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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
101
Amsterdam UMC
Amsterdam, Netherlands
OLVG
Amsterdam, Netherlands
Gelre Ziekenhuizen
Apeldoorn, Netherlands
Rijnstate
Arnhem, Netherlands
Amphia Ziekenhuis
Breda, Netherlands
Albert Schweitzer Ziekenhuis
Dordrecht, Netherlands
Medisch Spectrum Twente
Enschede, Netherlands
University Medical Center Groningen
Groningen, Netherlands
Zuyderland Ziekenhuis
Heerlen, Netherlands
Leiden University Medical Center
Leiden, Netherlands
...and 6 more locations
Number of patients who experience the combination of vascular death or non-fatal stroke (cerebral infarction, intracerebral haemorrhage, or subarachnoid haemorrhage)
Ischaemic stroke Clinical evidence of the sudden onset of an new neurological deficit, or an increase in an existing deficit, persisting for more than 24 hours, without evidence of a intracerebral haemorrhage on a CT or MRI scan or at post-mortem investigation. Intracerebral haemorrhage Clinical evidence of the sudden onset of a new neurological deficit, or an increase in an existing deficit, persisting for more than 24 hours, with a corresponding intracerebral haemorrhage on a CT or MR scan or at post-mortem investigation. Unclassified stroke Clinical evidence of the sudden onset of a new neurological deficit, or an increase in an existing deficit, persisting for more than 24 hours, without imaging or post-mortem investigations performed. Subarachnoid haemorrhage Subarachnoid haemorrhage (SAH) demonstrated by CT, lumbar puncture, or at post-mortem investigation. Vascular death See Outcome 2, Vascular death
Time frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience vascular death
Time frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience death from any cause.
Vascular death Death from cerebral infarction; intracerebral, subarachnoid, epidural, or subdural haemorrhage; unclassified stroke; myocardial infarction; extracranial haemorrhage; or systemic embolism. Death should have been unlikely without the events mentioned above. Other events classifying as vascular death: fatal arterial or gastric bleeding, terminal heart failure, fatal pulmonary embolism, and sudden death, defined as death within one hour after onset of symptoms.
Time frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience all stroke.
Ischaemic stroke Clinical evidence of the sudden onset of an new neurological deficit, or an increase in an existing deficit, persisting for more than 24 hours, without evidence of a intracerebral haemorrhage on a CT or MRI scan or at post-mortem investigation. Intracerebral haemorrhage Clinical evidence of the sudden onset of a new neurological deficit, or an increase in an existing deficit, persisting for more than 24 hours, with a corresponding intracerebral haemorrhage on a CT or MR scan or at post-mortem investigation. Unclassified stroke Clinical evidence of the sudden onset of a new neurological deficit, or an increase in an existing deficit, persisting for more than 24 hours, without imaging or post-mortem investigations performed. Subarachnoid haemorrhage Subarachnoid haemorrhage (SAH) demonstrated by CT, lumbar puncture, or at post-mortem investigation.
Time frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience ischaemic stroke.
Clinical evidence of the sudden onset of an new neurological deficit, or an increase in an existing deficit, persisting for more than 24 hours, without evidence of a intracerebral haemorrhage on a CT or MRI scan or at post-mortem investigation.
Time frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience intracerebral haemorrhage.
Clinical evidence of the sudden onset of a new neurological deficit, or an increase in an existing deficit, persisting for more than 24 hours, with a corresponding intracerebral haemorrhage on a CT or MR scan or at post-mortem investigation.
Time frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience other major extracranial haemorrhage
Major extracranial bleeding will be defined using the ISTH criteria.55 1) Fatal bleeding, and/or 2) Symptomatic bleeding in a critical area or organ, such as intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or 3) Bleeding causing a fall in haemoglobin level of 1.24 mmol L-1 or more, or leading to transfusion of two or more units of whole blood or red cells. 
Time frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience any intracranial haemorrhage other than ICH.
subdural haemorrhage: evidence of a subdural haematoma on a CT or MRI scan or at post-mortem investigations; epidural hematoma: evidence of an epidural haematoma on a CT or MRI scan or at post-mortem investigations.
Time frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience systemic embolism.
The diagnosis of systemic embolism requires a clinical history consistent with an acute loss of blood flow to a peripheral artery (or arteries) supported by evidence of embolism from surgical specimens, post-mortem investigations, angiography, vascular imaging, or other objective testing.
Time frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience myocardial infarction.
Detection of a rise and/or fall of cardiac biomarker values \[preferably cardiac troponin\] with at least 1 value above the 99th percentile upper reference limit and with at least 1 of the following: Symptoms of ischemia. New or presumed new significant ST-segment-T wave changes or new left bundle branch block. Development of pathological Q waves in the ECG. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. Identification of intracoronary thrombus by angiography or autopsy. Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were obtained, or before cardiac biomarker values would be increased.
Time frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience who experience a good functional outcome as assessed with the score on the modified Rankin Scale
Van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988 May;19(5):604-7.
Time frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
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