The winding path towards rationale anti-thrombotic therapy to prevent stroke in patients with atrial fibrillation

Stroke is a common and devastating complication of atrial fibrillation (AF). However, the randomized trials of warfarin represented a major turning point, demonstrating that two-thirds of strokes could be prevented. However, the uptake of this highly effective, evidence-based therapy was modest, due to the difficulties in prescribing and maintaining warfarin therapy, and the risks of major bleeding, including intracranial bleeding. To get around these limitations, a variety of anti-platelet regimes were studied as alternatives, including aspirin monotherapy, aspirin plus fixed, low-dose warfarin, and dual anti-platelet therapy with aspirin and clopidogrel. However, the reduction in stroke was only modest with aspirin compared with placebo, and aspirin in combination with either low-dose warfarin or clopidogrel was inferior to warfarin. Although the aspirin/clopidogrel combination was more effective at preventing thrombo-embolism than aspirin alone, it was associated with a significant increased risk of major bleeding. However; given its ease of use and perceived safety, aspirin use continued as stroke preventive therapy for many patients with AF in the 1990s and 2000s. Over the following decade, we gained a better understanding of patient-specific risks of both stroke and bleeding, through the development or risk-stratification schemes. These allowed clinicians to direct anti-thrombotic therapy at patients with the greatest risk of stroke, while helping to avoid bleeding risks due to overtreatment in low-risk individuals. Next came the advent of the direct oral anticoagulants (DOACs) which, compared with warfarin, were better at reducing stroke, minimizing major bleeding, or both. DOACs also overcame many of the practical barriers to anticoagulation with warfarin. Despite their novelty and cost, it was hoped that they would replace aspirin and warfarin as the standard stroke prevention therapy for most at-risk individuals with AF. The final, and most substantial argument against the use of aspirin came from another DOAC study, AVERROES, which demonstrated a 55% reduction in stroke and systemic embolism with apixaban compared with aspirin, with a risk of major bleeding that was statistically not different. For many, these findings signalled the end of aspirin monotherapy for AF, at least in regions where DOAC therapy is economically feasible. However, the use of aspirin for stroke prevention in patients with AF continued to receive limited support from guidelines in some regions, particularly for patients with lower stroke risk, and especially those whose only stroke risk is vascular disease. Although the benefit of aspirin for AF is modest at best, in such patients aspirin has perceived value for the treatment of vascular disease. Given the doubling of bleeding risk with the combination of aspirin and an anti-coagulant, in some regions aspirin monotherapy has maintained a niche role in some AF patients. More globally, important differences in the use of oral anti-coagulant therapy to treat patients with AF have been demonstrated, with guideline-based usage in China measured at approximately one-sixth the rate of Western Europe. These patterns have been driven by the observation of a greater risk of major and intracranial bleeding among Chinese patients with AF, as well as patient and physician biases. Regional differences in clinical practice are important considerations when evaluating the treatment of AF on a global level. In this issue of the journal, Verheught and colleagues prospectively enrolled 51 270 consecutive AF patients from >1000 randomly selected centres in 35 countries, over a 6-year period. Despite the presence of at least one stroke risk factor, one in five patients received an anti-platelet agent as their sole stroke prevention therapy. Patients receiving anti-platelet therapy tended to be younger, have new-onset or paroxysmal AF, and were less likely to be Caucasian. More than