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NOACs: Overview

Table 2: Phase III randomised controlled trials of non-VKA oral anticoagulants versus dose-adjusted warfarin RE-LY


Drug n

Dose (mg) Frequency

Initial dose reduction Dose reduction at baseline (%)

Dabigatran Rivaroxaban Apixaban Edoxaban 18,113

150, 110 BID No


14,264 20

QD 20/1 mg 21

18,201 5

BID 21,105

60¦30 QD

5/2.5mg 60/30mg 30/15mg

5 25; an

additional 7% were dose

reduced during the study

Mean CHADS2 score VKA naÏve (%)

Paroxysmal AF (%) Prior stroke, TIA (%) Design

Follow up (years)

2.1 50 32 20

3.5 38 18

55 Open label Double blind 2.0

bioavailability is very limited. By contrast, the bioavailability of the Factor Xa drugs is high, although in the case of rivaroxaban is dependent on the drug being taken with food (an important clinical instruction for the patients). Dabigatran has an important adverse effect of gastrointestinal (GI) intolerance, which limits its use in approximately 10–15% of patients. Dabigatran is not highly protein-bound and can be dialysed off in an emergency, but the other agents are too strongly bound to allow this.

NOAC Phase III trials All four drugs have been investigated extensively (Table 2) but all are also subject to further trials exploring new indications or stroke prevention in special situations in patients with or without AF. The drugs are also subject to the collection of post-approval ‘real- world’ data for regulatory purposes, or to extend the safety database for each of the compounds. The Phase III trials, RE-LY with dabigatran,9


rivaroxaban,10 ARISTOTLE with and ENGAGE-AF with were controlled studies

apixaban,11 edoxaban,12


against dose-adjusted warfarin, in most cases utilising a double-dummy technique. The RE-LY study used a PROBE (prospective, randomised, open, blinded endpoints) design in order not to conflict interpretation by adding the effects of regular International normalised ratio (INR) monitoring to the experience with dabigatran. In the case of 1.9

2.1 43 15 19

Double blind


2.8 41

25 28

Double blind 2.8

apixaban, a trial against aspirin was also undertaken (AVERROES) although the result was so much in favour of apixaban that it was discontinued prematurely.6

plasma concentrations of the NOAC) was compared against warfarin. In ENGAGE- AF, there was also the option to reduce the dose in both strategies for appropriate patients. RE-LY and ARISTOTLE studied relatively low-risk cases (mean CHADS2

= 2.1), whereas

ENGAGE-AF recruited a higher risk of cohort (mean CHADS2

= 2.8) and in

ROCKET-AF, the patients had the highest risk (mean CHADS2

= 3.5). These

differences are of importance when interpreting the trials and especially if any attempt is made to compare the results of the trials.


of the comparative studies against warfarin were very large – between approximately 6000 and 9000 patients per arm of the study. In the case of RE-LY and ENGAGE-AF, two doses or dosing strategies of NOAC were compared with warfarin treatment (three-armed studies) but in ARISTOTLE and ROCKET-AF, a single dose (with the possibility of using a lower dose for patients who might otherwise have high

All of the trials, when using the high dose (or higher dosing schedule) showed a numerical reduction in the proportion of patients with the common primary efficacy endpoint (stroke and systemic embolus) although using the intention- to-treat analysis, the reduction proved to be non-inferior to warfarin in ROCKET- AF and ENGAGE-AF and superior to warfarin in RE-LY and ARISTOTLE. Similarly there was a clear reduction of major bleeding (the primary safety endpoint) in ARISTOTLE and ENGAGE- AF and there was no significant difference in RE-LY and ROCKET-AF. The low dose/dosing schedule within RE-LY and ENGAGE-AF was associated with significantly less major bleeding. In all the trials, there was a significant reduction of intracranial haemorrhage, intracerebral bleeding and bleeding in other critical sites.

There were some interesting differences in the results of the studies. The endpoint of ischaemic stroke was significantly reduced only in the high- dose dabigatran limb of RE-LY, but bleeding in the elderly was also increased with this dose. GI bleeding was not increased in ARISTOTLE, but although numerically less than in the warfarin arm, was not a significant reduction. In the ENGAGE-AF trial, the lower dosing schedule with edoxaban was associated with lower rates of composite endpoints including death, stroke, and major bleeding.


Meta-analysis of the Phase III results demonstrates a highly significant reduction in stroke and systemic embolism and a strong trend towards the reduction of major bleeding.13 Intracerebral haemorrhage (safety endpoint) and haemorrhagic stroke (efficacy endpoint) are both significantly

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