LAUSR

During the several decades of clinical use of warfarin in patients with atrial fibrillation (AF), prescribers have been accustomed to the possibility of modulating the intensity of oral anticoagulation therapy (OAT). While the international normalized ratio (INR) range of 2.0–3.0 has long been identified as the optimal target intensity for most patients, allowing to balance efficacy on stroke prevention against safety in terms of bleeding events, different ranges of INR have been recommended in specific clinical contexts. For example, an INR ≤ 1.5 should be aimed at before elective surgery [1], whereas an INR of 2.5–3.5 should be maintained with some mechanical heart valves [2]. Since the modulation of the intensity of OAT with warfarin is achieved by individualizing the dose of the drug, the obvious question arises whether the same can be achieved with the direct oral anticoagulants (DOAC) dabigatran, rivaroxaban, apixaban, and edoxaban, each of which is available in two different doses (i.e. 150/110 mg, 20/15 mg, 5/2.5 mg, and 60/30 mg, respectively) [3]. In accordance with the first-order kinetics [4], the drug plasma concentration and anticoagulant effect, as measured by anti-factorXa activity, of factor-Xa inhibitors have been shown to be proportional to dose reduction [5–7]. At variance, in the presence of clinical and/or laboratory factors [including creatinine clearance (CrCl) 30–50 mg/dL for rivaroxaban; two or more of age ≥ 80 years, body weight ≤ 60 kg, and/ or serum creatinine ≥ 1.5 mg/mL for apixaban; and one or more of body weight ≤60 kg, CrCl 30–50 mg/dL, and/ or concomitant use of potent P-glycoprotein inhibitors for edoxaban], which all ultimately lead to an increase in drug plasma concentration and associated anticoagulant effect, the lowering of these two latter was less and not proportional to dose reduction [5–7]. Therefore, in the above contexts, reducing the dose of factor-Xa inhibitors did not aim at modulating (lowering) the intensity of OAT, but rather at not changing it compared with patients without the aforementioned factors receiving the higher dose. Indeed, apart from edoxaban, which at the lower dose was showing further excess safety compared with warfarin [3], no significant interaction as regard both efficacy and safety was observed in the three pivotal randomized clinical trials between higher and lower doses of factor-Xa inhibitors [3]. Differently from factor-Xa inhibitors, dabigatran, also showing a first-order kinetics [4], was randomly administered at two different doses to two identical AF populations (and therefore the same population) [3]. In accordance, a largely proportional 40% reduction in plasma concentration was observed when decreasing the dabigatran dose by about 30%, from 150 to 110 mg [8]. Indeed, in comparison with warfarin, higher safety and comparable efficacy was found with dabigatran 110 mg, whereas comparable safety and higher efficacy was reported with dabigatran 150 mg [3]. Therefore, reducing the dose of dabigatran truly aimed at modulating (lowering) the intensity of OAT. Whereas dose reduction of factor-Xa inhibitors is determined by specific clinical and/or laboratory patient variables, and is therefore mandatory, for dabigatran it is optional and is based on the aim of greater safety versus greater efficacy pursued by the prescriber (Fig. 1). A few exceptions to this rule need to be kept in mind. First, based on pharmacological considerations and/or post hoc analyses of the RE-LY trial [9, 10], the dabigatran 150 mg dose needs to be mandatorily reduced in North America to 75 mg when CrCl is 15–30 mL/min, and in Europe to 110 mg when age is ≥80 years and/or verapamil is administered concomitantly [3] (Fig. 1). Second, based on the design and results of the PIONEER AF-PCI trial [11], the rivaroxaban 20 mg dose * Andrea Rubboli [email protected]