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Supplementary material

Search strategy and data extraction

Databases accessed included MEDLINE (Ovid), EMBASE (Ovid), Cochrane library and Clinical trials registries (EU Clinical Trials Register and ClinicalTrials.gov) until October 2015. Relevant studies were identified using thesaurus subject headings (MEDLINE and EMBASE) and free text terms (supplemental Table e-1) limited to English language and human subjects. Our search strategy was based on previously developed strategies combining inclusive terms for ICH, AF and antithrombotic agents (anticoagulants and antiplatelet agents). References of relevant articles were screened for eligible studies. Pre-defined eligibility criteria were applied on studies by two independent investigators (EK, AD). Articles were shortlisted based on screening title and abstract. We considered studies that had enrolled at least in part ICH survivors with AF as indication for antithrombotic medication. Data were extracted using standardized data extraction forms. Discrepancies relating to eligibility or data extraction were discussed between the investigators. Uncertainties were resolved by a third investigator (RV). Corresponding authors of studies under consideration were asked to provide information on eligibility criteria and additional data.



Eligibility criteria

Pre-specified inclusion criteria were: (a) English language articles and original abstracts published between 1984 and October 1, 2015. Only papers from 1984 onwards were reviewed because brain imaging was not widely available before1; (b) Prospective or retrospective observational cohort, case-control studies, case series or randomized controlled trials; (c) ICH including intracerebral, subarachnoid, subdural haemorrhage (d) Any long-term outcome study looking at ICH recurrence and cerebrovascular thromboembolic events in ICH survivors with AF as indication for antithrombotic treatment; (e) Studies with description of drug exposure (antiplatelet medication or anticoagulants) regardless of dosage and timing of resumption for stroke prevention in AF patients; (f) Studies providing outcome ≥ 3 months after exposure to antithrombotic treatment. We also excluded studies that exclusively reported on patients with subarachnoid haemorrhage or with traumatic ICH only because of a different underlying pathophysiology of these conditions.



Table e-1: Search strategy

Search Areas

Thesaurus terms

Free Text Terms

MEDLINE

Subject Search in MeSH:

exp Atrial fibrillation,

exp Platelet Aggregation Inhibitors,

exp Aspirin,

exp Platelet activation/de

exp Blood Platelets/de

exp Anticoagulants/

exp Warfarin/

exp Heparin, Low Molecular-Weight

exp Heparin/

exp Antithrombins/

exp Blood Coagulation Factors/ai, de

exp Blood Coagulation/de

exp Thrombin/ai, de

exp Intracranial Hemorrhages/

Exp Hematoma

exp Hematoma, Subdural, Intracranial

exp Hematoma, Subdural, Acute

exp Hematoma, Subdural, Chronic

exp Cerebral Hemorrhage



((atrial or auricular) adj (fibrillation), ((antiplatelet* or anti-platelet* or antiaggreg*or platelet* adj5 inhibit*) or (thrombocyte*adj5inhibit*)), (acetylic salicylic acid* or acetylsalicylic acid or clopidogrel* or cilostazol or trifluzal), aspirin, clopidogrel, anticoagulants, anticoagulant*, (acenocoumarol* or dicoumarol* or ethyl biscoumacetate* or phenprocoumon* or warfarin* or coumarin*), warfarin*, heparin*, Vitamin K antagonist*, (anticoagulant* or antithrombo*), new oral anticoagulant*, Factor X inhibitor*, dabigatran, apixaban, rivaroxaba, edoxaban, ((brain or intracranial or cerebral or basal ganglia or intracerebral or putaminal) adj5 (haemorrhage* or hemorrhage*)), ((brain or cerebral or intracerebral or intracranial or subdural) adj5 (haematoma* or hematoma*))
Limit to English language and humans (1984-current)

EMBASE

Subject Search in emtree:

exp heart atrium fibrillation/

exp antithrombocytic agent/

exp acetylsalicylic acid/

exp clopidogrel

exp thrombocyte activating factor/ receptor affecting agent/

exp anticoagulant agent

exp warfarin/

exp heparin/

exp low molecular weight heparin/

exp antivitamin K/

exp thrombin inhibitor/

exp dabigatran etexilate/

exp dabigatran/

exp apixaban/

exp rivaroxaban/

exp edoxaban/

exp brain hemorrhage/

exp brain hematoma/

exp subdural hematoma/




((atrial or auricular) adj (fibrillation)), ((antiplatelet* or anti-platelet* or antiaggreg*) or (platelet* adj inhibit*) or (thrombocyt* adj inhibit*)), (acetylic salicylic acid* or acetylsalicylic acid or clopidogrel* or cilostazol or trifluzal), anticoagulant*, (acenocoumarol* or dicoumarol* or ethyl biscoumacetate* or phenprocoumon* or warfarin* or coumarin*), warfarin*, heparin*, Vitamin K antagonist*, new oral anticoagulant*, factor X inhibitor*, dabigatran, apixaban, rivaroxaban, edoxaban, ((brain or intracranial or cerebral or basal ganglia or intracerebral or putaminal) adj5 (haemorrhage* or hemorrhage*)), ((brain or cerebral or intracerebral or intracranial or subdural) adj5 (haematoma* or hematoma*))


Limit to English language and humans (1984-current)

Clinical trials

(EU Clinical Trials register and Clinical Trials.gov)




Not Applicable

("intracerebral hemorrhage" OR "intracranial hemorrhage") AND "atrial fibrillation" AND ("anticoagulant" OR "antiplatelet")

Cochrane Library

Not Applicable

("intracerebral hemorrhage" OR "intracranial hemorrhage") AND "atrial fibrillation" AND ("anticoagulant" OR "antiplatelet")

Table e-2: Characteristics of studies included in the systematic review.

Study

Type of publication

Design

Inclusion criteria

Type of ATM exposure

Arioli, 2015

abstract

prospective

pts with favorable clinical and radiological evolution without contraindication to DOAC


DOAC

Chong, 2012

full paper

prospective

first spontaneous ICH, >18 years

alive at 30 days



APA, no-ATM

Claassen, 2008

full paper

retrospective

warfarin-associated intracerebral hemorrhage, INR ≥ 1.5, current treatment with warfarin, discharge from hospital

VKA, no-VKA

De Vleeschouwer, 2005

full paper

prospective

OAC associated ICH

VKA, APA

Gathier, 2013

full paper

retrospective

OAC-associated intracerebral hemorrhage, INR >1.1 on admission, radiologically documented hemorrhage, acenocoumarol or phenprocoumon at the time of the ICH

VKA, APA,

no -ATM


Kuramatsu, 2015

full paper

retrospective

spontaneous intracerebral hemorrhage related to anticoagulation

VKA, no-VKA

Majeed, 2010

full paper

retrospective

warfarin associated ICH

VKA, no-VKA

Nielsen, 2015

full paper

retrospective

OAC associated ICH in AF pts (on OAC treatment), pts alive 6 weeks after the index event

VKA, APA,

No-ATM


Poli, 2014

full paper

prospective

ICH survivors on VKA

VKA

Stamplecoski, 2014

abstract

retrospective

> 65years with Intracerebral hemorrhage and AF

VKA, no-VKA

Teo, 2014

full paper

retrospective

warfarin-associated intracerebral haemorrhage survivors

VKA, APA,

No-ATM


Teo, 2014

abstract

retrospective

antiplatelet-related intracerebral hemorrhage survivors

APA, no-ATM

Vermeer, 2002

full paper

retrospective

all pts with primary intracerebral hemorrhage who returned home

VKA

Vidal-Jordana, 2012

full paper

retrospective

OAC associated intracerebral hemorrhage

OAC, APA

Viswanathan, 2006

full paper

prospective

spontaneous intracerebral hemorrhage, age > 55 y

APA, no-APA

Weimar, 2011

full paper

prospective

consecutive pts with spontaneous intracerebral hemorrhage who were discharged alive

VKA, APA,

No-ATM


Yung, 2012

full paper

retrospective

warfarin associated ICH, age ≥18

VKA, no-VKA

Pts = patients, INR = international normalized ratio, DOAC=Direct oral anticoagulants OAC: oral anticoagulants APA=antiplatelet agents ATM= antithrombotic medication VKA= Vitamin K antagonists AF: atrial fibrillation

Table e-3: Quality assessment of studies included in the meta-analysis







Selection Bias

Blinding of participants and personnel

Attrition bias

Reporting bias

Other bias







Random sequence generation

Allocation concealment

Consecutivity

Blinding of participants and personnel

Blinding of outcome assessment

Incomplete outcome data

Selective reporting*

Funding

Radiologically confirmed ICH

reasons for taking ATM described

1

Gathier, 2013

high risk

high risk

low risk

high risk

high risk

low risk

low risk

low risk

low risk

low risk

2

Kuramatsu, 2015

high risk

high risk

low risk

high risk

high risk

high risk

low risk

low risk

low risk

low risk

3

Majeed, 2010

high risk

high risk

low risk

high risk

high risk

low risk

low risk

low risk

low risk

low risk

4

Nielsen, 2015

high risk

high risk

low risk

high risk

high risk

low risk

low risk

low risk

unclear

low risk

5

Stamplecoski, 2014

high risk

high risk

unclear

high risk

unclear

unclear

low risk

low risk

unclear

low risk

6

Vidal-Jordana, 2012

high risk

high risk

high risk

high risk

high risk

high risk

low risk

low risk

low risk

low risk

7

Viswanathan, 2006

high risk

high risk

low risk

high risk

low risk

low risk

low risk

low risk

low risk

low risk

*Data were provided directly by co-authors after personal communication.

Table e-4: Results from single variable meta-regression analyses exploring the impact of mean age, gender, timing of antithrombotic medication resumption and type of ICH (all intracranial vs. intracerebral haemorrhage only) on both outcomes across different treatment groups (p-values).

Meta-regression analysis

(p-values)

By age

By gender (female)

By time to resumption

By type of ICH

VKA vs No-VKA IS


0.976

0.777

0.858

0.677

VKA vs No-VKA recurrent ICH


0.426

0.114

0.304

0.390

VKA vs APA IS


0.894

0.903

0.426

0.976

VKA vs APA recurrent ICH


0.904

0.774

0.734

0.758

VKA vs No-ATM IS


0.901

0.684

0.924

0.715

VKA vs No-ATM recurrent ICH


0.574

0.068

0.141

0.075

APA vs No-ATM IS


0.571

0.498

0.932

0.958

APA vs No-ATM recurrent ICH


0.720

0.747

0.207

0.324

Table e-5: Distribution of different types of ICH and (subarachnoidal/subdural/parenchymal) in the study by Nielsen et al. and the stroke rate/recurrence rate of ICH according to different baseline subtypes


Ischaemic stroke: Rate/100 person-years



Intracerebral

Subdural

Subarachnoid

No treatment

11.6

6.0

1.8

OAC treatment

8.8

1.5

3.6

ASA therapy

14.4

5.4

0.0

Haemorrhagic stroke: Rate/100 person-years




Intracerebral

Subdural

Subarachnoid

No treatment

4.0

12.0

1.8
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