little represented in studies with DOACs [2, 3]. However, from October 2010 to December 2011, vis-àvis 3.5 gastrointestinal bleedings and 2.4 intracranial hemorrhages/100,000 days at risk in new users of warfarin, 1.6 gastrointestinal bleedings and 0.8 intracranial hemorrhages/100,000 days at risk occurred among new users of Dabigatran in the every day practice in the USA [4]. At variance with the large majority of cases, there are special conditions and clinical settings (Table 2) in which the anticoagulant effect of DOACs should be measured [5]. However, peak concentrations of Rivaroxaban (&200 ng mL) are determined by HPLC methods that are not suitable for routine practice [6]. On the other hand, in healthy volunteers, a 20 % prolongation of the aPTT has been observed for single Apixaban doses ranging from 25 to 50 mg [7]. Moreover, depending on the reagent employed, the concentrations of Rivaroxaban that double the aPTT range from 389 to 617 ng mL [8]. Thus, the aPTT does not accurately assess the anticoagulant effect of Rivaroxaban or of Apixaban. A concentration-dependent prolongation of the aPTT occurs by spiking Dabigatran in human plasma [9]. However, such prolongation is linear only at Dabigatran concentrations [200 ng mL (expected drug exposure being 50–300 ng mL), and the effects on the aPTT vary up to 26 % between the most and least sensitive reagent [10]. Thus, the aPTT is not suitable for an accurate measurement of the anticoagulant effect of (high) Dabigatran concentrations. At variance with Apixaban, Rivaroxaban prolongs the PT in a dose-dependent manner. However, at approved dose regimens (10–20 mg), the changes observed are small, and the results depend on the reagents employed. Accordingly, rather than quantitative, this accessible clotting method provides qualitative estimates of the anticoagulant effect of Rivaroxaban [11]. Likewise, significant effects in the PT-INR (i.e., INR [1.2) are only found in response to concentrations of Dabigatran [200 ng mL [9]. Moreover, depending on the thromboplastin reagent used, major differences are observed in the results of the assays [10]. Thus, in its current form, the prothrombin time (PT), standardized as the International Normalized Ratio (INR), is not suitable for assessing the anticoagulant effect of Dabigatran. Nor is standardization between reagents and laboratories available for the very sensitive thrombin time (TT). [12] As a whole, while the PT and the aPTT provide little help distinguishing between treatment failure and non-adherence of patients, these routinely available clotting methods may be useful to establish whether the anticoagulant effect of a DOAC is higher than expected [an aPTT value twice the highest normal limit (i.e., [80 s) 12 h after the last administration of Dabigatran argues for G. Di Minno (&) E. Ricciardi A. Scalera Dipartimento di Medicina Clinica e Chirurgia, Clinica Medica, Università degli Studi di Napoli ‘‘Federico II’’ Napoli, Via S. Pansini 5, 80131 Naples, Italy e-mail: [email protected]