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NOACs: Overview


collected from the Veterans Trial RE-LY


ROCKET-AF ARISTOTLE


ENGAGE TIMI 48* Combined


Stroke and systemic embolism


p 0.0001 0.12 0.012 0.10 0.81 0.5 Favours DOAC 1 <0.0001 0.86 0.5 Favours DOAC 1 Major bleeding p 0.34 0.72 <0.0001 0.0002 0.06


Administration Database by investigators including the US Food and Drug Administration (FDA), it was shown that patients newly starting therapy with dabigatran suffered approximately 28% more gastrointestinal bleeds than those commencing treatment with dose- adjusted warfarin. This same database, however, also demonstrated that strokes, intracranial bleeds and mortality were less with dabigatran, and myocardial infarction was not increased (Table 3).14 There are no studies reported in which rivaroxaban or apixaban are compared with warfarin, but in the case of rivaroxaban, early reports suggest adverse event profiles that are similar to relevant randomised trials.15


Some Result Efficacy


Ischaemic stroke 665/ 29292


Haemorrhagic stroke


Myocardial Infarction


All cause mortality


Safety


Intra-cranial haemorrhage


Gastrointestinal bleeding


204/ 29287


751/ 29287


425/ 29211


591/ 29211


0.48 1.25


0.39– 0.59


1.01– 1.55


<0.0001 0.043


0.25 Favours NOAC 1


Figure 1: Pre-specified meta-analysis of phase III trial of non-VKA oral anticoagulants versus dose adjusted warfarin all high dose patients; modified from Ruff C, et al. Lancet 2014 Mar 15;383(9921):955-62.


Table 3: Comparison of matched new-user cohorts treated with dabigatran etexilate 150mg or 75mg* or warfarin for non-valvular AF based on 2010–2012 Medicare data Incidence rate


per 1000 person-years Ischaemic stroke


Intracranial haemorrhage Major GI bleeding Acute MI Mortality


Dabigatran etexilate Warfarin 11.3 3.3


13.9 9.6


34.2 15.7 32.6


26.5 16.9 37.8


Adjusted HR (95% CI)


0.80 (0.67–0.96) 0.34 (0.26–0.46) 1.28 (1.14–1.44) 0.92 (0.78–1.08) 0.86 (0.77–0.96)


*Primary findings are based on analysis of both doses (no stratification by dose) From: Graham DJ, et al. Circulation. 2014


reduced. Mortality is reduced by 10% but ischaemic stroke is not. GI bleeding is significantly increased by approximately 25% (Figure 1).


Real-life experience Post-approval experience has been


collected assiduously for all NOACs that have been in use for some time. Initial concerns about excessive bleeding with dabigatran were shown, in part, to be related to inappropriate dosing in patents with renal impairment. However, in a large database (134,000 patients)


2 130/


29292 413/


29292


2022/ 29292


724/ 29221


263/ 29221


432/ 29221


2245/ 29221


0.92 0.49 0.97 0.90


0.83– 1.02


0.38– 0.64


0.78– 1.20


0.851– 0.95


0.10 <0.0001 0.97 0.0003


Pooled DOAC


Events/ total


Pooled warfarin


Events/ total


Risk ratio


95% p CIs


registries have demonstrated that although patients persist with NOAC therapy to a better extent than with VKA therapy, adherence is not as good as is theoretically needed with stroke prevention drugs that have short half-lives.16,17 Large longitudinal databases that are designed to span the introduction of NOAC therapy have already


demonstrated that the uptake of NOACs has been slow, no doubt due predominantly to financial concerns, but also to a reluctance on the part of some patients and doctors to forego the reassurance of regular routine monitoring of anticoagulation status.18 However, in many parts of the world, the registries show an increase in the proportion of at-risk AF patients who receive anticoagulants and a decrease in the use of aspirin or aspirin/ anticoagulant combination.19–23


reason, low-risk cases continue to be more often anticoagulated than is expected, perhaps because of repeated cardioversions and electrophysiological studies or ablation procedures. In some registries, these lower-risk cases seem to be more often treated with NOACs. As yet, only short-term outcome data available from these registries, and there is no information on whether outcomes differ according to which NOAC is chosen.


Outstanding issues with NOACs For the foreseeable future, NOACs, by virtue of their development costs, will remain expensive therapies that will not therefore be available to all of those with AF in need of thrombo-prophylaxis. It seems from one relatively small dose-


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For some


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