New thrombin and factor Xa inhibitors for primary and secondary prevention of ischaemic stroke

Atrial fibrillation is a major risk factor for first and recurrent ischaemic stroke, and anticoagulation, mainly by use of coumarin medications, is an effective strategy for reducing ischaemic stroke occurrence in these patients. However, the coumarin medications have disadvantages. Over the past decade, important strides have been made towards developing improved anticoagulant medications. This review discusses these new developments and what they mean for the future of primary and secondary ischaemic stroke prevention in patients with atrial fibrillation. Relevant papers were identified with electronic searches of the Medline and EMBASE databases. Ongoing trials were checked using the Trials Results Centre website. The direct thrombin inhibitors, and the factor Xa inhibitors are the two major new anticoagulant drug classes under development at present. In phase III trials, dabigatran and rivaroxaban demonstrated at least as good performance as warfarin at reducing the rate of ischaemic stroke, systemic embolus, and haemorrhagic ischaemic stroke, whilst maintaining a comparable or lower rate of major bleeding events. Drug level monitoring was not required due to stable pharmacodynamics. AZD0837, apixaban, YM-150, edoxaban and betrixaban all showed promising results in phase II trials, as did S35972 in animal, in vitro and ex vivo models. The future of these new anticoagulants looks encouraging, although there are still some significant challenges to overcome. We need to consider the accumulation of long-term safety and efficacy data, and the development of effective means of reversal of anticoagulation for the direct thrombin inhibitors and factor Xa inhibitors.