Apixaban After Anticoagulation-associated Intracerebral Haemorrhage in Patients With Atrial Fibrillation

Apixaban Versus Antiplatelet Drugs or no Antithrombotic Drugs After Anticoagulation-associated Intracerebral Haemorrhage in Patients With Atrial Fibrillation: A Randomised Phase II Clinical Trial

There is a marked lack of evidence on the optimal prevention of ischaemic stroke in patients with atrial fibrillation and a recent intracerebral haemorrhage (ICH) during treatment with oral anticoagulation. These patients are currently treated with vitamin K antagonists, DOACs, antiplatelet drugs, or no antithrombotic treatment, depending on personal and institutional preferences. Treatment with a direct oral anticoagulant like apixaban might be an attractive alternative in terms of a low risk of recurrent ICH, while at the same time being effective for the prevention of ischaemic stroke. This study aims 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 antiplatelet drugs or no antithrombotic drug at all.

This study has a multi-centre, phase II, randomised, open-label clinical trial with blinded outcome assessment design.

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 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 six years. All patients will be followed up for the duration of the study, but at least for six months.

Inclusion Criteria:

• Intracerebral haemorrhage (including including isolated spontaneous intraventricular haemorrhage), documented with CT or MRI, during treatment with anticoagulation (VKA, any direct thrombin inhibitor, any factor Xa inhibitor, or (low molecular weight) heparin at a therapeutic dose).
• The haemorrhage has occurred between 7 and 90 days before randomization.
• Diagnosis of (paroxysmal) non-valvular AF, documented on electrocardiography.
• A CHA2DS2-VASc score ≥ 2.
• Score on the modified Rankin scale (mRS)≤4.
• Equipoise regarding the optimal medical treatment for the prevention of stroke.
• Age ≥ 18 years.
• Written informed consent by the patient or by a legal representative

Exclusion Criteria:

• Conditions other than atrial fibrillation for which the patient requires long-term anticoagulation
• A different clinical indication for the use of an antiplatelet drug even if treated with apixaban, such as clopidogrel for recent coronary stenting.
• Mechanical prosthetic heart valve (biological prosthetic heart valves are allowed) or rheumatic mitral valve disease.
• Serious bleeding event in the previous 6 months, except for intracerebral haemorrhage.
• High risk of bleeding (e.g., active peptic ulcer disease, a platelet count of <100,000.mL-1 or haemoglobin level of <6.2 mMol.L-1, ischaemic stroke in the previous 7 days (patients are eligible thereafter), documented haemorrhagic tendencies, or blood dyscrasias).
• Current alcohol or drug abuse.
• Life expectancy of less than 1 year.
• Severe renal insufficiency (a serum creatinine level of more than 221 μmol per liter or a calculated creatinine clearance of <15 ml per minute).
• Alanine aminotransferase or aspartate aminotransferase level greater than 2 times the upper limit of the normal range or a total bilirubin more than 1.5 times the upper limit of the normal range, unless a benign causative factor (e.g. Gilbert's syndrome) is known or identified.
• Allergy to apixaban.
• Use of strong cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) inhibitors (e.g. systemic azole-antimycotics as ketoconazole or HIV protease inhibitors such as ritonavir).
• Pregnancy or breastfeeding.
• Women of childbearing potential: any woman who has begun menstruation and is not postmenopausal or otherwise permanently unable to conceive. A postmenopausal woman is defined as a woman who is over the age of 45 and has not had a menstrual period for at least 12 months.