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

NCT ID: NCT02565693

Last Updated: 2021-04-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 101 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-09-30
• Study Completion Date: 2021-01-31

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.

Conditions

Cerebral Hemorrhage; Atrial Fibrillation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

Apixaban

Intervention Type: DRUG

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

Group Type: OTHER

Aspirin

Intervention Type: DRUG

Carbasalate calcium

Intervention Type: DRUG

Clopidogrel

Intervention Type: DRUG

Dipyridamole

Intervention Type: DRUG

No antithrombotic treatment

Intervention Type: OTHER

Interventions

Apixaban

Intervention Type: DRUG

Aspirin

Intervention Type: DRUG

Carbasalate calcium

Intervention Type: DRUG

Clopidogrel

Intervention Type: DRUG

Dipyridamole

Intervention Type: DRUG

No antithrombotic treatment

Intervention Type: OTHER

Other Intervention Names

Eliquis; Acetylsalicylic acid

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dutch Heart Foundation

OTHER

Sponsor Role: collaborator

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

UMC Utrecht

OTHER

Sponsor Role: lead

Responsible Party

H. Bart van der Worp

Co-Coordinating Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Catharina JM Klijn, MD PhD

Role: STUDY_CHAIR

Radboud University Medical Center

H Bart van der Worp, MD PhD

Role: STUDY_CHAIR

UMC Utrecht

Locations

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

Maastricht University Medical Center

Maastricht, , Netherlands

Radboud University Medical Center

Nijmegen, , Netherlands

Erasmus MC

Rotterdam, , Netherlands

Haaglanden MC

The Hague, , Netherlands

Elisabeth-Tweesteden Ziekenhuis

Tilburg, , Netherlands

UMC Utrecht

Utrecht, , Netherlands

Countries

Netherlands

References

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.

Reference Type: DERIVED

PMID: 36700520 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34687635 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34022170 (View on PubMed)

Other Identifiers

2014-000112-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NTR4526

Identifier Type: REGISTRY

Identifier Source: secondary_id

U1111-1154-5474

Identifier Type: REGISTRY

Identifier Source: secondary_id

NL47761.041.14

Identifier Type: -

Identifier Source: org_study_id