Restarting Anticoagulant Treatment After Intracranial …/media/Non-Clinical/Files-PDFs-Excel... · 2015-10-14 · stroke and/or mortality, but with a small increase in major bleeding

DOI: 10.1161/CIRCULATIONAHA.115.015735

1

Restarting Anticoagulant Treatment After Intracranial Haemorrhage in

Patients With Atrial Fibrillation and the Impact on Recurrent Stroke,

Mortality and Bleeding: A Nationwide Cohort Study

Running title: Nielsen et al.; Anticoagulant treatment after intracranial haemorrhage

Peter Brønnum Nielsen, MSc, PhD1,2; Torben Bjerregaard Larsen, MD, PhD1,2;

Flemming Skjøth, MSc, PhD1,2; Anders Gorst-Rasmussen, MSc, PhD1,2;

Lars Hvilsted Rasmussen, MD, PhD1,2; Gregory Y.H. Lip, MD2,3

1Dept of Cardiology, Atrial Fibrillation Study Group, Aalborg University Hospital, Aalborg,

Denmark; 2Aalborg Thrombosis Research Unit, Dept of Clinical Medicine, Faculty of Health,

Aalborg University, Aalborg, Denmark; 3University of Birmingham Centre for Cardiovascular

Sciences, City Hospital, Birmingham, United Kingdom

Address for Correspondence:

Gregory Y.H. Lip, MD

City Hospital Birmingham

Dudley Road, B18 7QH

United Kingdom

Tel: +44 121 507 5080

Fax: +44 121 507 5097

E-mail: [email protected]

Journal Subject Code: Stroke treatment - medical:[70] Anticoagulants

Lars Hvilsted Rasmussen, MD, PhD1,2; Gregory Y.H. Lip, MD2,333

1DeDeDeptptpt oooff f CaCC rdddioioiolllogy, Atrial Fibrillation Study yy GrGrGroup, Aalborg UUUniveeersrsrsity Hospital, Aalborg,

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Sciences, City Hospital, Birmingham, United Kingdom

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Abstract

Background—Intracranial haemorrhage is the most feared complication of oral anticoagulant

treatment. The optimal treatment option for atrial fibrillation patients surviving an intracranial

haemorrhage remains unknown. We hypothesised that restarting oral anticoagulant treatment

was associated with a lower risk of stroke and mortality compared to not restarting.

Methods and Results—Linkage of three Danish nationwide registries in the period between

1997 and 2013 identified atrial fibrillation patients on oral anticoagulant treatment with incident

intracranial haemorrhage. Patients were stratified by treatment regimens (no treatment, oral

anticoagulant treatment or antiplatelet therapy) post the intracranial haemorrhage. Event rates

were assessed 6 weeks after hospital discharge and compared with Cox proportional hazard

models. In 1,752 patients (one year of follow-up) the rate of ischemic stroke/systemic embolism

and all-cause mortality (per 100 person-years) for oral anticoagulant treatment treated patients

were 13.6, compared to 27.3 for non-treated patients and 25.7 for patients receiving antiplatelet

therapy. For recurrent intracranial haemorrhage: 8.0 for oral anticoagulant treated, compared to

8.6 for non-treated, and 5.3 for antiplatelet therapy. The adjusted hazard ratio of ischemic

stroke/systemic embolism and all-cause mortality was 0.55 (95%CI 0.39-0.78) in patients on oral

anticoagulant treatment compared to no treatment. For ischemic stroke/systemic embolism and

for all-cause mortality HRs were 0.59 (95%CI 0.33-1.03) and 0.55 (95%CI 0.37-0.82),

respectively.

Conclusions—Oral anticoagulant treatment was associated with a significant reduction in

ischemic stroke/all-cause mortality rates, supporting oral anticoagulant treatment reintroduction

post-intracranial haemorrhage as feasible. Future trials are encouraged to guide clinical practice

in these patients.

Key words: stroke, anticoagulant, hemorrhage, cerebral infarct

and all-cause mortality (per 100 person-years) for oral anticoagulant treatment treeeatatatededed pppatatatieieientntntsss

were 13.6, compared to 27.3 for non-treated patients and 25.7 for patients receivinggg antttiiiplllatttellel ttt

herapy. For recurrent intracranial haemorrhage: 8.0 for oral anticoagulant treated, compared to

8.6 66 fofoforrr non-n-n-trtrreateteedd,d and 5.3 for antiplatelet therappyy.y The adjusted hahh zarddrd rrratio of ischemic

tttroooke/systemic cc ememe boboolllismsmsm aaandndnd aaallllll-c-c-cauaua ssse mororrtaaality wwwas 0.0.0.555555 (((95959 %C%C%CIII 00.0 3339--0.7778)8)8) iiin nn papapatienenentsss ooonn n orororatt

ananntiiicocc agulant t t treeattmennnt commmpaaared to oo nnno treaaatmmmentt. FFFor r r isisischchemememic stttroke///syystemememic embmbmboliismmm annndd

for alalalll-l-cacacauususe momoortrtalalalititityy HRHRHRs weeererere 000.59 (9(9(95%5%5%CICICI 00.33333-1.11 030303))) anannddd 0.555555 (((95955%C%C%CI I 0.373737-0-00.82)),

espectively

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Introduction

Patients with atrial fibrillation (AF) are increasingly treated with oral anticoagulation (OAC),

which has been shown to reduce the risk of stroke/systemic embolism and all-cause mortality,

compared to control 1. Until recently, OAC usually meant Vitamin K Antagonists (VKA, e.g.

warfarin), and the most feared complication was major bleeding, particularly intracranial

haemorrhage (ICH). More recently, the Non-VKA Oral Anticoagulants (NOACs) have been

introduced into clinical practice and are associated with relatively lower – but not zero – risk of

ICH, when compared to warfarin 2,3. The acute development of ICH confers a poor prognosis

with a high rate of mortality and disability, whether or not a NOAC is used.

Patients with AF who survive an ICH are at an increased risk of subsequent ischaemic

stroke 4,5. Thus, a major unanswered question is the efficacy and safety of restarting OAC

treatment, relative to not restarting OAC, following a presentation with ICH 6–9. Patients with

prevalent ICH were excluded from randomized clinical trials of OAC for stroke prevention, and

only small case control or cohort studies are available 10–13. Currently, the optimal treatment

option is unknown and requires balancing the competing risk of ischemic stroke and recurrent

ICH in AF patients.

Using Danish nationwide registries cohort, we investigated the hypothesis that, amongst

AF patients presenting with an ICH, restarting OAC was associated with a lower risk of recurrent

stroke and/or mortality, but with a small increase in major bleeding (particularly ICH) compared

to not restarting.

Methods

We used the civil registration number assigned to all Danish residents to link three nationwide

Patients with AF who survive an ICH are at an increased risk of subsequenenent t t isisischchchaeaeaemimimicc c

troke 4,5. Thus, a major unanswered question is the efficacy and safety of restarting OAC

reatmtmtmenenent,t,t, rrrelelelativvvee to not restarting OAC, followwwinininggg a presentation with h h ICICICH 6–9. Patients with

ppprevvvalent ICH wwwerre eeexcxcxclululudededed d d frfrfromomm rrrannndoomimiizezezed cllinnnicalalal tttriririalala sss offf OOOACACAC fffooorrr strorookekeke ppprerereveveventntntiooon,n,n, aaandndnd

onnnlylyly ssmall cccasasase cococontroool or coohohoorort stttuduu ieieesss areee aavavailabbble 10–10–10–13. . CuCuCurrrrenenentlly,yy ttthee optptp imimimal tttrerereatmemeent

opopoptititiononon iiisss unnunknknknowoownnn anananddd rererequqquiririreseses bbbalalalaaancncncinininggg thththeee cococompmpmpetetetinininggg riririsksksk ooofff isisischchchemememicicic ssstttrororokekeke aaandndnd rrrecececurrurrererentntnt




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databases 14–16 as follows: (i) discharge diagnoses classified by the International Classification of

Diseases (ICD), admission and discharge dates were obtained from the Danish National Patient

Registry; (ii) dispensed prescriptions identified by the Anatomical Therapeutic Chemical (ATC)

classification code, date of purchase, package size and volume of the medication since 1994 were

obtained from the Danish National Prescription Registry; and (iii) information on age, sex, date

of birth, emigration and vital status were attained from the Danish Civil Registration System.

Retrospective studies do not require ethical approval in Denmark.

Study population

All Danish citizens with an incident nonvalvular AF diagnosis between January 1997 and

December 2013 were identified. Patients with a subsequent incident ICH (ICD10: I60-I62;

S063C; S064-S066) requiring admission to a hospital were included. Exclusion criteria were

valvular AF defined as presence of mitral stenosis or mechanical heart valve (ICD10: I05 and

Z952-Z954). Patients with ICH or complications from ICH (ICD10: I690-692) prior to their AF

diagnosis were also excluded. We further required patients to be in OAC treatment defined as a

claimed VKA or NOAC prescription within 6 months prior to the ICH event. This was done to

support the assumption that included patients were indeed in OAC treatment at the time of the

incident ICH event. Patients were followed in the National Patient Registry after a ‘quarantine

period’ defined as 6 weeks after hospital discharge. This period was chosen to ensure that events

could reasonably be attributed to treatment regimens rather than inadequate correction of the

initial coagulation deficit, i.e. reversal of the incident ICH (and adjacent) event 9,17–20 . Further,

the use of a relatively long quarantine period can reduce confounding by indication, as those

patients initially deemed at a very high risk of recurrent ICH would probably not be advised to

resume anticoagulation within this period (e.g. patients with lobar haemorrhage 21).

December 2013 were identified. Patients with a subsequent incident ICH (ICD10:0:: III606060-I-I-I626262;;;

S063C; S064-S066) requiring admission to a hospital were included. Exclusion criteria were

valvvulululararar AAAFFF dedd fiiinenened as presence of mitral stenosisisisss ooor mechanical heart vvvalaa ve (ICD10: I05 and

ZZZ95525 -Z954). Paaattitieentststs wwwititithhh ICICICH H H ororr cccomomompplicatatatiooons fffroomom IIICHCHCH (((ICICICDD1D 0:00: II69696900-69992)2)2) ppriririororor to oo thththeieieirrr AFAFAF

diiiagagagnnon sis wewewerrre aaalso exxxcludededd. WeWW fufufurttheheher r reeeququuiredd pppattieieiennnts tooo bbbe e innn OOOAAC treeeatatatmmmenttt dddefinneeed asss aa

clclclaiaiaimememeddd VKVKVKAAA ororor NNNOAOAOACCC prprpresesescrcrcripipiptititiononon wititithihihinnn 666 momomontntnthshshs pppriririororor tttooo thththeee ICICICHHH eveevenenenttt. TTThihihisss waawasss dododonenene tttooo




5

Exposure to antithrombotic treatment

We identified all prescriptions of antiplatelet therapy (aspirin/thienopyridines) and OAC

treatment (VKA/NOAC) to classify patients by treatment regimens as: ‘No antithrombotic

treatment’, ‘Antiplatelet therapy’ or ‘OAC treatment’. The following ATC codes were utilised to

account for OAC treatment: B01AA (coumarin derivatives), B01AE07 (dabigatran etexilate);

B01AF01-02 (rivaroxaban and apixaban). For antiplatelet therapy the following ATC codes were

utilised: B01AC06 (aspirin) and B01AC04, B01AC22 and B01AC24 (Thienopyridines). When

discharged from the hospital, all included patients were initially assigned to ‘no antithrombotic

treatment’ and if antithrombotic therapy was reinitiated, to either ‘Antiplatelet therapy’ or ‘OAC

treatment’ categories, whichever prescription was claimed first [Figure 1]. Treatment exposure

was consequently considered as a time-dependent covariate.

Outcome measures

The primary analysis plan used the principal outcomes of ischemic stroke/systemic embolism

(SE), all-cause mortality and recurrent ICH. Given the severity of the studied outcomes, we only

considered events if the patient was admitted to the hospital 22; hence, we did not consider

ambulatory diagnosis. Additionally, emergency room coded diagnoses were not included in this

study due to poor validity 23. The primary study endpoint was a combined endpoint of ischemic

stroke/SE (ICD10 diagnosis: I63; I64; I74) and all-cause mortality, given the positive impact of

OAC on stroke and mortality 1 and recognising that in registry data, some deaths may be due to

undiagnosed stroke/SE as neither post-mortems nor cerebral imaging are mandated.

Secondary analyses were carried out for ischemic stroke/SE; for recurrent ICH; for major

extra cranial bleeding (ICD10: D62; J942; H113; H356; H431; N02; N95; R04; R31; R58; K250

K260 K270 K280 K290), and for all-cause mortality. If, in the primary analysis, antithrombotic

reatment’ categories, whichever prescription was claimed first [Figure 1]. Treatmemementntnt eeexpxpxposososururure

was consequently considered as a time-dependent covariate.

Outctccomomome e e mememeasurururesee

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6

therapy did show benefit versus being left untreated (commonly seen in practice post-ICH 5,24), a

secondary analysis calculating net clinical benefit (NCB) of resuming antithrombotic therapy (vs

no antithrombotic therapy) was calculated by the methods previously proposed balancing

ischaemic stroke reduction versus the increased risk of ICH 25. NCB with 95% confidence

intervals (CI) were based on rate differences and standard errors estimated obtained using

Poisson regression. We applied a weight of 1 for ischemic stroke/SE and all-cause mortality and

a weight of 1.5 for recurrent ICH as proposed by Singer et al 25. Accompanying the NCB

analysis, we also investigated the event rate for the composite outcome of ischemic

stroke/SE/major bleeding (including recurrent ICH). Additionally, we carried out a sensitivity

analysis by altering the quarantine period when investigating the outcome of ischemic stroke/SE

and all-cause mortality and recurrent ICH. This was done to assess if the choice of quarantine

period would differ from the main analysis (using a 6 weeks quarantine period).

Patient characteristics and concomitant medication

Comorbidities were ascertained from preceding hospital diagnoses until discharge from the

incident ICH event. Filled prescriptions 1 year prior to baseline defined other concomitant

medication. The cardiovascular comorbidity and risk of stroke at baseline were assessed by the

CHA2DS2-VASc [congestive heart failure, hypertension, age >75 years, diabetes mellitus, stroke,

vascular disease, age 65–75 years, and female sex)] score 26,27. We calculated the HAS-BLED

[hypertension, abnormal renal/liver function, stroke/thromboembolism, bleeding history, labile

international normalized ratio (not included), elderly (age >65 years), drug consumption/alcohol

excess (aspirin was not included due to status of exposure)] score for each patient to assess the

bleeding risk 28. Supplementary Table 1 provides detailed description on outcomes and

concomitant medication.

analysis by altering the quarantine period when investigating the outcome of ischehehemimimic cc stststrororokekeke/S/S/SE

and all-cause mortality and recurrent ICH. This was done to assess if the choice of quarantine

periiododod wwwouououldldld diffffefefer r from the main analysis (usinnng g g aa a 6 weeks quarantineee ppperiod).

PPPattitient characccteteterriststticicicsss ananandd d cococoncnccomommitititant mememedicaattionnn

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7

Statistical analyses

Patients were followed until occurrence of the following censoring events: a claimed prescription

indicating dual treatment regimen (both OAC and antiplatelet treatment), occurrence of a study

endpoint, emigration, end-of-study, or death whichever came first [Figure 1]. For outcome

analyses events were ascertained from 6 weeks after hospital discharge. Exposure to

antithrombotic treatment was regarded as two time-dependent covariates (one for OAC treatment

and one for antiplatelet therapy) with one irreversible binary transition (from 0 to 1). We

calculated crude events rates at 1 and 5 years by dividing the number of events occurring during

follow-up with the person-years of follow-up for each treatment group. To compare event rates

associated under antithrombotic treatment regimens vs no antithrombotic treatment, crude and

adjusted hazard ratios (HR) were estimated by means of the Cox proportional hazards model.

The adjusted analyses included information on age (restricted cubic spline); gender (binary); year

of inclusion (categories of five years); time since last claimed OAC prescription before the

incident ICH event (restricted cubic spline); and categories of the CHA2DS2-VASc score (0; 1;

2 points) and HAS-BLED score (0-2; 3 points). We additionally used information on ischemic

stroke/SE and/or recurrent ICH events during the quarantine period (binary). The reasoning

behind this adjustment was that such events could affect the choice of antithrombotic treatment

before the observation time commenced. Additionally, a sensitivity analysis was conducted by

excluding patients who experienced an event within the quarantine period.

To depict the overall five year prognosis, we obtained the Kaplan-Meier estimates. The

patients were stratified according to purchase of OAC (respectively, antiplatelet drugs) during

the quarantine period (6 weeks landmark) and patients with dual treatment exposure were

excluded (prescription claim of both an OAC and antiplatelet drug). To assess the impact of

associated under antithrombotic treatment regimens vs no antithrombotic treatmenenent,t,t, cccrururudedede aaandndnd

adjusted hazard ratios (HR) were estimated by means of the Cox proportional hazards model.

The e adadadjujujustststededed anaaalylylyses included information on agagageee (restricted cubic splililinnne); gender (binary); yea

oofof iiinncn lusion ((caaateteteggoriririesese ooofff fffiveveve yyeeaearsrsrs););) time siss nnnce laast ccclalalaimimimededed OOOACACAC pprereresccriptptptioioionn bebebefofoforerere thehehe

nnncicc dededent ICHHH eveeenntnt (reeestttrictededed cccubu icicic sppplinnne))); ; ; annnd ccattteggoorririess offf ththt eee CHCHCHAAA2DDS222-V-V-VASccc ssscorre (0; 1;

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8

allowing more time for claiming a prescription used for treatment regimen allocation, we made a

sensitivity analysis by setting the landmark to 180 days.

We used a two-sided p-value threshold of p<0.05 for statistical significance. Statistical

analyses were performed by using SAS 9.3 (SAS Institute) and Stata version 13 (StataCorp LP).

Results

A total of 6,138 patients with non-valvular AF who suffered an incident ICH were identified in

the period from January 1st 1997 to December 31st 2013. Within the quarantine period of 6 weeks

1,652 patients died, while 32 patients were excluded due to insufficient follow-up time (i.e.

encountered study-end within the quarantine period). The study population was comprised of

1,752 patients who fulfilled the inclusion criteria by having claimed an OAC prescription within

six months of the incident ICH event and were still alive after the 6 weeks quarantine period; see

Figure 1 for flowchart and Table 1 for study population characteristics. The proportion of

patients included in the analysis with prior OAC treating receiving VKA was 65%, and the

combination of VKA and antiplatelet therapy in 33%. With NOACs, the proportion was 2%

while <1% received combination therapy with a NOAC and antiplatelet therapy. The mean

CHA2DS2-VASc score was 3.9 and the mean HAS-BLED score was 3.2, indicating a study

population at high risk of both thromboembolic events as well as high risk of bleeding.

Of the patients who resumed OAC treatment (n=621), 77% claimed an OAC prescription

within first 3 months after hospital discharge, with an overall median days of 34 to first claimed

prescription. For those who received antiplatelet therapy (n=759), 65% claimed a prescription

within first 3 months, with an overall median time of 24 days. During the first year of follow-up,

218 patients either shifted treatment or initiated dual antithrombotic treatment and were

encountered study-end within the quarantine period). The study population was cococompmpmpriririsesesed d d ofofof

1,752 patients who fulfilled the inclusion criteria by having claimed an OAC prescription within

ix momomontntnthshshs ooof ff theee inini cident ICH event and were stststililillll alive after the 6 weeekekeks quarantine period; see

FFFiggugure 1 for fflooowcwcw hahaarrrt aaandndnd TaTaTablblble ee 111 fffororor sstudydydy ppopulullatiooon n n chchcharararacctetteririri tststiciccs.ss TTheee ppprrropopoportrtrtiooonn n ofofof

paaatitt enenents inclululudedd dd d iinin thhhe analylyysisisis ss wiiiththth pppriiioor OAOAOAC ttreeeatiiinggg reececeeeiviviv ngngng VVVKAAA waasas 6665%,, aaand thhhe

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9

accordingly censored.

Stroke/SE and all-cause mortality

A total of 39 patients suffered an ischemic stroke/SE during the quarantine period of 6 weeks; of

those, 5 patients had already claimed an OAC prescription, while 11 patients received

antiplatelet therapy. The overall event rates (expressed as per 100 person-years) using 1 year of

follow-up of the combined endpoint of ischemic stroke/SE and all-cause mortality in OAC

treated vs no antithrombotic treatment were 13.6 vs 27.3 (adjusted HR: 0.55, 95%CI 0.39-0.78),

and 25.7 for antiplatelet therapy (adjusted HR: 0.87, 95%CI 0.67-1.14) [Table 2 and Figure 2].

The event rates for ischemic stroke/SE in OAC treated vs no antithrombotic treatment were 5.3

vs 10.4 at one year of follow-up (adjusted HR: 0.59, 95%CI 0.33-1.03), whilst for antiplatelet

therapy, 10.3 (adjusted HR: 0.98, 95%CI 0.65-1.49). For all-cause mortality, the event rates were

9.7 for OAC treated vs 19.1 for no antithrombotic treatment (adjusted HR: 0.55, 95%CI 0.37-

0.82), and 19.5 for antiplatelet therapy (adjusted HR: 0.90, 95%CI 0.67-1.21). The crude and

adjusted analyses contrasting treatment regimens were comparable. Supplementary Table 2

provides event rates based and adjusted hazard ratios based on 5 years of follow-up, showing

consistency.

Figure 3 depicts the Kaplan-Meier estimates of 5 year survival in patients who resumed

OAC treatment, respectively received antiplatelet therapy, and those who did not. A landmark at

6 weeks (quarantine period) was used to allocate patients treatment regimens: 1,089 were

assigned to the no antithrombotic treatment group; 303 to OAC treatment; and 360 to the

antiplatelet therapy group.

Recurrent ICH and major bleeding

Of a total of 298 recurrent ICH events, 177 events (60%) occurred during the quarantine period,

vs 10.4 at one year of follow-up (adjusted HR: 0.59, 95%CI 0.33-1.03), whilst fororr aaantntntipipiplalalatetetelelelettt

herapy, 10.3 (adjusted HR: 0.98, 95%CI 0.65-1.49). For all-cause mortality, the event rates were

9.7 fofofor r r OAOAOACCC trt eaaateteted vs 19.1 for no antithrombotitiiccc trtrtreatment (adjusted HRHRHR: 0.55, 95%CI 0.37-

000.8222), and 19.5 ffoforr ananntttiplplplatatateeeleeet t t thththeeeraapapyyy (aadjdjjuuustteted HRHRR: 0.0.0.909090, 959595%C%C%CI I I 00.0 676767-11.21)1)1)... ThThTheee crcc ududude ananand d d

adddjujujuststs ed anaaalylylysees ccoc ntttraaastinnggg trtrtreae tmmmennnt rrer gigigimememens wwwereee cccommmparararababbleee. SuSS pppppplememementarrryy y Taabble 2

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10

i.e. before the observation time commenced; of these 27 patients had claimed an OAC

prescription, while 35 patients received antiplatelet therapy. For recurrent ICH using one year of

follow-up, the rates were 8.6 for OAC treated vs 8.0 for no antithrombotic treatment (adjusted

HR: 0.91, 95%CI 0.56-1.49), and 5.3 for antiplatelet therapy (adjusted HR: 0.60, 95%CI 0.37-

1.03). The event rates of major extra cranial bleedings in OAC treated vs no antithrombotic

treatment were 1.5 vs 1.5 (adjusted HR: 0.92, 95%CI 0.30-2.76), and 2.6 for antiplatelet therapy

(adjusted HR: 1.57, 95%CI 0.62-3.92) [Table 2 and Figure 2]. The crude and adjusted analyses

contrasting treatment regimens for bleeding outcomes were broadly comparable.

Secondary analysis

The one-year event rate for the combined endpoint of ischemic stroke/SE/major bleeding

(including ICH) was 27.4 for no antithrombotic treatment, 17.1 for OAC treatment, and 23.2 for

patients who receiving antiplatelet therapy. As OAC did demonstrate a significant reduction in

stroke/SE and all-cause mortality, we calculated the one year NCB of OAC or antiplatelet

therapy use versus no antithrombotic treatment. The NCB was calculated as a weighted sum of

rate differences for the combined endpoint of ischemic stroke/SE and all-cause mortality and

recurrent ICH. The NCB for OAC vs versus no antithrombotic treatment was 14.6 (95%CI 6.4-

22.8), while the NCB was non-significant for antiplatelet therapy vs versus no antithrombotic

treatment, 6.5 (95%CI -2.1-15.2).

Sensitivity analysis

A sensitivity analysis of the Kaplan-Meier estimates stratified according to treatment regimens

using a landmark at 180 days (relative to hospital discharge) for treatment allocation is shown in

Supplementary Figure S1. A total of 1541 patients contributed to this analysis, and the survival

curves were alike to those presented in Figure 3 supporting OAC treatment.

The one-year event rate for the combined endpoint of ischemic stroke/SE/major blbleeeee didingngng

including ICH) was 27.4 for no antithrombotic treatment, 17.1 for OAC treatment, and 23.2 for

patienenntststs wwwhohoo receieie viv ng antiplatelet therapy. As OOOACACAC did demonstrate aa sisisignificant reduction in

tttroooke/SE and d alalallll-ccaausususe momomortrtrtalalalititity,y,y, wwwe cacac lculululatatteed thehee onnene yyeaeaearrr NNNCBCBCB oof ff OAOOAC ororor aantntntipipiplall tetetelllet t t rr

hhheere apapapyy use veveversususus no annntithrrrommmbottticicic ttrerereata mmemennnt. TTheee NCNCNCB B wawawas caaalccculululatedeed asss a weww iggghththted suuum ooof f

aaatetete dddifififfefeferererencncnceseses fffororor ttthehehe cccomomombibibineneneddd enenendpdpdpoioiointntnt ooofff isisischchchemememicicic ssstrtrtrokokoke/e/e/SESESE aaandndnd aaallllll cc-cauaausesese mmmororortatatalililitytty aaandndnd




11

Altering the quarantine period ranging from 2 weeks to 10 weeks did essentially not

affect the primary outcome of ischemic stroke/SE and all-cause mortality, see Figure 4. The total

number of patients contributing to these analyses was 1.838; 1.793; 1.752; 1.732; 1.712 using 2;

4; 6; 8; and 10 weeks quarantine period, respectively. Contrary, the outcome of recurrent ICH

was somewhat affected by the choice of quarantine period. The HR contrasting OAC treatment

vs no treatment was ranging from 0.41 (95%CI 0.27-0.63) for 2 weeks quarantine period, to HR

1.42 (95%CI 0.83-2.43) when applying a 10 weeks quarantine period. The obtained results on

HR contrasting treatment regimens were generally not affected by excluding those patients who

experienced an event (ischemic stroke/SE and/or recurrent ICH) during the quarantine period.

However, the outcome of recurrent ICH for patients on OAC treatment displayed an adjusted HR

of 1.30 (95%CI 0.75-2.27).

Discussion

In this analysis we found that AF patients who suffer an ICH are very high risk of ischaemic

stroke and mortality, if they are not on antithrombotic therapy. Patients who were not on OAC

treatment had the worse adverse outcomes, which were similar to rates seen with antiplatelet

therapy. Importantly, OAC treatment was associated with a significant reduction in subsequent

ischaemic stroke and all-cause mortality.

ICH is the most feared complication of OAC treatment, being associated with a high

mortality and morbidity, and survivors often have greater disability. Patients with ICH were not

included in randomised trials, and it is an open problem to decide the best time window to

reintroduce OAC treatment following a presentation with ICH. Our analysis does not define the

best time window to reintroduce OAC but makes the observation in this non-randomised

However, the outcome of recurrent ICH for patients on OAC treatment displayeddd aaan n n adadadjujujustststededed HHHR

of 1.30 (95%CI 0.75-2.27).

DDDisscscussion

nnn tthihihis analysysysisii wwwee e foununund thaatat AAAF papapatieeenttst wwwhohoo suffffeeer aaann n ICCHH H ararareee vveveryryry hhhigggh rririsksksk of isisisccchaaemmmic

tttrororokekeke aaandndnd mmmororortatatalililitytty, ififif ttthehehey ararareee nononottt ononon aaantntntititithrhrhromomombobobotititiccc thththerereraaapyppy. PPPatatatieieientntntsss whhwhooo weewererere nnnototot ooonnn OAOAOACCC aa




12

observational cohort that OAC use was associated with significantly lower risks of ischaemic

stroke and all-cause mortality.

The risk of recurrent ICH was also high in our patients, and was equally high amongst

non-OAC treated or OAC-treated, while slightly lower in patients who received antiplatelet

therapy. Factors contributing to recurrent ICH have been reported in different studies 8,9,29,30 and

include increasing age, concomitant use of aspirin or NSAIDs, uncontrolled hypertension, etc.

As previously shown in clinical trial and nationwide registries, the HAS-BLED score is the only

bleeding risk score that is predictive of major bleeding risk, and reflects the risk factors

commonly associated with this complication 4,28,31.

Common practice is to consider no antithrombotic treatment or antiplatelet therapy

(commonly aspirin) as a ‘safer’ alternative to OAC following a presentation with ICH, and the

AHA/ASA guideline provides a Class IIb recommendation of antiplatelet therapy after all types

of ICH (and “OAC might be considered after non-lobar ICH”) 32. Our data do not support such

an approach with a higher ischaemic stroke and substantially higher mortality, with a non-

significant reduction in recurrent ICH amongst antiplatelet therapy users. Even in randomised

trials of stroke prevention in AF, the risk of ICH (and major bleeding) is no different between

OAC and aspirin treated patients, especially in the elderly 33,34. Also, our secondary analyses

show that the NCB for OAC treatment was positive, vs no antithrombotic therapy – whilst the

NCB for aspirin vs no antithrombotic therapy was non-significant.

The present study has clinical implications, in that it supports OAC re-introduction as

soon as clinically feasible. However, given the non-randomized design and data limitations

caution on over-interpretation the results are warranted: we were not able to distinguish between

the severities of risk factors, which may reflect physician’s choices of OAC resumption.

Common practice is to consider no antithrombotic treatment or antiplateleeettt thththerererapapapy y y m

commonly aspirin) as a ‘safer’ alternative to OAC following a presentation with ICH, and the

AHA/A/A/ASASASA A A guguguidelelelinini e provides a Class IIb recommmmememendation of antiplateeelelelet tt therapy after all types

oofof IIICHC (and “OOOAACAC mmmigigighththt bbbee cccoononsisis dededereeed afffteteter non nn-looobaaarrr ICICICH”H”H”) 323232. OuOuOur rr daddata dddooo nononottt sususupppporoo t t t sususuchchch

annn apppppproach h h wiww thhh aaa higgghheh r issschchchaaea mimimiccc stttroooke nannd suubbbstaaantttiallllly hihih gggheeer momomorttalititity,y,y, withhh aaa noonnn-

iiigngngnififificicicanananttt rereredudductctctioioionnn ininin rrrecececurrurrererentntnt IIICHCHCH aaamomomongngngststst aaantntntipipiplalalatetetelelelettt thththerererapapapy ussusererersss. EvEEvenenen iiinnn rararandndndomomomisisisededed




13

Potentially correctable risk factors for ICH should be addressed including assessment of the

HASBLED score, correction of uncontrolled high blood pressure, concomitant use of aspirin or

NSAIDs, etc. ICH can sometimes be related to trauma or a vascular anomaly, and for the latter,

liaison with a neurosurgical service is important.

Limitations

We did not have data on INR values hence no estimate of OAC intensity, and we also recognise

the importance of the quality of anticoagulation control, as reflected by time in therapeutic range

35,36. VKAs are associated with a relatively higher rate of ICH compared to NOACs, but the latter

were only used in a minority of patients in our study. We also did not have any cerebral imaging

data, to distinguish the subtypes of ICH, but our principal hypothesis pertained to the simple

question of whether or not restarting OAC after ICH was associated with a beneficial effect on

stroke and mortality, in patients with AF. Indeed, the presence of microbleeds is an important

risk for ICH, and many stroke physicians would be cautious about restarting OAC in a patient

with widespread cerebral microbleeds 37,38.

There is a potential risk of misclassification of recurrent ICH events due to routine

procedures after hospital discharge: patients are likely to be re-admitted to a hospital for a

follow-up computerized tomography scan examining re-bleedings. This re-admission could

inherit the coding from the incident ICH with no evidence of any recurrent bleeding. This

conjecture was supported by the sensitivity analyses of altering the quarantine period, and also

by excluding those patients who experienced an event during the quarantine period. On the other

hand, with the lack of information on cause of death, the number of ischemic events or recurrent

ICH could be underestimated if they carried a terminal outcome. Our analysis on treatment

were only used in a minority of patients in our study. We also did not har ve any cerererebebebrararal l l imimimagagaginining

data, to distinguish the subtypes of ICH, but our principal hypothesis per rtained to the simple

quessstititiononon ooofff whww etttheheher or not restarting OAC after IIICHCHCH was associatedrr wititith h h a beneficial effect on d

tttroooke and morrrtatatalittyy, iinin pppatatatieieientntntsss wiwiwiththth AAAFF. InInInddedeed,, thhhe prprpreeesenenencecece ooof mmmicicicrororobbleeedsdsds iiis s ananan impmpmpororortatatantntn f

iisksksk ffforo ICHHH, , , ana dd d mmam nnyny strokkke phphphysysysicici iaaannsns wwwououould bbbe cauuutititiouusss abababououut t t reeests aaarttinggg OOOAC innn a papapatiennnt

wiiwiththth widididesesesprprpreaeaeaddd cececerererebrbrbralalal mmmicicicrororoblblbleeeeeedsdsds 37,37,,3838.




14

initiation was performed using an assumption of adherence to treatment (unless changed from

OAC to antiplatelet therapy or vice versa), recognising the limitations of a ‘real world’ cohort

design, where patients could change from treatment (and doses) to no treatment over time. We

also only included patients with an index hospitalisation for AF, and documented ICH – thus,

confounding by indication and selection bias could be evident, and our results may not be

generalizable to the ‘general’ non-hospitalised AF population. Nonetheless, most patients with

an ICH would require hospitalisation, and AF-related hospitalisations are common (and

increasing); thus, our analysis would reflect the likely burden of AF patients in healthcare

systems. Although this was a nationwide study, the ethnic background of the Danish population

is presumably Caucasian, and thus the obtained results might not generalise to all ethnic

groups39.

In conclusion, AF patients who suffer an ICH are at very high risk of ischaemic stroke

and death, and our data indicates positive clinical benefit from anticoagulant treatment. OAC

treatment resulted in a significant reduction in subsequent ischaemic stroke and all-cause

mortality. As such, this study supports OAC reintroduction post-ICH, but due to risk of bias by

unmeasured confounding, future randomized controlled trials investigating resumption of OAC

treatment post-ICH are encouraged to provide further evidence to guide clinical practice.

Funding Sources: The Obel Family Foundation partly funded this research by an unrestricted

grant. The sponsor had no role the design and conduct of the study; collection, management,

analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Conflict of Interest Disclosures: Professor Lip has served as a consultant for Bayer, Astellas,

Merck, AstraZeneca, Sano , BMS/Pfizer and Boehringer Ingelheim, and has been on the speaker

bureaus for Bayer, BMS/Pfizer, Boehringer Ingelheim and Sano . Associate Professor Larsen

s presumably Caucasian, and thus the obtained results might not generalise to all l l etetethnhnhnicicic

groups39.

InInIn ccconononcluuusioioi n, AF patients who suffer annn IIICHCHC are at very high rrrisisisk kk of ischaemic stroke

ananandd d death, andd oooururu ddatatata ininindididicacacatetetes s popoposisiititit vve clililiniical beeenefefefititit fffrrorommm ananantiiicocoagagagullant t t trtrtreaeaeatmtmtmenene t.tt OOOACACAC

reeaeatmtmtment reeesususulteede in aaa ssis gniffficicicanana t rerereduduductttioi n n innn subbseeequuuenenent isisiscchchaeaeaemmmic cc n strorroke aaandndnd allll-c-c-causse

momomortrtrtalalalititity. AAAsss sussuchchch, thththisisis ssstuttudyddy sssuppuppopoportrtrtsss OAOAOACCC rerereininintrtrtrodododuccuctititiononon ppposososttt-ICICICHHH, bbbuttut dddueeue tttooo riririsksksk ooofff bibibiasasas bbby




15

has served as an investigator for Janssen Scientific Affairs, LLC and Boehringer Ingelheim.

Associate Professor Larsen and Professor Rasmussen have been on the speaker bureaus for

Bayer, BMS/Pfizer, Roche Diagnostics, Boehringer Ingelheim and Takeda Pharma. Other

authors – none declared.

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3133 55.5




19

Table 1. Baseline characteristics of the cohort.

Total population

Intracerebral bleeding

Subdural bleeding

Subarachnoid bleeding

Number of patients 1,752 812 755 185 Age, median (IQR) 78 (71-83) 78 (71-83) 78 (71-83) 75 (70-82) Male gender No. (%) 1,081 (62) 471 (58) 502 (67) 109 (59) Prior antithrombotic treatment no. (%) VKA 1,145(65) 507 (62) 508 (67) 130 (70) NOAC 28 (2) 11 (1) 12 (2) 5 (3) VKA and APT 571 (33) 290 (36) 232 (31) 49 (27) NOAC and APT 8 (<1) 4 (<1) 3 (<1) 1 (<1)

Comorbidity no. (%) Congestive heart failure 485 (28) 198 (24) 220 (29) 67 (36) Hypertension 1,112 (63) 494 (61) 490 (65) 128 (69) Age 65-74 years 498 (28) 221 (27) 212 (28) 65 (35) Age >75 years 1,068 (61) 500 (62) 470 (62) 98 (53) Diabetes mellitus 323 (18) 134 (17) 149 (20) 40 (22) Prior thromboembolism 656 (37) 373 (46) 226 (30) 57 (31) Vascular disease 358 (20) 152 (19) 160 (21) 46 (25) Concomitant medication no. (%) Beta-blockers 1,035 (59) 460 (57) 454 (60) 121 (65) Calcium channel blockers 613 (35) 271 (33) 280 (37) 62 (34) Renin-angiotensin system

inhibitors (ACEi/ARBs) 914 (52) 425 (52) 393 (52) 96 (52)

Loop diuretics 703 (40) 299 (37) 315 (42) 89 (48) Statin 688 (39) 285 (35) 315 (42) 88 (48) NSAID 381 (22) 172 (21) 172 (23) 37 (20) Digoxin 853 (49) 376 (46) 386 (51) 91 (49) Amiodarone 120 ( 7) 49 ( 6) 58 ( 8) 13 ( 7) CHA2DS2-VASc no. (%) 0 31 (2) 14 (2) 13 (2) 4 (2) 1 123 (7) 44 (5) 62 (8) 17 (9) 2-9 1,598 (91) 754 (93) 680 (90) 164 (89) HAS-BLED no. (%) 0-2 363 (21) 155 (19) 170 (23) 38 (21) 3 1,389 (79) 657 (81) 585 (77) 147 (79) ICH: Intracranial haemorrhage. IQR: Interquartile range. VKA: Vitamin K-antagonist. APT: Antiplatelet therapy. NOAC: Non-vitamin K oral anticoagulant. NSAID: Non-steroidal anti-inflammatory drug. ACEi/ARBs: Angiotensin-Converting Enzyme inhibitors/Angiotensin II Receptor Antagonists.

Age >75 years 1,068 (61) 500 (62) 470 (62) 98 8 8 (5(5( 3)3)3) Diabetes mellitus 323 (18) 134 (17) 149 (20) 44400 0 (2(2(22)2)2) Prior thromboembolism 656 (37) 373 (46) 226 (30) 57 (31) Vascular disease 358 (20) 152 (19) 160 (21) 46 (25)

Concccomomomitititananant t mememedidd cation no. (%)BeBeBetatata-blockkkeeers 1,035 (59) 460 (57) 454 (60) 121 (65) CaCaalcium channnnenenel blllocoo kekekersrsrs 661333 (((355) 272727111 (3(3(33)3)3 22288080 (37377) ) ) 626262 (((343434) ) )ReReRenin-angiotennsiin syyysttem inininhihihibib torsrss (((ACACACEii/ARBRBRBs)

9914 (((5222) 444252525 (((5222) 399933 (5552))) 966 (((52)

Loop dddiiuiuretics 70707033 (4(4(40) 2299999 (37373 ) 315 ((42) 889 (48)8 Statin 688 (39) 285 (35) 315 (42) 88 (48)




20

Table 2. Event rates of various outcomes according to stratification on treatment regimen using 1 year of follow-up.

Outcome No antithrombotic treatment OAC treatment Antiplatelet therapy Ischemic stroke/SE/ and all-cause mortality Events 179 43 83 Person-time (100 years) 655 316 335 Event rate (95% CI) 27.3 (23.6 - 31.6) 13.6 (10.1 - 18.3) 25.7 (20.7 - 31.9) Ischemic stroke/SE Events 69 17 34 Person-time (100 years) 666 322 329 Event rate (95% CI) 10.4 (8.2 - 13.1) 5.3 (3.3 - 8.5) 10.3 (7.4 - 14.4) All-cause mortality Events 130 32 69 Person-time (100 years) 682 330 353 Event rate (95% CI) 19.1 (16.0 - 22.6) 9.7 (6.9 - 13.7) 19.5 (15.4 - 24.7) Recurrent ICH Events 57 25 18 Person-time (100 years) 662 313 339 Event rate (95% CI) 8.6 (6.6 - 11.2) 8.0 (5.4 - 11.8) 5.3 (3.3 - 8.4) Major extracranial bleeding Events 10 5 9 Person-time (100 years) 677 329 349 Event rate (95% CI) 1.5 (0.8 - 2.7) 1.5 (0.6 - 3.7) 2.6 (1.3 - 5.0)

on-time (100 years) 666 322 3232329 9 9nt rate (95% CI) 10.4 (8.2 - 13.1) 5.3 (3.3 - 8.5) 1000.333 ((7.7.7.44 4 -- 141414.4.4.4) ) )ause mortalitynts 130 32 69 on-time (100 years) 682 330 353nt raatetete (((959595% % % CICICI) ) ) 19.1 (16.0 - 22.6) 9.7 (6.9 - 13.7) 19.5 (15.4 - 24.7)rrrenee t t t ICII H nnnts 57575 252525 181818 onoo -t-t- ime (100 years) 66662 31333 3333 999nnnt tt aaratet (95% CI) ) ) 8.6 (6(( 66.6 - 11.2))) 8.0 00 (5(( .4 --- 11.8) 5...33 3(33.3 - 8 4.44) r xexextrtrtracacacrarar nialall bbbleleleed nningnts 10 5 99on t-tiiime (1(1(1000000 years))) 676767777 323232999 343434999




21

Figure Legends:

Figure 1. Flowchart of the study design and population.

Figure 2. Forest plot of adjusted hazard ratios on treatment regimen of various outcomes using

one-year follow-up (adjusted for sex, age, year of inclusion, time since last claimed OAC

prescription, and occurrences of ischemic stroke/SE and recurrent ICH events during the

quarantine period).

Figure 3. Five years Kaplan-Meier survival curve for restarting OAC treatment, receiving

antiplatelet therapy, and for not receiving antithrombotic treatment using a landmark at 6 weeks

(relative to discharge from hospital) for treatment regimens stratification.

Figure 4. Sensitivity analysis investigating the outcomes of ischemic stroke/SE and all-cause

mortality and recurrent ICH, stratified according to treatment regimen and to applied quarantine

period.

Figure 3. Five years Kaplan-Meier survival curve for restarting OAC treatment, rererecececeivivivinining g g

antiplatelet therapy, and for not receiving antithrombotic treatment using a landmark at 6 weeks

relatatativivive ee tototo dddisii chhharrrge from hospital) for treatmennntt t rereegimens stratificatiooon.n..

FiFiigugugurerr 4. Senenensitiitiviity aaannan lysiiis s inininveestststigaaatiini ggg thththeee ouutcccommmeeses oofff ischchc emememicicc stttrooke/e/e/SESESE andndnd all--caaauseee

momomortrtrtalalalititity anananddd rererecuccurrrrrrenenenttt ICICICHHH, ssstrtrtraaatititifififiededed aaaccccccororordididingngng tttooo trtrtreaeaeatmtmtmenenenttt rereregigigimememennn anananddd tototo aaapppppplililiededed qqquaauarararantntntininineee



Figure 1 by guest on September 23, 2015http://circ.ahajournals.org/Downloaded from








SUPPLEMENTAL MATERIAL

Supplementary Table 1: Definitions of outcomes and medication

International Classification of

Diseases 10th revision (ICD-10)

code

Anatomical Therapeutic Chemical

(ATC) code

Condition

Congestive heart failure I11.0; I13.0; I13.2; I42.0; I50 CO3C

Left ventricular dysfunction I50.1; I50.9

Hypertension See specified definition*

Diabetes mellitus E10.0; E10.1; E10.9; E11.0; E11.1;

E11.9

A10

Ischemic stroke I63; I64

Systemic embolism I74

Transient ischemic disease G45

Aortic plaque I70.0

Peripheral arterial disease I70.2-I70.9; I71; I73.9; I74

Myocardial infarction I21-I23

Abnormal renal function I12; I13; N00-N05; N07; N11;

N14; N17-N19; Q61

Abnormal hepatic function B15.0; B16.0; B16.2; B19.0;

K70.4; K72; K76.6; I85

Prior Bleeding I60-I62; D62; J94.2; H11.3; H35.6;

H43.1; N02; N95; R04; R31; R58;

K25.0; K26.0; K27.0; K28.0;

K29.0; S06.3C; S06.4; S06.5;

S06.6

Alcohol intake E22.4; E52.9A; F10; G31.2;

G62.1; G72.1; I42.6; K29.2; K70;

K86.0; L27.8A; O35.4M; T51;

Z71.4; Z72.1

Atrial fibrillation I48

Major bleeding D62 J942 H113 H356 H431 N02

N95 R04 R31 R58

Intracranial bleeding

Traumatic intracranial bleeding

Retinal bleeding

Sequelae of cerebrovascular disease

I60 I61 I62

S063C S064 S065 S066

H356

I690; I691; I692

Medication

Dabigatran

Rivaroxaban

B01AE07

B01AE07

Apixaban B01AF02

Coumarin derivatives B01AA

Aspirin B01AC06

Thienopyridines B01AC04; B01AC24; B01AC22

Beta-blockers

Calcium channel blockers

Renin-angiotensin system

inhibitors (ACEi/ARBs)

Loop diuretics

Statin

Digoxin

Amiodarone

C07

C07F; C08; C09BB; C09DB

C09

C03C

C10

C01AA05

C01BD01

Non-steroidal anti-inflammatory drugs M01A

* We identified subjects with hypertension from combination treatment with at least two of the following classes of

antihypertensive Drugs:

I. Alpha adrenergic blockers (C02A, C02B, C02C)

II. Non-loop diuretics (C02DA, C02L, C03A, C03B, C03D, C03E, C03X, C07C, C07D, C08G, C09BA, C09DA,

C09XA52)

III. Vasodilators (C02DB, C02DD, C02DG, C04, C05)

IV. Beta blockers (C07)

V. Calcium channel blockers (C07F, C08, C09BB, C09DB)

VI. Renin-angiotensin system inhibitors (C09).

Supplementary Table 2: Event rates and adjusted hazard ratios of various outcomes according to stratification on treatment regimen using

5 years of follow-up.

Outcome No OAC therapy OAC therapy Antiplatelet therapy

Ischemic stroke/SE and

all-cause mortality

Events 326 106 240

Person-time (100 years) 1392 996 1204

Event rate (95% CI) 23.4 (21.0 - 26.1) 10.6 (8.8 - 12.9) 19.9 (17.6 - 22.6)

Adjusted hazard ratio (95%CI) Reference 0.54 (0.43 – 0.67) 0.85 (0.81 – 1.00)

Ischemic stroke/SE

Events 108 35 76


Event rate (95% CI) 7.6 (6.3 - 9.2) 3.5 (2.5 - 4.8) 6.2 (5.0 - 7.8)


All-cause mortality

Events 266 91 227


Event rate (95% CI) 18.1 (16.0 - 20.4) 8.5 (6.9 - 10.4) 16.0 (14.0 - 18.2)


Recurrent ICH

Events 72 36 34


Event rate (95% CI) 5.1 (4.1 - 6.4) 3.6 (2.6 - 4.9) 2.6 (1.8 - 3.6)


Major extra cranial bleeding

Events 20 14 26


Event rate (95% CI) 1.4 (0.9 - 2.1) 1.3 (0.8 -2.2) 1.9 (1.3 - 2.8)


Supplementary Figure S1: Five years Kaplan-Meier survival curve for restarting OAC treatment, receiving antiplatelet therapy, and for

not receiving antithrombotic treatment using a landmark at 180 days (relative to discharge from hospital) for treatment regimens

stratification. A total of 505 patients were allocated to ‘no antithrombotic treatment; 509 to OAC treatment; 527 patients to the antiplatelet

therapy group.

Lars Hvilsted Rasmussen and Gregory Y.H. LipPeter Brønnum Nielsen, Torben Bjerregaard Larsen, Flemming Skjøth, Anders Gorst-Rasmussen,

StudyCohortFibrillation and the Impact on Recurrent Stroke, Mortality and Bleeding: A Nationwide

Restarting Anticoagulant Treatment After Intracranial Haemorrhage in Patients With Atrial

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2015 American Heart Association, Inc. All rights reserved.

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