Navigating the fine line between benefit and risk in chronic atrial fibrillation: Rationale and design of the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY)

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Abstract

Background

Health outcomes associated with atrial fibrillation (AF) continue to be poor and standard management often does not provide clinical stability. The Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY) compares the efficacy of a post-discharge, nurse-led, multi-disciplinary programme to optimise AF management with usual care.

Methods

SAFETY is a prospective, multi-centre, randomised controlled trial with blinded-endpoint adjudication. A target of 320 hospitalised patients with a chronic form of AF will be randomised (stratified by “rate” versus “rhythm” control) to usual post-discharge care or the SAFETY Intervention (SI). The SI involves home-based assessment, extensive clinical profiling and the application of optimal gold-standard pharmacology which is individually tailored according to a “traffic light” framework based on clinical stability, risk profile and therapeutic management. The primary endpoint is event-free survival from all-cause death or unplanned readmission during 18–36 months follow-up. Secondary endpoints include rate of recurrent hospital stay, treatment success (i.e. maintenance of rhythm or rate control and/or application of anti-thrombotic therapy without a bleeding event) and cost-efficacy.

Results

With study recruitment to be completed in early 2012, the results of this study will be available in early 2014.

Conclusions

If positive, SAFETY will represent a potentially cost-effective and readily applicable strategy to improve health outcomes in high risk individuals discharged from hospital with chronic AF.

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with a lifetime risk of around one in four among North Americans and Europeans [1], [2]. Described as the next cardiac “epidemic” [2], the consequences will not be benign given that chronic AF is independently associated with substantial morbidity and mortality [3], [4]. Accordingly, contemporary studies suggest that both the primary care [5] and hospital burden [3], [6] attributable to AF is increasing in parallel with ageing populations in whom cardiac risk factors and other forms of heart disease are highly prevalent [6]. AF has also started to appear in historically high numbers in low-to-middle income countries [7]. From a cardiovascular perspective, the nexus between AF and two common causes of death and disability, stroke and chronic heart failure (CHF), is of concern given a two-way “cause and effect” relationship—AF is associated with a 4–5 fold increase in the risk of stroke [8] and is found in up to 25% patients with an acute ischaemic stroke. Moreover, AF-related strokes are more severe and more debilitating than those associated with other aetiologies with worse short and long-term survival [9]. Similarly, individuals with AF are approximately 2.5-fold more likely to develop CHF [10]. Data from the EuroHeart Failure Survey showed that one third of patients hospitalised for CHF had AF prior to hospitalisation and 9% were diagnosed with new onset AF during that admission [11]. A recent meta-analysis of 16 studies reported a two-fold increase in mortality associated with AF in those with both preserved and impaired systolic function [12]. Overall therefore, AF poses a significant public health and clinical challenge that has many parallels to that of CHF. For example, the evolution of anti-thrombotic therapy was recently advanced with the results of the ARISTOTLE Study [13] demonstrating that apixaban (a direct factor Xa inhibitor) was superior to warfarin in preventing stroke or embolism whilst being associated with less bleeding and more prolonged survival. However, treatment discontinuation rates were high in both groups. Unfortunately, a conservative approach by clinicians has resulted in a substantial treatment “gap” in AF management to date [14], [15], [16]. Moreover, the number of older individuals with chronic forms of AF in whom residual issues of the real-world effectiveness and safety will need to be addressed is likely to rise [17]. In CHF, this critical issue was addressed through the development of dedicated management programmes that simultaneously reduced recurrent hospital stay and prolonged survival [18].

This paper reviews the challenges and clinical conundrums that have shaped the design of the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY), with respect to balancing the fine line between benefit and risk in applying modern therapeutics in typically elderly and fragile patients who have been hospitalised with a chronic form of AF. Preliminary studies have explored the benefits of applying AF-specific disease management via home-based management [19] and a specialist AF clinic [20]. This prospective, multicentre, randomised study will determine if a multidisciplinary, nurse-led, home-based programme of AF-specific management delivered post-acute hospitalisation will improve health outcomes relative to standard management in patients with chronic AF.

Section snippets

Therapeutic targets in AF

There are three key priorities underlying the management of AF (particularly chronic forms), which vary in importance according to the clinical profile of the affected individual:

  • 1.

    Reduce the risk of a thrombo-embolic event: an ischaemic stroke, as the most common and deadly form of such events, is the primary target for prevention. The intensity and potency of treatment is dependent on the risk of stroke and is balanced by the counter risk of bleeding events (e.g. a fatal haemorrhagic stroke).

  • 2.

Study design

Fig. 1 shows the design of the SAFETY study. A target of 320 eligible patients will be recruited from three tertiary referral hospitals in South Australia, Victoria and the Australian Capital Territory. Patients will be subject to stratified randomisation (according to baseline intention to apply “rate” or “rhythm” control) to either usual care (UC) or the nurse-led, home-based SAFETY intervention (SI) at a ratio of 1:1.

To our knowledge, the SAFETY study will be the first prospective,

Discussion

The burden and consequences imposed by a modern epidemic of chronic forms of AF in our ageing populations in whom pre-existing risk factors and established heart disease are prevalent requires an urgent response. A rising epidemic of CHF was similarly addressed. Part of the current response has to focus not only on developing new therapeutic options that shift the benefit-to-risk ratio of treatment into much safer territory, but also developing cost-effective management programmes that can

Acknowledgements

The SAFETY study is funded by a National Health and Medical Research Council of Australia Program Grant (519823). In addition, MC, JB and SS are supported by the National Health and Medical Research Council of Australia. This research is supported in part by the Victorian Government's Operational Infrastructure Support Program.

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

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