Elsevier

International Journal of Cardiology

Volume 180, 1 February 2015, Pages 246-254
International Journal of Cardiology

Review
Non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in Asian patients with atrial fibrillation: Time for a reappraisal

https://doi.org/10.1016/j.ijcard.2014.11.182Get rights and content

Highlights

  • Data for Asians vs non-Asians were systemically reviewed in 4 megatrials of NOACs.

  • Warfarin induced more major bleeding and intracranial haemorrhage in Asians.

  • Bleeding events were generally lower for NOACs than Warfarin in Asians.

  • NOACs were superior or non-inferior to warfarin in stroke prevention in Asians.

  • NOACs should be preferentially indicated for stroke prevention in Asians with AF.

Abstract

Non-vitamin K antagonist oral anticoagulants (NOACs) have changed the landscape for stroke prevention in atrial fibrillation (AF). Given the huge burden of AF in Asians, more attention to stroke prevention is clearly needed. Aiming to provide an overview and reappraisal of stroke prevention in Asians with AF, we searched MEDLINE for information on NOACs in Asians. In addition, abstracts from national and international cardiovascular meetings were studied to identify unpublished studies.

In the 4 recent Phase 3 trials comparing NOACs to warfarin, a consistent pattern is evident. For efficacy endpoints in the comparison of NOACs vs warfarin, a significant reduction in stroke/systemic embolization was seen for dabigatran 150 mg [HR 0.45 (0.28–0.72)], with non-significant trends seen for lower stroke/systemic embolization with other NOACs, except edoxaban 30 mg. A similar pattern was seen for ischaemic stroke, with a significant reduction for dabigatran 150 mg [HR 0.55 (0.32–0.950]. For haemorrhagic stroke, all NOAC regimes, except rivaroxaban 20 mg, had significantly lower hazard ratios. No evidence of increased myocardial infarction was found for NOACs. All-cause mortality was significantly lowered amongst Asian patients on edoxaban 60 mg compared to warfarin [HR 0.63 (0.40–0.98)] with non-significant trends to lower mortality with dabigatran 150 mg, rivaroxaban and edoxaban 30 mg. For safety endpoints, all the NOAC regimes, except rivaroxaban 20 mg, significantly reduced major bleeding and ‘all bleeding’ events. Intracranial haemorrhage was consistently lowered by all NOACs. None of NOACs increased gastrointestinal bleeding. These information suggested that NOACs should be preferentially indicated for stroke prevention in Asians with AF.

Introduction

Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia, and represents a global problem [1]. Whilst the prevalence is broadly similar to epidemiological data from Western countries, given the size of the increasingly elderly Asian population (for example, in China), the absolute numbers of patients with AF in Asia are substantially higher than Europe or the United States [2]. Given the AF confers a substantial risk of mortality and morbidity from stroke, thromboembolism, heart failure, cognitive impairment and poor quality of life, the public health and healthcare burden associated with AF is huge.

Stroke prevention is central to the management of AF, given the increased risk of stroke and thromboembolism associated with this arrhythmia. Strokes associated with AF are associated with a higher mortality, greater disability, longer hospital stays and lower rates of discharge to one's own home.

Whilst it is well established that effective stroke prevention requires oral anticoagulation (OAC), the problem until recently was compounded by the substantial numbers of patients in Asia that are not treated with OACs (usually Vitamin K Antagonists (VKAs, e.g. warfarin), and even those managed with VKAs have poor quality anticoagulation control (as reflected by poor time in therapeutic range (TTR)) or not having access to a structured anticoagulation monitoring service [2], [3]. High quality anticoagulation control (e.g. average individual TTRs > 70%) has been associated with low rates of stroke and bleeding [4], [5], [6]. Thus, stroke rates whilst on warfarin therapy in some ‘real world’ Asian cohorts (where TTR is poor) are no different to those on aspirin or those untreated [7].

The availability of Non-VKA Oral Anticoagulants (NOACs, previously referred to as new or novel OACs) [8] has changed the landscape for stroke prevention in AF. These drugs offer relative efficacy, safety and convenience compared to the VKAs. The NOACs fall into 2 categories — the oral direct thrombin inhibitors (e.g. dabigatran) and the oral Factor Xa inhibitors (e.g. rivaroxaban, apixaban and edoxaban) and have been compared to warfarin in large Phase 3 clinical trials. These trials were conducted as global trials, and substantial numbers of patients from Asian countries were participants.

The objective of this review is to provide an overview and reappraisal of stroke prevention in Asian patients with AF, with particular focus on the data on NOACs in Asians.

Section snippets

Search strategy

We searched MEDLINE using the following terms individually and/or in combination: ‘Asians’, ‘atrial fibrillation’, ‘stroke’, ‘thromboembolism’ ‘anticoagulation’, ‘antiplatelet therapy’, ‘dabigatran’, ‘rivaroxaban’, ‘apixaban’, ‘edoxaban’, ‘direct thrombin inhibitors’, ‘Factor Xa inhibitors’, and ‘NOACs’. In addition, abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. The extensive detailed literature on the underlying pathophysiology

Epidemiology — a brief overview

Much of the epidemiology of AF comes from Western countries. A recent systematic review of epidemiology of AF in regions outside North America and Europe found that the reported prevalence of AF varied amongst countries, with different ranges in community- and hospital-based studies (0.1%–4% and 2.8%–14%, respectively) [1]. The use of anticoagulant therapy varied widely amongst countries and studies, as did the reported prevalence of stroke in patients with AF (2.8%–24.2%).

Specific data on

Aspirin in Asian patients

What about antiplatelet therapy? In the historical trials, aspirin had a small and non-significant 19% reduction in stroke, with no impact on mortality [33]. This 19% reduction was driven by the one single positive trial (SPAF-1) which had major internal heterogeneity for the aspirin effect against placebo/control, reducing stroke by 94% in anticoagulation-eligible patients and by only 8% in anticoagulation-ineligible patients. The SPAF-1 trial used aspirin 325 mg daily and had been stopped

Data on warfarin in Asians

In the 4 recent Phase 3 trials comparing NOACs to warfarin, a consistent pattern is evident. There were generally higher rates of stroke/systemic embolism (the primary efficacy endpoint), ischaemic stroke and haemorrhagic stroke on warfarin in Asians vs non-Asians, despite similar or lower CHADS2 scores (Fig. 1) [16], [17], [18], [19]. All-cause mortality was higher in Asians on warfarin, compared to non-Asians in RE-LY, but not in the other 3 trials. Myocardial infarction events tended to be

A practical approach

Rather than focus on targeting ‘high risk’ patients for OAC use, a clinical practice shift is needed, so that the initial step is identification of the ‘truly low risk’ patients with AF. These ‘truly low risk’ patients are those ‘age < 65 and lone AF (both male and female)’, essentially a CHA2DS2-VASc score = 0 (male) or 1 (female). Subsequently, OAC can be offered to all other patients with ≥ 1 stroke risk factors. Ultimately effective stroke prevention requires OAC use, whether delivered as a

Conclusions

Given the huge burden of AF and its complications related to stroke/SE in Asian countries, more attention to stroke prevention is clearly needed. Patients place more emphasis on stroke prevention than physicians. In one recent study, patients were prepared to sustain 4 major bleeds, just to avoid one stroke which was viewed as a fate worse than death [53]. In contrast, physicians were more concerned with bleeding, at the cost of patients sustaining strokes [54]. Unless VKA management improves

Author contribution

G.Y.H. Lip made main contributions in study conception, data interpretation and manuscript drafting/revisions. KL Wang made the primary contribution in data collection, figure drawing, and manuscript drafting/revisions. CE Chiang made the contribution to study conception, data interpretation and manuscript revisions. All authors contributed to the interpretation of results, revising the manuscript critically for important intellectual content, and all approved the final manuscript.

Conflict of interest

Dr. Lip has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi Aventis, BMS/Pfizer, Biotronik and Boehringher Ingelheim and has been on the speakers bureau for Bayer, BMS/Pfizer, Boehringher Ingelheim, and Sanofi Aventis. Dr. Wang has been on the speakers bureau for Astrazeneca, and Bayer. Dr. Chiang has been on the speakers bureau for Astrazeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, GSK, MSD, Novartis, Pfizer, Roche, Sanofi-aventis, Servier, Tanabe, Takeda,

Acknowledgements

This work was supported, in part, by grants from the Taiwan Ministry of Health and Welfare (MOHW103-TDU-B-211-113-003), the National Science Council in Taiwan (NSC102-2628-B-075-004-MY3), and intramural grants from the Taipei Veterans General Hospital (V103B-024; V103C-051; V100D-002-3).

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