Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and is associated with an increased risk of stroke and other thromboembolic events. Approximately one in five of all strokes are caused by AF,1
with the risk of stroke increased by fourfold to fivefold in patients with AF compared with the general population.2
The condition is often asymptomatic,3
but mortality in patients with chronic AF has been reported to be up to 2.5 times higher than in the general population, with the relative risk of death higher in women than in men.4
The economic burden of AF is also high, with a key cost-driver being hospitalisation. This economic burden of AF has increased significantly over the last few decades, and is expected to increase even more in future due to ageing populations.5
Oral anticoagulants form the current standard of care for patients with AF considered at intermediate to high risk of stroke, and are effective therapies for stroke prevention.1
For many decades, warfarin was the only anticoagulant available; for now, three novel oral anticoagulant agents (dabigatran etexilate (later referred to as dabigatran), apixaban and rivaroxaban) have demonstrated superiority or non-inferiority to warfarin with respect to the primary efficacy outcome of stroke or systemic embolism in phase III randomised controlled trials (RCT).7–9
In RE-LY (n=18 113; intention-to-treat (ITT) population), dabigatran at a dose of 150 mg twice daily was associated with a lower rate of stroke or systemic embolism (relative risk (RR), 95% CI 0.65, 0.52 to 0.81; p<0.001 for superiority) and did not significantly increase major bleeding (RR, 95% CI 0.93, 0.81 to 1.07; p=0.32) when compared with warfarin. At a lower dose (110 mg, twice daily), dabigatran was associated with rates of stroke or systemic embolism that were similar to warfarin (RR, 95% CI 0.90, 0.74 to 1.10; p<0.001 for non-inferiority) but significantly reduced major bleeding compared with warfarin (RR, 95% CI 0.80, 0.70 to 0.93; p=0.003).7
In ARISTOTLE (n=18 201; ITT population), apixaban (5 mg, twice daily) was associated with a lower rate of stroke or systemic embolism (hazard ratio (HR), 95% CI 0.79, 0.66 to 0.95; p<0.001 for non-inferiority; p=0.01 for superiority) and reduced rates of major bleeding (HR, 95% CI 0.69, 0.60 to 0.80; p<0.001) when compared with warfarin.9
In ROCKET-AF (n=14 171; ITT population), rivaroxaban (20 mg, once daily) was associated with a similar rate of stroke or systemic embolism compared with warfarin (HR, 95% CI 0.88, 0.75 to 1.03; p<0.001 for non-inferiority, p=0.12 for superiority; ITT population) with no significant improvement in the rate of major bleeding (HR, 95% CI 1.04, 0.90 to 1.20; p=0.58, safety on treatment population).8
Of these three anticoagulants, only dabigatran and rivaroxaban were approved in Europe for stroke prevention in patients with AF at the time of study conduct and peer-review11
Although these three RCTs have demonstrated that the three new anticoagulants are superior or non-inferior to warfarin in terms of stroke prevention, these studies applied specific inclusion and exclusion criteria that may have excluded patients who would otherwise be treated in real-life clinical practice, currently with warfarin. Therefore, it is unknown as to whether the patient populations included in RE-LY, ARISTOTLE and ROCKET-AF reflect ‘real-world’ patients with AF, and therefore whether the study results can be generalised to the wider patient population.
To date there have been no studies comparing the eligibility criteria of these three trials. This study (RADAR: R
nd generalisability of the d
pixaban and r
ivaroxaban clinical trial populations to real-world AF patients in the UK) aimed to assess the differences between the three trial populations of RE-LY, ARISTOTLE and ROCKET-AF and the real-world patients with AF recorded within the General Practice Research Database (GPRD) in the UK. An analysis on patients at intermediate or high risk of stroke allowed a focus on patients for whom, according to current clinical guidelines,1
an anticoagulant could be prescribed. Risk of stroke is commonly assessed using stroke risk scores, such as the CHADS2
-VASc score has also been introduced and, based on multiple validation studies, is more accurate in identifying truly low-risk patients who do not require anticoagulation therapy and is at least as good as (possibly superior to) CHADS2
in identifying high-risk patients who develop thrombembolism.16
-VASc scores were used to stratify patients in the current study. The CHA2
-VASc scoring became available after the three clinical studies had been initiated.
It was hypothesised that the trial populations within RE-LY, ROCKET-AF and ARISTOTLE, as selected by the trial protocol inclusion and exclusion criteria, would vary in their representativeness to real-world AF populations, particularly for those eligible for anticoagulant treatment based on current guidelines.