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Atrial fibrillation

apixaban- and edoxaban-dosing was reduced in these patients, but dabigatran dosing was not. In the Phase III trials, in patients with AF randomised to NOAC or warfarin, renal impairment was associated with higher rates of stroke and bleeding. Compared with warfarin, in terms of efficacy and safety the benefits of apixaban,20

and rivaroxaban21 were

maintained regardless of renal function.22 Irrespective of renal function, the efficacy of both dosages of dabigatran was maintained as well; however for major bleeding there were significant interactions between treatment and renal function.23

A meta-analysis of ten

randomised controlled trials identified 40,693 patients with renal insufficiency who were randomised to rivaroxaban, apixaban and dabigatran or comparator (VKA, aspirin, low-molecular weight heparin). In patients with mild or moderate CKD (CrCl 30–50ml/min), these NOACs were associated with decreased rates of thromboembolism compared to warfarin. Among patients with mild CKD (CrCl 50–79ml/min), major bleeding was also significantly decreased in patients who received NOACs; however, in patients with moderate CKD (CrCl 30–49ml/min) the overall bleeding rate was similar to warfarin, except for apixaban for which the risk bleeding was 50% less.24


meta-analysis on the efficacy and safety of NOACs versus warfarin subgroups of AF patients with varying degrees of renal dysfunction participating in Phase III trials has been conducted as well. NOACs had similar efficacy and safety compared to warfarin across different levels of renal function. With the caveats that accompany indirect comparisons of drugs in different trials, apixaban and edoxaban were associated with a better safety profile in patients with moderate renal impairment.25

In conclusion, these results support the use of NOACs in patients with mild to moderate CKD. In patients using NOACs, renal function should be monitored at least yearly. More frequent monitoring, that is, at six-month intervals, is recommended in patients ≥75 years of age using dabigatran, and quarterly monitoring of renal function is recommended in patients with CrCl 15–30ml/min.26

Assessment of dosing regimen There is a need for frequent monitoring and dose-adjustment of VKA-therapy

because of dietary- and drug-drug interactions, narrow therapeutic window and interindividual differences in metabolism of VKA. This need for monitoring is absent for NOAC therapy. Interestingly, in the lay press monitoring of VKA therapy is now sometimes presented as a means to ensure compliance with therapy. As with any drug, NOACs will not work if patients do not take them. Compliance to anticoagulation is of utmost importance to ensure adequate SPAF. Educational interventions involving patients, their family members, or both, can be effective in improving adherence, as well as simplifying the regimen to daily dosing. Although simple dosing (one pill, once daily) may help to maximise adherence,27 it is not known whether this will increase anticoagulant compliance for SPAF as well. A total of 50% of the patients with AF are using five to nine different drugs.28 Several cohort studies suggest that regular users of cardiovascular drugs as well as high-risk cardiovascular patients have better adherence than the (low risk) reference group, with no increase in medication possession ratio when QD dosing is compared to BID dosing.29–31 The pharmacokinetics of QD versus BID dosed drug may even favour their use in compliant patients. The pharmacokinetic equivalent of a single missed QD-dose are two to three sequentially missed BID doses, the likelihood of which is ~50% of the probability of the omission of a single QD-dose.32

In summary, in the absence of comparative data, a recommendation of QD dosed NOACs over BID dosed NOACs cannot be given, and the choice may be led by the patient’s preference.

Assessment of concomitant medication

NOACs do not require dose adjustment on the basis of coagulation tests. However, concomitant medication may necessitate dose adjustment. Personalised NOAC therapy therefore should include an accurate assessment of concomitant prescription and over the counter drugs. All NOACs are subject to intestinal re-secretion over a P-gp transporter. Verapamil, dronedarone and quinidine are examples of P-gp inhibitors that increase NOAC plasma levels. P-gp inducers such as rifampicin will reduce NOAC plasma levels and should generally be avoided. As dabigatran has a lower bioavailability than the other NOACs

(~7% vs ≥50%), P-gp inhibitors will affect dabigatran levels most.

CYP3A4 metabolism is involved in hepatic clearance of rivaroxaban and, to a lesser extent, of apixaban and edoxaban, but not of dabigatran. Strong CYP3A4 inducers or inhibitors will influence their plasma levels, especially rivaroxaban levels.

The concomitant use of a P-gp and/or strong CYP3A4 inhibitor per se does not necessarily indicate dose adjustment; however, in the presence of other risk factors that increase the risk of bleeding (for example, reduced CrCl) dose adjustment may be indicated. In general, for dabigatran, dose reduction should be considered in patients with moderate CKD (CrCl <50ml/min) and concomitant use of weak inhibitors of both CYP3A4 and P-gp inhibitors (for example, verapamil, amiodarone, quinidine). Concomitant use of dabigatran and strong P-gp inducers (for example, rifampin) should be avoided.

For apixaban, rivaroxaban and edoxaban, no dose adjustment is required when co-administered with the less potent inhibitors of P-gp and/or CYP3A4. Concomitant use of strong inhibitors of both CYP3A4 and P-gp inhibitors (for example, ketoconazole), or HIV protease inhibitors (for example, ritonavir) is not recommended. An extensive overview of the effect on NOAC plasma levels from drug–drug interaction and

recommendations for dose adjustment can be found in Heidbüchel et al.26

NOACs in the elderly Elderly patients treated with anticoagulants are at increased risk for major bleeding. More than one third of patients with AF are ≥75 years of age.1 When compared with warfarin, in terms of efficacy and safety, the benefits of apixaban,33 dabigatran36

rivaroxaban,34 edoxaban35

and were consistent regardless of

age. The efficacy of dabigatran for stroke prevention was independent of age as well, but the benefit in reducing major bleedings was attenuated with similar and higher bleeding rates compared to warfarin for dabigatran 110mg BID and 150mg QD, respectively.37 Dose reduction of NOACs seems prudent in patients with an additional bleeding risk factor or with concomitant use of drugs that increase NOAC plasma levels or drugs that increase bleeding risk.


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