Primary Objective: to obtain reliable estimates of the rates of vascular death and non-fatal stroke in patients with atrial fibrillation and a recent anticoagulation-associated ICH who are treated with apixaban versus those who are treated with APDs…
ID
Source
Brief title
Condition
- Cardiac arrhythmias
- Central nervous system vascular disorders
- Embolism and thrombosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The combination of vascular death or non-fatal stroke (cerebral infarction,
intracerebral haemorrhage, or subarachnoid haemorrhage) during follow-up.
Secondary outcome
Vascular death.
Death from any cause.
All stroke.
Ischaemic stroke.
Intracerebral haemorrhage.
Other major extracranial haemorrhage
Any intracranial haemorrhage other than ICH.
Systemic embolism.
Myocardial infarction.
Functional outcome as assessed with the score on the modified Rankin Scale at 6
and 12 months; thereafter annually and at the end of the study.
Background summary
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. Patients are currently treated with vitamin K
antagonists (VKAs), direct oral anticoagulant drugs (DOACs), 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 VKAs reduce the risk of ischaemic stroke and other
thrombo-embolic events, but increase the risk of bleeding as compared to no
anticoagulant therapy. In a more recent large randomised trial, the direct oral
anticoagulant (DOAC) apixaban was superior to VKAs in preventing stroke or
systemic embolism, caused less bleeding, and resulted in lower mortality. Other
DOACs had similar effects. Unfortunately, DOACs have not been tested in
patients with AF and a recent ICH. 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.
Study objective
Primary Objective: to obtain reliable estimates of the rates of vascular death
and non-fatal stroke in patients with atrial fibrillation and a recent
anticoagulation-associated ICH who are treated with apixaban versus those who
are treated with APDs or no antithrombotic drugs.
Secondary Objective: to compare the rates of vascular death and non-fatal
stroke, all-cause death, disabling stroke, recurrent ICH, other major
haemorrhage, systemic embolism, and functional outcome between patients treated
with apixaban and those who are treated with APDs or no antithrombotic drugs.
Study design
This will be a phase II, randomized, open, multi-centre clinical trial with
masked outcome assessment (PROBE design), comparing apixaban with APDs or no
antithrombotic treatment in patients with AF and a recent
anticoagulation-associated ICH.
The adjudication of the endpoints will be performed by an adjudication
committee blinded to treatment allocation.
A total of 100 patients will be included in 16 regional and academic centres in
the Netherlands over a period of 5.5 years. Follow-up will continue until six
months after inclusion of the last patient. The total study period will be six
years.
Intervention
Patients will be randomised between:
* apixaban 5 mg orally twice daily
* treatment with one or two oral APDs (ATC group B01AC; acetylsalicylic acid,
carbasalate calcium, clopidogrel, or dipyridamole) or no antithrombotic
treatment at all, at the discretion of the treating physician.
Study burden and risks
For all antithrombotic drugs, a recent ICH is a relative contra-indication to
their use and current clinical evidence on this topic is scarce or
non-existent. Practitioners have to rely on their personal clinical judgment to
weigh the benefits and risks in prescribing or withholding any antithrombotic
therapy in this group. APDs, DOACS such as apixaban, VKAs, and withholding
antithrombotic drugs are all strategies used by clinicians today. In this
trial, we will include patients in whom there is equipoise on the optimal
antithrombotic strategy.
POTENTIAL RISKS
Both a previous ICH and antithrombotic therapy are risk factors for recurrent
ICH. There is a potential increased risk of ICH or other major bleeding for all
participants, but this is likely to be higher when treated with apixaban or an
APD. The risk for a new intracranial haemorrhage is probably higher when
treated with apixaban compared to treatment with APDs. Conversely, the risk of
ischaemic stroke or other thrombo-embolism is probably increased in patients in
whom antithrombotic therapy is withheld. The risk for thrombo-embolic
complications is probably higher when using APDs than when using apixaban. The
risk/benefit ratio of all proposed treatments is uncertain.
Apixaban use is a contra-indication for intravenous thrombolysis for acute
ischaemic stroke. Patients using apixaban therefore cannot be treated with
thrombolysis in case of ischaemic stroke during follow-up. However, the risk of
ischaemic stroke in patients treated with apixaban will most likely be lower
than in patients without antithrombotic therapy or treated with APD, and
therefore we consider this potential disadvantage of apixaban acceptable.
Aside from the bleeding risk, participants allocated to the use of apixaban or
an APD are exposed to other side effects of these drugs, as reported in their
SmPCs. The risk of these other side effects however appears acceptable.
Investigators will be provided with a protocol regarding the management of
bleeding in patients using apixaban.
POTENTIAL BENEFIT
The main potential benefit in patients allocated apixaban is better protection
against ischaemic stroke and thrombo-embolism, compared to patients allocated
APD or no antithrombotic treatment. The risk for thrombo-embolism is probably
higher during treatment with APDs compared to the risk during treatment with
apixaban.
BENEFIT/RISK ASSESSMENT
Because both drugs are currently used in this group of patients without any
reliable evidence for their net benefit, and because we only include patients
in whom clinical equipoise with regard to the optimal treatment strategy
exists, we feel we do not expose participants to a significant additional risk
in participating in this study compared to current clinical practise.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
Intracerebral haemorrhage (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 CHA2DS2VASc score * 2. The item Stroke in the Stroke/TIA/TE item refers to
ischaemic stroke, not haemorrhagic stroke.*
Score on the modified Rankin scale (mRS) *4.
Equipoise regarding the optimal medical treatment for the prevention of stroke.
The clinical equipoise should be self-reported by the attending neurologist
after reviewing the all relevant information available for the individual
patient.
Age * 18 years.
Written informed consent by the patient or by a healthcare proxy
Exclusion criteria
Conditions other than atrial fibrillation for which the patient requires
long-term anticoagulation.
A different clinical indication for the use of an APD even when 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 (see protocol chapter 7.1.4) 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 or haemoglobin level of <6.2 mMol/L, 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 *mol 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 an 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-000112-33-NL |
| CCMO | NL47761.041.14 |
| Other | NTR4526, NCT02565693 |
| OMON | NL-OMON27026 |