Clinical trial NCT02565693: Apixaban After Anticoagulation-associated Intracerebral Haemorrhage in Patients With Atrial Fibrillation
Official title: Apixaban Versus Antiplatelet Drugs or no Antithrombotic Drugs After Anticoagulation-associated Intracerebral Haemorrhage in Patients With Atrial Fibrillation: A Randomised Phase II Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cerebral Hemorrhage
Atrial Fibrillation
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: Dutch Heart Foundation
name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2015-10-01
Enrollment: 101
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of patients who experience the combination of vascular death or non-fatal stroke (cerebral infarction, intracerebral haemorrhage, or subarachnoid haemorrhage)
timeFrame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Secondary outcomes:
measure: Number of patients who experience vascular death
timeFrame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
measure: Number of patients who experience death from any cause.
timeFrame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
measure: Number of patients who experience all stroke.
timeFrame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
measure: Number of patients who experience ischaemic stroke.
timeFrame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
measure: Number of patients who experience intracerebral haemorrhage.
timeFrame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
measure: Number of patients who experience other major extracranial haemorrhage
timeFrame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
measure: Number of patients who experience any intracranial haemorrhage other than ICH.
timeFrame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
measure: Number of patients who experience systemic embolism.
timeFrame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
measure: Number of patients who experience myocardial infarction.
timeFrame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
measure: Number of patients who experience who experience a good functional outcome as assessed with the score on the modified Rankin Scale
timeFrame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Amsterdam
country: Netherlands
facility: OLVG
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuizen
city: Arnhem
country: Netherlands
facility: Rijnstate
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Den Haag
country: Netherlands
facility: Haaglanden MC
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Heerlen
country: Netherlands
facility: Zuyderland Ziekenhuis
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Tilburg
country: Netherlands
facility: Elisabeth-Tweesteden Ziekenhuis
city: Utrecht
country: Netherlands
facility: UMC Utrecht
Study officials:
affiliation: Radboud University Medical Center
name: Catharina JM Klijn, MD PhD
role: STUDY_CHAIR
affiliation: UMC Utrecht
name: H Bart van der Worp, MD PhD
role: STUDY_CHAIR
References:
citation: Schreuder FHBM, van Nieuwenhuizen KM, Hofmeijer J, Vermeer SE, Kerkhoff H, Zock E, Luijckx GJ, Messchendorp GP, van Tuijl J, Bienfait HP, Booij SJ, van den Wijngaard IR, Remmers MJM, Schreuder AHCML, Dippel DW, Staals J, Brouwers PJAM, Wermer MJH, Coutinho JM, Kwa VIH, van Gelder IC, Schutgens REG, Zweedijk B, Algra A, van Dalen JW, Jaap Kappelle L, Rinkel GJE, van der Worp HB, Klijn CJM; APACHE-AF Trial Investigators. Apixaban versus no anticoagulation after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF): a randomised, open-label, phase 2 trial. Lancet Neurol. 2021 Nov;20(11):907-916. doi: 10.1016/S1474-4422(21)00298-2.
citation: Li L, Poon MTC, Samarasekera NE, Perry LA, Moullaali TJ, Rodrigues MA, Loan JJM, Stephen J, Lerpiniere C, Tuna MA, Gutnikov SA, Kuker W, Silver LE, Al-Shahi Salman R, Rothwell PM. Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies. Lancet Neurol. 2021 Jun;20(6):437-447. doi: 10.1016/S1474-4422(21)00075-2.