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    Clinical Trial Results:
    Early versus Late initiation of direct oral Anticoagulants in post-ischaemic stroke patients with atrial fibrillatioN (ELAN): an international, multicentre, randomised-controlled, two-arm, assessor-blinded trial

    Summary
    EudraCT number
    		 2017-000236-34
    Trial protocol
    		 AT   FI   BE   DE   SK   PT   IT  
    Global end of trial date
    21 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Mar 2024
    First version publication date
    06 Mar 2024
    Other versions
    Summary report(s)
    		 NEJM_ELAN
    NEJM_ELAN_Supplementary material

    Trial information

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    Trial identification
    Sponsor protocol code
    ELAN
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03148457
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Inselspital (University Hospital) Bern
    Sponsor organisation address
    Freiburgstrasse 10, Bern, Switzerland, 3010
    Public contact
    Neuroclinical Trial Coordination , Inselspital (University Hospital) Bern, nctu@insel.ch
    Scientific contact
    Neuroclinical Trial Coordination , Inselspital (University Hospital) Bern, nctu@insel.ch
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Dec 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective is to determine the net benefit of early versus late initiation of DOACs in patients with acute ischaemic stroke related to AF. Net benefit is estimated by a composite outcome that combines the outcomes of interest (recurrent ischaemic stroke and systemic embolism) to estimate efficacy and the bleeding outcomes of interest (intracerebral and extracranial major bleeding) as well as vascular death to estimate safety.
    Protection of trial subjects
    Safety evaluations were conducted in regular intervals, in order to monitor patient safety and to assess the risk/benefit. Based on this, the IDMC gave recommendations on the continuation/stop of the trial. Furthermore, both investigators and the sponsor-investigators made a causality assessment of the serious adverse events to the trial drug based on the latest ICH guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 81
    Country: Number of subjects enrolled
    Portugal: 28
    Country: Number of subjects enrolled
    Slovakia: 15
    Country: Number of subjects enrolled
    Austria: 97
    Country: Number of subjects enrolled
    Belgium: 183
    Country: Number of subjects enrolled
    Finland: 83
    Country: Number of subjects enrolled
    Germany: 195
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Switzerland: 505
    Country: Number of subjects enrolled
    United Kingdom: 482
    Country: Number of subjects enrolled
    Japan: 192
    Country: Number of subjects enrolled
    India: 55
    Country: Number of subjects enrolled
    Israel: 34
    Country: Number of subjects enrolled
    Ireland: 17
    Country: Number of subjects enrolled
    Greece: 25
    Worldwide total number of subjects
    2013
    EEA total number of subjects
    745
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    257
    From 65 to 84 years
    1307
    85 years and over
    449

    Subject disposition

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    Recruitment
    Recruitment details
    		 2032 participants were enrolled at 103 sites in 15 countries between November 6, 2017, and September 12, 2022.

    Pre-assignment
    Screening details
    		 All patients of 18 years or older with an acute ischaemic stroke related to AF were screened for this trial. Primary responsibility for recruitment of patients will lie with the PI at each site. A total of 36,643 participants were screened.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    All data for the primary endpoint was collected with a telephone interview by an assessor, who was not aware of treatment allocation, if possible. All events deemed potentially primary outcomes for the trial by the local investigators were reviewed by the independent CEC, who was not aware of treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Early DOAC treatment
    Arm description
    		 Early treatment was defined as initiation of a DOAC within 48 hours after stroke onset in participants with minor or moderate stroke and on day 6 or 7 in those with major stroke.
    Arm type
    		 Early treatment start

    Investigational medicinal product name
    Apixaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Anticoagulant and preservative solution for blood
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg 2x/d or 2.5 mg 2x/d

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Anticoagulant and preservative solution for blood
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg 1xd or 15 mg 1x/d

    Investigational medicinal product name
    Dabigatran
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Anticoagulant and preservative solution for blood
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg 2x/d or 110 mg 2x/d

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Anticoagulant and preservative solution for blood
    Routes of administration
    Oral use
    Dosage and administration details
    60 mg 1x/d or 30 mg 1x/d

    Arm title
    		 Late DOAC treatment
    Arm description
    		 Later treatment was defined as initiation of a DOAC in participants with a minor stroke on day 3 or 4 after stroke onset, in participants with a moderate stroke on day 6 or 7, and in participants with a major stroke on day 12, 13, or 14.
    Arm type
    		 Late treatment start

    Investigational medicinal product name
    Apixaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Anticoagulant and preservative solution for blood
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg 2x/d or 2.5 mg 2x/d

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Anticoagulant and preservative solution for blood
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg 1xd or 15 mg 1x/d

    Investigational medicinal product name
    Dabigatran
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Anticoagulant and preservative solution for blood
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg 2x/d or 110 mg 2x/d

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Anticoagulant and preservative solution for blood
    Routes of administration
    Oral use
    Dosage and administration details
    60 mg 1x/d or 30 mg 1x/d

    Number of subjects in period 1
    		Early DOAC treatment Late DOAC treatment
    Started
    1006
    1007
    Completed
    949
    946
    Not completed
    57
    61
         Adverse event, serious fatal
    45
    49
         Consent withdrawn by subject
    9
    10
         Lost to follow-up
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Early DOAC treatment
    Reporting group description
    		 Early treatment was defined as initiation of a DOAC within 48 hours after stroke onset in participants with minor or moderate stroke and on day 6 or 7 in those with major stroke.

    Reporting group title
    Late DOAC treatment
    Reporting group description
    		 Later treatment was defined as initiation of a DOAC in participants with a minor stroke on day 3 or 4 after stroke onset, in participants with a moderate stroke on day 6 or 7, and in participants with a major stroke on day 12, 13, or 14.

    Reporting group values
    		 Early DOAC treatment Late DOAC treatment Total
    Number of subjects
    		 1006 1007 2013
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 133 124 257
        From 65-84 years
    		 645 662 1307
        85 years and over
    		 228 221 449
    Gender categorical
    Units: Subjects
        Female
    		 459 456 915
        Male
    		 547 551 1098

    End points

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    End points reporting groups
    Reporting group title
    Early DOAC treatment
    Reporting group description
    		 Early treatment was defined as initiation of a DOAC within 48 hours after stroke onset in participants with minor or moderate stroke and on day 6 or 7 in those with major stroke.

    Reporting group title
    Late DOAC treatment
    Reporting group description
    		 Later treatment was defined as initiation of a DOAC in participants with a minor stroke on day 3 or 4 after stroke onset, in participants with a moderate stroke on day 6 or 7, and in participants with a major stroke on day 12, 13, or 14.

    Primary: Primary endpoint

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    End point title
    		 Primary endpoint
    End point description
    The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization.
    End point type
    Primary
    End point timeframe
    30 days
    End point values
    		 Early DOAC treatment Late DOAC treatment
    Number of subjects analysed
    984
    991
    Units: integers
        Major extracranial bleeding
    3
    5
        Symptomatic intracranial hemorrhage
    2
    2
        Recurrent ischemic stroke
    14
    25
        Systemic embolism
    4
    9
        Death from vascular cause
    11
    10
    Statistical analysis title
    		 Primary endpoint
    Statistical analysis description
    The primary composite outcome was analyzed with the use of a penalized logistic-regression model to account for low event rates. The risk difference with 95% confidence intervals was derived from the estimated odds ratio and its standard error.
    Comparison groups
    Early DOAC treatment v Late DOAC treatment
    Number of subjects included in analysis
    1975
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.14
    Notes
    [1] - The main aim of the trial was to estimate the effect of early initiation as compared with later initiation of anticoagulation and to estimate the degree of precision of these estimates. Therefore, no statistical hypotheses as to superiority, inferiority, or noninferiority were tested.

    Secondary: Secondary endpoint

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    End point title
    		 Secondary endpoint
    End point description
    Secondary outcomes assessed at 30 and 90 days were: recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, vascular death, nonmajor bleeding, death from any cause, a binary outcome of a score of 0 to 2 versus 3 to 6 on the modified Rankin scale (a 7-point scale with a range from 0 to 6; scores of 0, 1, and 2 indicate slight or no disability and a score of 6 indicates death), and an ordinal shift in the distribution of scores.
    End point type
    Secondary
    End point timeframe
    30 and 90 days
    End point values
    		 Early DOAC treatment Late DOAC treatment
    Number of subjects analysed
    1006
    1007
    Units: integers
        Major extracranial bleeding
    3
    8
        Symptomatic intracranial hemorrhage
    2
    2
        Recurrent ischemic stroke
    18
    30
        Systemic embolism
    4
    10
        Vascular death
    17
    16
        Death from any cause
    45
    48
        Non-major bleeding
    39
    41
        Modified Rankin scale score ≤ 2
    659
    654
        Any serious adverse event
    132
    157
    Statistical analysis title
    		 Secondary endpoint
    Statistical analysis description
    Secondary binary outcomes were analyzed with the use of penalized logistic regression (dichotomized scores on the modified Rankin scale). Ordinal scores on the modified Rankin scale were analyzed with the use of ordinal logistic regression. Binary outcomes were also analyzed as time-to-event outcomes with the use of penalized survival models to estimate cause-specific hazard ratios and nonparametric cumulative incidence, from which risk differences and odds ratio.
    Comparison groups
    Early DOAC treatment v Late DOAC treatment
    Number of subjects included in analysis
    2013
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.99
    Notes
    [2] - The main aim of the trial was to estimate the effect of early initiation as compared with later initiation of anticoagulation and to estimate the degree of precision of these estimates. Therefore, no statistical hypotheses as to superiority, inferiority, or noninferiority were tested.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events and serious adverse events were recorded throughout the entire duration of the trial, from November 2017 to December 2022.
    Adverse event reporting additional description
    The adverse event reporting period for each patient encompassed the time from when the participant signed the consent form until the last protocol-specific procedure has been completed, including a safety follow-up period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Details on all serious and non-serious adverse events can be found in the supplementary material.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2017
    Version 1.1: Modification of background and rationale to include ethical considerations; specification of assumed event rate; introduction of post-hoc consent; addition of TIA and undetermined stroke as secondary outcomes; clarification of anonymisation procedures; update of preventive measures for female paticipants of childbearing potential; clarification of follow-up procedures; listing of relevant AEs; administrative changes.
    27 Oct 2017
    Version 1.3: Administrative changes
    02 Aug 2018
    Version 1.2: Clarification of trial schedule; modification of consenting procedure to include LAR; specification of major bleeding; clarification of stroke classification; update of safety monitoring strategy; administrative changes
    07 Feb 2019
    Version 1.5: Addition of separate appendices for country-specific information; addition of information on the future use of data; administrative changes.
    03 Oct 2019
    Version 1.4: Update of trial schedule; administrative changes
    15 Jan 2021
    Version 2.0: Deletion of IMP brand names; clarification of the primary outcome to emphasize the two main components of “major bleeding” (i.e. “extracranial major bleeding” and “symptomatic intracranial haemorrhage”); specification of the components of “major bleeding” (i.e. symptomatic intracranial haemorrhage and individual components of major extracranial bleeding) as secondary outcomes; modification of eligibility criteria to expand inclusion (1) to those with moderate renal impairment / (2) after transient DAPT; specification of criteria for IMP discontinuation; update of criteria for IMP dose reduction; administrative changes.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37222476
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