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Atrial fibrillation

Table 1: NOACs: renal excretion and dosing Dabigatran

Renal excretion Recommended dosing 80% 150mg BID

CrCl 30–49ml/min 150mg BID

Dosing if chronic kidney disease

Additional dosing adjustments as per SmPC

Consider 110mg BID if high risk of bleeding

CrCl 15–30ml/min: 75mg BID (US only)


Apixaban 27%

5mg BID

CrCl 15–29ml/min: 2.5mg BID

– – If two of:

• creatinine ≥1.5 mg/dl • age ≥80 years • <60kg 2.5mg BID

Contra-indicated/not recommended

Contraindicated: CrCl <30ml/min

Not recommended: CrCl <15ml/min

Not recommended: CrCl <15ml/min

Rivaroxaban 35%

20mg QD

CrCl 15–49ml/min: 15mg QD

– – –

Edoxaban 50%

60mg QD

CrCl 15–49ml/min: 30mg QD

– –

If any of: • ≤60kg

• concomitant therapy with dronedarone, ketoconazole, ciclosporin, erythromycin

Not recommended: CrCl <15ml/min

year, and initiation of anticoagulation is not recommended. In AF patients with one additional CHA2DS2-VASc risk, the annual ischaemic embolic risk varies from 0.5 to 1.3%/year,5,6

leading to a neutral or positive net clinical benefit of

anticoagulation. According to the class IIa level B recommendation in the European Society of Cardiology Guidelines, in these patients: “anticoagulation should be considered based upon an assessment of the risk of bleeding complications and the patient’s preference”.7

In AF patients with

CHA2DS2-VASc score ≥2, there is an obvious net clinical benefit of anticoagulation.7

Most risk factors for stroke, however, are also risk factors for bleeding. The HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs) bleeding risk score assigns one point for each of its constituents (hypertension >160mmHg). HAS-BLED scores ≥3 indicate a high risk of bleeding. A HAS-BLED score of ≥3, however, should not be used to exclude patients from anticoagulation therapy, but to address modifiable bleeding risks. Net clinical benefit analyses suggest that the effect of anticoagulation is even more positive in patients with a high HAS- BLED score.8


Choice of anticoagulation AF-related thrombi are fibrin-rich ‘red’ clots, opposed to platelet-rich ‘white’ clots as seen in coronary artery disease. This explains the superior efficacy of warfarin over aspirin for SPAF: in patients with AF, dose-adjusted warfarin with a target INR of 2.0–3.0 reduces the risk of stroke

whereas antiplatelet therapy reduces the risk of stroke by only 19%.10 Thus, considering that the bleeding risks for aspirin are not significantly different to that of vitamin K antagonists (VKAs),8 aspirin should not be used for SPAF. More recently, the efficacy and safety of the direct thrombin inhibitor dabigatran, and the factor Xa inhibitors apixaban, rivaroxaban and edoxaban for SPAF have been established in pivotal Phase III trials.11–14

by 62%,9 Besides similarities,

there are distinct differences between the Phase III NOAC trials. Given the heterogeneity of the different trials and in the absence of head-to-head studies, the comparative efficacy of the individual NOACs cannot be assessed. In a meta-analyses of these trials, NOACs compared with warfarin significantly reduced the risk of stroke (hazard ratio (HR) 0.81; 95% CI 0.73– 0.91). This 19% reduction was mainly driven by a 51% reduction in haemorrhagic stroke (HR 0·49; 95% CI 0·38–0·64). Furthermore, the use of NOACs was associated with a non- significant decrease of major bleeding (HR 0·86; 95% CI 0·73–1·00), but increased risk for gastrointestinal bleeding (HR 1·25; 95% CI 1·01–1·55).15 When interpreting these results, differences between trial populations, individual NOACs and, where applicable, between doses should be appreciated. Based on their favourable benefit–risk ratio, the use of NOACs is now recommended for SPAF in international guidelines.7,16

The effectiveness of NOACs in the real- life setting compares well to the Phase III results,17,18

and is consistent across

multiple subgroups examined, with no interaction for age or creatinine clearance.15

Therefore, once the need for anticoagulation has been established, based on their net clinical benefit, a NOAC should be considered rather than dose-adjusted VKA.7,16

Which NOAC best fits a patient should be based on individualised choices. To reduce the risk of adverse events, it is essential to select the appropriate patients for treatment with the appropriate NOAC. Decisive in the choice for a particular NOAC are

pharmacological properties such as renal clearance and dosing schedule on the one hand, and patient-related clinical parameters, such as comedications, risk of stroke and bleeding and renal function on the other hand. Individualised NOAC treatment allows for optimised stroke prevention in patients with a low risk of bleeding, and optimal bleeding prevention in patients with high risk of bleeding.

Use of NOACs in chronic kidney disease

In patients with AF, renal failure is a risk factor for both stroke and bleeding.19 Renal clearance of the individual NOACs varies considerably, from 25–50% for the Factor Xa inhibitors to 80% for dabigatran (Table 1). By contrast, renal clearance of warfarin is <1%. Chronic kidney disease (CKD) of moderate severity (creatinine clearance (CrCl) 30–49ml/min) was present in 16–20% of patients with AF who were randomised to a NOAC or warfarin in Phase III trials. As pre-specified per protocol, rivaroxaban-,

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