Summary

Rationale

There is a marked lack of evidence on the optimal prevention of ischaemic stroke and other thrombo-embolic events in patients with non-valvular atrial fibrillation (AF) and a recent intracerebral haemorrhage (ICH) during treatment with oral anticoagulation. These patients are currently treated with oral anticoagulants, antiplatelet drugs, or no antithrombotic treatment, depending on personal and institutional preferences. Randomised trials in patients with AF but without ICH have convincingly shown that vitamin K antagonists (VKAs, such as warfarin) reduce the risk of ischaemic stroke and other thrombo-embolic events, but increase the risk of bleeding as compared to no anticoagulant therapy. In the recent ARISTOTLE trial, the direct oral anticoagulant (DOAC) apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. In other trials, the other DOACs, rivaroxaban, edoxaban, and dabigatran had a similar benefit as compared with warfarin. DOACs have not been tested in patients with AF and a recent ICH. Apixaban is the only DOAC tested against aspirin in a large randomised trial, in which patients with AF who were treated with apixaban had a lower risk of stroke or systemic embolism than those treated with aspirin, whereas ICH rates were similar in both treatment groups. We hypothesize that in patients with AF who survived an anticoagulation-associated ICH, apixaban is an attractive alternative to antiplatelet drugs or no antithrombotic treatment at all in terms of a low risk of recurrent ICH, while at the same time being more effective for the prevention of ischaemic stroke.

Objective

  1. To obtain reliable estimates of the rates of vascular death or non-fatal stroke in patients with atrial fibrillation and a recent anticoagulation-associated intracerebral haemorrhage who are treated with apixaban versus those who are treated with an antiplatelet drug or no antithrombotic drugs.
  2. To compare the rates of all-cause death, stroke, ischaemic stroke, ICH, other major haemorrhage, systemic embolism, and functional outcome between patients treated with apixaban and those who are treated with an antiplatelet drug or no antithrombotic drugs.

Study design

A randomised, open, multi-center clinical trial with masked outcome assessment.

Study population

100 adults with a history of atrial fibrillation and a recent intracerebral haemorrhage during treatment with anticoagulation in whom clinical equipoise exists on the optimal stroke prevention therapy.

Intervention

Apixaban 5 mg twice daily versus antiplatelet therapy or no antithrombotic drugs.

Primary outcome

Vascular death or non-fatal stroke during follow-up.

Time frame

We aim to include 100 patients in 5 years. All patients will be followed up for the duration of the study, but at least for one year.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness

The main risks associated with this study are the risk of bleeding (ICH, other major bleeding, minor bleeding) and the risk of ischaemic stroke or systemic embolism. It is currently uncertain which of the treatment strategies mentioned above is most effective and safe. The burden will consist of 3 visits in the first year, with yearly follow-up thereafter.