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

NCT02565693 | Completed Phase 2 DMC

• 4 other identifiers: NL47761.041.142014-000112-33NTR4526U1111-1154-5474
• Study Type: interventional
• Target: 101
• Locations: 1 country
• Sites: 16

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.

Conditions

Cerebral Hemorrhage; Atrial Fibrillation

Outcome Measures

Primary Outcomes (1)

• 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

  Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.

Secondary Outcomes (10)

• Number of patients who experience vascular death

  Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.

• Number of patients who experience death from any cause.

  Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.

• Number of patients who experience all stroke.

  Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.

• Number of patients who experience ischaemic stroke.

  Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.

• Number of patients who experience intracerebral haemorrhage.

  Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.

Study Arms (2)

Apixaban

EXPERIMENTAL

Apixaban: oral, 5 mg twice daily. If two of the three following criteria are met, the dose will be reduced to 2.5 mg twice daily: * Age ≥ 80 years * Body weight ≤ 60 kg * Serum creatinine ≥ 133 μmol. Additionally, if the creatinin clearance is below 30 ml per minute, the dose will be reduced to 2.5 mg twice daily.

Drug: Apixaban

Avoiding oral anticoagulants

OTHER

The following treatment regimens are allowed in the comparator arm: \- No antithrombotic treatment or: * Acetylsalicylic acid 80 mg once daily * Carbasalate calcium 100 mg once daily * Clopidogrel 75 mg once daily * Acetylsalicylic acid 80 mg once daily and dipyridamole 200 mg twice daily * Carbasalate calcium 100 mg once daily and dipyridamole 200 mg twice daily

Drug: Aspirin; Drug: Carbasalate calcium; Drug: Clopidogrel; Drug: Dipyridamole; Other: No antithrombotic treatment

Interventions

Apixaban DRUG

Also known as: Eliquis

Apixaban

Aspirin DRUG

Also known as: Acetylsalicylic acid

Avoiding oral anticoagulants

Carbasalate calcium DRUG

Avoiding oral anticoagulants

Clopidogrel DRUG

Avoiding oral anticoagulants

Dipyridamole DRUG

Avoiding oral anticoagulants

No antithrombotic treatment OTHER

Avoiding oral anticoagulants

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• UMC Utrecht: lead
• Dutch Heart Foundation: collaborator
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (16)

Amsterdam UMC

Amsterdam, Netherlands

Location

OLVG

Amsterdam, Netherlands

Location

Gelre Ziekenhuizen

Apeldoorn, Netherlands

Location

Rijnstate

Arnhem, Netherlands

Location

Amphia Ziekenhuis

Breda, Netherlands

Location

Albert Schweitzer Ziekenhuis

Dordrecht, Netherlands

Location

Medisch Spectrum Twente

Enschede, Netherlands

Location

University Medical Center Groningen

Groningen, Netherlands

Location

Zuyderland Ziekenhuis

Heerlen, Netherlands

Location

Leiden University Medical Center

Leiden, Netherlands

Location

Maastricht University Medical Center

Maastricht, Netherlands

Location

Radboud University Medical Center

Nijmegen, Netherlands

Location

Erasmus MC

Rotterdam, Netherlands

Location

Haaglanden MC

The Hague, Netherlands

Location

Elisabeth-Tweesteden Ziekenhuis

Tilburg, Netherlands

Location

UMC Utrecht

Utrecht, 3584CX, Netherlands

Location

Related Publications (3)

• Cochrane A, Chen C, Stephen J, Ronning OM, Anderson CS, Hankey GJ, Al-Shahi Salman R. Antithrombotic treatment after stroke due to intracerebral haemorrhage. Cochrane Database Syst Rev. 2023 Jan 26;1(1):CD012144. doi: 10.1002/14651858.CD012144.pub3.

  PMID: 36700520 DERIVED

• 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.

  PMID: 34687635 DERIVED

• 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.

  PMID: 34022170 DERIVED

MeSH Terms

Conditions

Cerebral Hemorrhage; Atrial Fibrillation

Interventions

apixaban; Aspirin; carbaspirin calcium; Clopidogrel; Dipyridamole

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Arrhythmias, Cardiac; Heart Diseases

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrimidines

Study Officials

• Catharina JM Klijn, MD PhD

  Radboud University Medical Center

  STUDY CHAIR

• H Bart van der Worp, MD PhD

  UMC Utrecht

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Co-Coordinating Investigator

Study Record Dates

• First Submitted: August 27, 2015
• First Posted: October 1, 2015
• Study Start: September 1, 2014
• Primary Completion: January 31, 2021
• Study Completion: January 31, 2021
• Last Updated: April 14, 2021

Record last verified: 2021-04

Locations

NL (16)