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Patient management

Figure 3: Conversion of NOAC to VKA

were no bleeding events, the prophylactic use of haemostatic blood products, such as prothrombin complex concentrate (PCC), for reversal of the effects of NOAC is not recommended.5,6 However, in cases of severe bleeding, PCC should be considered.

What is the difference between coagulation monitoring and measurement?

NOACs show predictable pharmacokinetics and

pharmacodynamics in Phase I and Phase II studies, and coagulation had not been measured routinely in any of the Phase III studies, further confirming that routine coagulation monitoring is not required. However, in practice, coagulation measurement may be useful in certain clinical


circumstances and patient populations, such as in suspected overdose, in patients with a haemorrhagic or thromboembolic events during treatment with an anticoagulant, in those with acute renal failure, or in patients who require urgent surgery. Coagulation tests for quantitative assessment of drug levels by measuring anti Xa- or anti IIa activity in the blood have become commercially available; however, there are currently no clinical data showing an association between the measured trough or peak drug levels and thrombotic or bleeding risk.6 When interpreting a coagulation assay in a patient treated with a NOAC, in contrast to VKA coagulation monitoring, it is paramount to know exactly when the NOAC was administered relative to the time of blood sampling.5

Which patient characteristics play a major role for the management of NOACs?

The patient’s age, renal and hepatic function, body weight and the intake of concomitant medications play a major role for the management of NOACs and may be decisive for dose selection. However, there are differences among the various NOAC compounds and the specific recommendations of the manufacturers need to be followed. As NOACs are mainly (dabigatran), or to some extent, renally excreted, renal function should be assessed in all patients, ideally using the Cockcroft– Gault formula to estimate the CrCl, before initiating long-term NOAC therapy, and at least once annually thereafter for the direct Factor Xa inhibitors, and more frequently for dabigatran. However, close monitoring of renal function and assessment of plasma drug level is also recommended with the direct Factor Xa inhibitors in patients with a CrCl of 15–29ml/min, to ensure that there is no accumulation of the drug.

In contrast to VKAs, NOACs have few clinically relevant interactions with other drugs such as drugs affecting the CYP3A4 and P-gp pathways; these interactions are detailed by the manufacturers for each NOAC, and recommendations should be followed. Co-administration of anticoagulants with agents that also affect the haemostatic system, such as antiplatelet agents and non-steroidal anti- inflammatory drugs, increases the risk of bleeding. Therefore, these co- medications should be given with caution.

Interestingly, a recent analysis of data from the ENGAGE AF-TIMI 48 trial correlated edoxaban dose, plasma concentration, and anti-Factor Xa activity and compared efficacy and safety outcomes with warfarin stratified by dose reduction status. In ENGAGE AF-TIMI 48, edoxaban doses were halved at randomisation or during the trial if patients had CrCl 30–50ml/min, body weight 60kg or less, or concomitant medication with potent P-glycoprotein interaction. The authors showed that tailoring of the dose of edoxaban on the basis of clinical factors alone prevented an excess drug concentrations and therefore, routine measurements of drug levels would not further increase the safety of this drug.7

Conclusions In contrast to VKAs, NOACs are given in fixed dosing regimens. These dosing regimens are not adjusted to coagulation testing but may be adjusted to patient characteristics, for example, renal function, co-medications and other parameters. The management of patients treated with NOACs has become easier than with VKAs; however, some basic principles need to be followed. l

References 1. Hirsh J et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119(Suppl): 8S–21S.

2. Heidbuchel H et al. EHRA Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34:2094–106.

3. Savelieva I, Camm AJ. Practical considerations for using novel oral anticoagulants in patients with atrial fibrillation. Clin Cardiol 2014;37: 32–47.

4. Eikelboom JW, Weitz JI. Update on antithrombotic therapy - new anticoagulants. Circulation 2010;121:1523–32.

5. Heidbuchel H et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625–51.

6. Haas S et al. Practical guidance for using rivaroxaban in patients with atrial fibrillation: balancing benefit and risk. Vasc Health Risk Manag 2014;10:101–14.

7. Ruff CT et al. Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015;385(9984):2288–95.

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