Is Atrial Fibrillation a Stroke Risk Factor or Risk Marker? An Appraisal Using the Bradford Hill Framework for Causality

Atrial fibrillation (AF) is strongly associated with stroke risk but association on its own does not necessarily imply causality. Is AF a cause (risk factor) of stroke? Would treatment that reduces AF burden also reduce the burden of stroke? Or, perhaps, AF is a risk marker associated with a vascular syndrome in which there is co-existing atrial structural and electrical remodelling that results in the clinical manifestation of AF and the risk of stroke in parallel. A number of recent studies appear to detach AF as a direct cause of stroke. Studies in which cardiac implantable devices have been used to collect AF data preceding stroke appear to show no immediate temporal relationship. The Global Anticoagulant Registry in the Field - Atrial Fibrillation (GARFIELD-AF) a large worldwide registry of non-valvular AF, has shown that the risk of death exceeds the risk of stroke and that mortality, together with stroke and bleeding risk, is predicted by other vascular risk factors, defined by the CHA₂DS₂VASc score. Sir Bradford Hill proposed criteria to assess whether two associated factors are causal, more than 50 years ago. This method of analysing cause and effect in a complex scenario could be applied to AF and stroke. This paper aims to clinically appraise the evidence for each criterion outlined by Bradford Hill to single out whether the collective data supports one or the other.