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Stroke prevention in atrial fibrillation: 08 December 2015BCS Editorial By: Farhan Shahid
Stroke prevention in atrial fibrillation: Focus on optimal risk stratification and anticoagulation in Asian population Introduction Atrial Fibrillation (AF) is a global epidemic [1]. With the emergence of improved therapies for the management of cardiovascular disease it is estimated that by 2050, 16 million American will have AF [2]. Although traditionally described as a diagnosis of the elderly, a growing population with high prevalence of cardiovascular risk factors and overt cardiovascular disorders make the problem of AF relevant in Asian countries. This is particularly true as industrial development leads to increased life expectancy and consequently even greater number of AF patients in the region, one of the most populated regions in the world. With high mortality, morbidity and healthcare costs attributable to AF-related strokes optimisation of stroke prevention strategies adjusted for ethnic differences of the Asian population is of great importance [3, 4]. The diagnosis and management of AF should be made on an individual basis, with a patient-centered and symptom directed approach. However, irrespective of whether a rate or rhythm control strategy is chosen in individual subjects’ adequate stroke prevention is crucial for all of them. There is accumulating evidence that within different ethnic backgrounds effectiveness of standard approaches for diagnosis and management of AF can vary [5] [6]. This review article discusses issues associated with the global burden of AF and analyses current risk stratification and management of AF in Asian patients. The article overviews current practices and recommendations for reduction of stroke and bleeding risk in Asian patients with AF. Risk stratification of patients with AF The risk of AF related stroke is not homogenous among different patients and is based on the risk factor profile of the patient. Risk stratification tools allow the quick and effective assessment of AF related stroke on an individual basis and help guide recommendations for OAC. The CHA2DS2-VASc score is the main clinical scoring system that has been extensively validated in different patient populations [7] and is now recommended by the American College of Cardiology (ACC), the European Society of Cardiology (ESC) and the NICE guidelines [8-10]. The additional use of the HAS-BLED score of risk of bleeding is helpful in balancing the risk and benefits of OAC and this can be particularly helpful for risk management in Asian patients due to the higher bleeding tendancy in this population. In fact, this scoring system has also been validated in patients of Asian origin and has been shown to be a predictor of major bleeding complications for patients on warfarin (i.e., HAS-BLED score of >3) [11]. Of note, a high HAS-BLED score is not a reason to withhold indicated OAC but it flags up patients at risk of bleeding and in need for more careful review and follow-up to address the potentially correctable risk factors for bleeding. Early guidelines were often based on the older CHADS2 scoring system but various studies, including those in Asian cohorts have shown that even a CHADS2 score 0 still leaves a proportion of patients exposed to risk of stroke without OAC. The stroke rates were as high as 3.2%/year in patients with CHADS2 score 0, if left untreated [12, 13]. Introduction of the CHA2DS2-VASc score has addressed this issue and it was able to further refine stroke risk stratification [12, 13]. Indeed, a recent systematic review conducted in Asian cohorts of AF patients found that the CHA2DS2-VASc score outperformed the CHADS2 score in identifying ‘low risk’ patients [14]. One of the largest community based Asian cohort studies of elderly (>85 years of age) patients found that such patients are at higher risk of AF related stroke and death, but had broadly similar major bleeding rates compared to younger AF patients [15]. Underutilisation of OAC, inaccurate risk stratification and suboptimal time in therapeutic range (TTR) when using warfarin have been proposed as a cause for this heightened stroke risk. Using the Taiwan national insurance database, Chao et al [16] studied nearly 13,000 patients with AF without OAC and identified that a CHA2DS2-VASc score of 1 in males and 2 in females equates to an overall ischaemic stroke rate of 3.75%/year in males and 3.5%/year in females. Therefore, in line with the current ESC and NICE guidelines, patients with ‘moderate risk’ defined as CHA2DS2-VASc score 1 and females with a CHA2DS2-VASc score 2 should be considered for OAC within the Asian population. A Japanese study compared using the CHA2DS2-VASc score against a modified version that excluded female sex and concluded that female sex did not add to the predictive value of the CHA2DS2VASc score in Japanese patients who were non-anticoagulated at baseline [17]. However, this study should be interpreted with caution as only baseline antithrombotic therapy was known and whether OAC was started during follow up was unknown nor adjusted for [17]. In summary, based on the available evidence, the CHA2DS2-VASc score should be used to assess AF related stroke risk in the Asian population. The first step is to identify patients in truly at ‘low risk’ of stroke (CHA2DS2-VASc score 0 in males and 1 in females) who do not need OAC. In those patients with ≥1 risk factor(s) for stroke except gender, OAC should be used unless firmly contraindicated. What evidence do we have for NOACS in the Asian population? Four large well-conducted randomised clinical trials compared NOACS to warfarin in AF [18-21]. All NOACS were proven to be non-inferior to warfarin with regards to prevention of stroke and systemic thromboembolism. High dose dabigatran and apixaban were found to be superior to warfarin for this purpose. Apixaban and low dose edoxaban reduced all cause mortality. All these trials have consistently shown a lower incidence of haemorrhagic stroke and intracerebral haemorrhage with NOACs compared to warfarin. Apart from apixaban higher rates of gastrointestinal bleeding were found with NOACs. A meta-analysis of the trials has demonstrated a significant overall 19% reduction in stroke/systemic embolic events in the 42,000 patient taking a NOAC globally[22]. Reduced dose NOAC regimens provided stroke/systemic embolisation protection not inferior to that with warfarin but had a more favourable bleeding profile [22]. The expense of added safety was a significantly higher rate of ischaemic strokes compared to higher doses of the same NOACs [22]. Wang et al performed a meta-analysis of data from Asian participants of the 5 major trials of NOACs (RE-LY, ROCKET AF, J ROCKET AF, ARISTOTLE, ENGAGE AF-TIMI 48) [23]. It included analysis 5250 Asian patients taking a NOAC and 3678 patients receiving warfarin. The effect of NOACs for prevention of stroke and systemic embolization was significantly more prominent in the Asian cohort (p for interaction = 0.045). NOACs were also more effective in Asians for reduction in all cause mortality [23]. Furthermore standard doses of NOACs were also found to have a superior safety profile in Asians vs. non-Asians in the same meta analysis [23]. This was applicable for both major bleedings and intra cerebral haemorrhage. Also the rate of gastrointestinal bleeding was not increased in Asians receiving NOACs, as was the case in the non-Asian population. The meta-analysis thus supports wider usage of NOACs in AF patients in Asian countries (Figure 4 and Figure 5). When assessing the health economic effectiveness of the NOACs higher direct costs of the drugs need further adjustment for the overall benefits achieved. Health economic analyses specific to the Asian population are limited and carry small patient numbers and conclusions often rely on data from Western populations [24-26]. When other variables are considered in addition to the drug costs (e.g., fewer unfavorable outcomes and no need for monitoring) NOACs appear to be cost-effective [27]. All 3 NOACs available at the time of appraisal (dabigatran, rivaroxaban, apixaban) have been deemed cost effective by NICE compared warfarin [28] Conclusion With an ever-ageing population the prevalence of AF will continue to increase [1]. The prevalence of AF in Asian countries is on a steep rise compared to other countries and at present identification and management of AF patients in these countries remains suboptimal [29]. Continued use of the older risk scores will fail to identify truly low risk patients and will expose patients to AF related stroke that would otherwise warrant anticoagulation if the CHA2DS2VASc score was used [14]. Use of a lower INR target range does not provide optimal stroke prevention in Asians and a higher bleeding risk in Asian population should be minimized by attention to the TTR. Large patient cohort studies suggest that warfarin might not be the best choice in Asian patients, partly do to presence of specific genetic polymorphisms. However there is evidence that this ethnic group can particularly benefit from NOACs compared to non-Asian populations [23]. NOACs provide an attractive management option in view of their efficacy, safety and convenience of use. A shift away from vitamin K antagonists to NOACs is expected and encouraged in the Asian population with the provision for optimal stroke prevention and reductions in bleeding. References 1. Chugh, S.S., et al., Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation, 2014. 129(8): p. 837-47.
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