Apixaban After Anticoagulation-associated Intracerebral Haemorrhage in Patients With Atrial Fibrillation (APACHE-AF)

April 10, 2021 updated by: H. Bart van der Worp, UMC Utrecht

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
101

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Amsterdam, Netherlands
        • OLVG
      • Amsterdam, Netherlands
        • Amsterdam UMC
      • Apeldoorn, Netherlands
        • Gelre Ziekenhuizen
      • Arnhem, Netherlands
        • Rijnstate
      • Breda, Netherlands
        • Amphia Ziekenhuis
      • Den Haag, Netherlands
        • Haaglanden MC
      • Dordrecht, Netherlands
        • Albert Schweitzer Ziekenhuis
      • Enschede, Netherlands
        • Medisch Spectrum Twente
      • Groningen, Netherlands
        • University Medical Center Groningen
      • Heerlen, Netherlands
        • Zuyderland Ziekenhuis
      • Leiden, Netherlands
        • Leiden University Medical Center
      • Maastricht, Netherlands
        • Maastricht University Medical Center
      • Nijmegen, Netherlands
        • Radboud University Medical Center
      • Rotterdam, Netherlands
        • Erasmus MC
      • Tilburg, Netherlands
        • Elisabeth-TweeSteden Ziekenhuis
      • Utrecht, Netherlands, 3584CX
        • UMC Utrecht

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Apixaban

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
Other Names:
  • Eliquis
Other: Avoiding oral anticoagulants

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: Clopidogrel
Drug: Aspirin
Other Names:
  • Acetylsalicylic acid
Drug: Dipyridamole
Drug: Carbasalate calcium
Other: No antithrombotic treatment

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Number of patients who experience the combination of vascular death or non-fatal stroke (cerebral infarction, intracerebral haemorrhage, or subarachnoid haemorrhage)
Time Frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.

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 Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of patients who experience vascular death
Time Frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience death from any cause.
Time Frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
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.
Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience all stroke.
Time Frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.

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.
Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience ischaemic stroke.
Time Frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
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.
Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience intracerebral haemorrhage.
Time Frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
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.
Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience other major extracranial haemorrhage
Time Frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.

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.


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.
Time Frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
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.
Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience systemic embolism.
Time Frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
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.
Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.
Number of patients who experience myocardial infarction.
Time Frame: Throughout the study. Patients will be followed up between 12 (minimum) and 72 (maximum) months.

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
UMC Utrecht

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Dutch Heart Foundation
ZonMw: The Netherlands Organisation for Health Research and Development

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Catharina JM Klijn, MD PhD, Radboud University Medical Center
  • Study Chair: H Bart van der Worp, MD PhD, UMC Utrecht

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 1, 2014

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 31, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 31, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 27, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 29, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 1, 2015

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 14, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 10, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NL47761.041.14
  • 2014-000112-33 (EudraCT Number)
  • NTR4526 (Registry Identifier: Nederlands Trialregister)
  • U1111-1154-5474 (Registry Identifier: WHO Universal Trial Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Atrial Fibrillation

Clinical Trials on Clopidogrel

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings