Factor XI inhibitors: a new class of anticoagulants that may reduce the risk of bleeding

More patients than ever before are being given NOACs due to their relative stability and safety, but the risk of gastrointestinal bleeding with NOACs is higher than with warfarin. This has led researchers to look for new ways of anticoagulating patients. At the Atrial Fibrillation Symposium (AF symposium; Orlando, USA) Elaine Hylek (Boston University School of Medicine, Boston, USA) presented the case for factor XI as a potential new target for the prevention of arterial thrombosis.

The number of patients treated with NOACs remains relatively stable across the range of CHA₂D₂– VASc scores, at around 13% (around 30% of patients are on warfarin [ASA], around 1% are on ASA+P2Y12, 15% on ASA only and the rest on no anti-coagulation), and around 48–59% of patients are still taking NOACs after initial treatment. Stroke caused by atrial fibrillation (AF) has a 24% mortality rate at 30–days and successfully anticoagulating patients is a major way of reducing this.

Because of the risks associated with NOACs, it is important to optimise the benefits of taking NOACs (reducing the risk of stroke) while reducing the risks (haemorrhage), particularly after stroke.

In patients with AF, anticoagulation treatment is considered in patients with a CHA₂D₂–VASc score of one or more—a consensus statement from the European Society of Cardiology said that in the general AF population “most patients with a high CHA₂D₂– VASc score could benefit from OAC even if their bleeding risk is high. Only in a few patients with a relatively low stroke risk and an extremely increased risk of bleeding may the withholding of OAC be considered.”¹

In practice, an unexpectedly high proportion of prescriptions for apixaban, rivaroxaban and dabigatran are given at lower doses: in the US 16% of patients receive low dose dabigatran and apixaban at 2.5mg is used around 25% of the time.² Low dose NOACs are less effective at preventing ischaemic stroke.

Factor XI Inhibitors provide a potential alternative, reducing the potential for stroke without increasing the risk of haemorrhage. A study by Buller et al looked at Factor XI in elective knee surgery.³ They gave three subcutaneous doses of factor XI antisense oligonucleotide during the first week of treatment (36 days pre-op) and followed up with four once-weekly doses, then six hours preoperatively and one three days post-operation. They found that factor XI contributes to postoperative venous thromboembolism and reducing factor XI levels in patients was an effective method for its prevention, and appeared to be safe with respect to the risk of bleeding.

Research into factor XI and its uses is still in the preliminary stage but the clinical potential of factor XII- and factor XI-directed anticoagulation represent an exciting new era in anticoagulation that may one day reduce the risk of bleeding without compromising efficacy.

References

1. Eurospace (2011) 13, doi:723–746 / europace/eu126
2. Graham DJ Circulation 2015 ;131:157-64. Giugliano RP. NEJM 2013
3. Buller HR, et al. N Engl