MA Finbrinolisis en CRAO

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Copyright 2015 American Medical Association. All rig hts reserved.

Intravenous Fibrinolytic Therapy in Central Retinal

Artery Occlusion

A Patient-Level Meta-analysis

Matthew Schrag, MD; Teddy Youn, MD; Joseph Schindler, MD; Howard Kirshner, MD; DavidGreer, MD

IMPORTANCE Centralretinal artery occlusion (CRAO)is an ophthalmologic emergencythat

can result in blindness. At present, no proventherapy for CRAO exists. Treatment with

fibrinolytic agentshas shown promise but remains of unproven benefit.

OBJECTIVES To assess theefficacy of systemic fibrinolytic therapy for patients with CRAO and

to define a time windowof efficacy.

DATA SOURCES We systematically queried PubMed, Web of Science, andScopususingthe

following index terms: “retinal artery occlusion” OR “retinal ischemia” AND “thrombolysis” OR

“fibrinolysis” OR “tissue plasminogen activator” OR “streptokinase” OR “urokinase.” Searchwasnot limited by year of publication or language andwas conducted in August 2014. In

addition, we evaluatedthe references from relevant review articles.

STUDY SELECTION We assembled observationalstudies reporting on visual acuity outcomes

after CRAO.Inclusion criteria were complete reporting of visual outcomes after CRAO (with or

without fibrinolytic therapy) anda series of more than 5 patients forfibrinolysistreatment or

more than 20 cases when untreated or treated with conservativemodalities.

DATA EXTRACTIONAND SYNTHESIS Patient-level data were sought for studies reporting

outcomes of treatment with fibrinolysis. Summary statistics were obtained for conservative

treatment and natural history studies. The studies were weighted by the inverse of variance

and mergedin a random-effects model.

MAIN OUTCOMESAND MEASURES Rateof visual recovery (defined as improvement of visual

acuity from 20/200or worse at presentation to 20/100or better)was calculatedfor patients

treated with fibrinolytic and conservativetherapiesand those whoreceived no treatment.

RESULTS We obtained summarystatistics from 7 studies thatincluded 396patients who

received no treatment after CRAO and from 8 studies that included 419 patients treatedwith

ocular massage, anterior chamber paracentesis, and/or hemodilution (conservative

treatment). Patient-level datawere obtained for 147 patients treatedwith systemic

fibrinolysis.We found that fibrinolysis wasbeneficial at 4.5 hours or earlier after symptom

onset compared with the natural historygroup (17of 34 [50.0%] vs 70 of 396[17.7%]; odds

ratio, 4.7 [95% CI, 2.3-9.6]; P < .001). Absolute risk reduction was32.3%, with a number

needed to treat of 4.0 (95% CI, 2.6-6.6). We also found that conservative treatment

significantly worsened visual acuity outcomes and recovery rates after CRAO compared with

the natural historygroup (31of 419 [7.4%; 95%CI, 3.7%-11.1%] vs 70 of 396[17.7%; 95% CI,

13.9%-21.4%]; P < .001; number needed to harm, 10.0 [95% CI, 6.8-17.4]).

CONCLUSIONS AND RELEVANCE Our analysis suggests thata clinical trial of early systemic

fibrinolytic therapy for CRAO is warranted and that conservative treatmentsare futile and

may be harmful.

JAMA Neurol . 2015;72(10):1148-1154. doi:10.1001/jamaneurol.2015.1578Published online August 10,2015.

Author Affiliations: Department of Neurology, Yale University, NewHaven, Connecticut(Schrag, Youn,Schindler, Greer);Department of Neurology, Vanderbilt University,Nashville, Tennessee (Kirshner).

Corresponding Author: MatthewSchrag, MD,Department of Neurology, Yale University,15 York St,Floor LCI-9,New Haven, CT 06510([email protected]).

Research

Original Investigation

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Central retinalartery occlusion (CRAO) is an ophthalmo-

logicemergency anda causeof acquired blindness.This

acute, painlesscondition is typically theresult of throm-

bosis or embolism leading to ischemia of the retina and optic

nerveheadwithprofound loss ofvision.The sourceof throm-

bosis or embolism in CRAO is thought to arise predominantly

from atherosclerotic plaques, carotid stenosis, inflammatory

vasculardisease, or cardiacabnormalities. Oncethe centralreti-

nal artery is occluded, survival of the retina depends on the

degree of collateralization and the duration of retinal ische-

mia before theoffending embolus or thrombusis dislodgedor

autolyzed; however, most patients develop blindness. An ex-

perimental study of CRAO in rhesus monkeysfound that com-

plete ischemia to the retina lasting more than hours re-

sulted in severe neuronal loss. Current standard treatment

options for acute CRAO management include sublingual iso-

sorbide dinitrate, topical timolol maleate, systemic pentoxi-

fylline, inhalation of % carbondioxide,hyperbaric oxygen,

ocular massage, intravenous acetazolamide, mannitol, ante-

rior chamber paracentesis, hemodilution, and corticoste-

roids.Nonehasbeen shownto bemore effective than placebo.

Fiftyyears of experience with various fibrinolytictreatments

for acute CRAO has included systemic and local or intra-

arterial delivery. These treatments have demonstrated prom-

ising results, but the first randomized clinical trial, the Euro-

pean Assessment Group for Lysis in the Eye (EAGLE) trial,

evaluatedintra-arterial deliveryof fibrinolysis from. to .

hours after the onset of symptoms and did not demonstrate

improved visual outcome with treatment. Systemic fibrino-

lytictherapiesare simplerandfasterto deploy andmay be safer.

Rapidadministrationof systemicfibrinolytic agents hasproved

tobe a feasibleand effective treatment foracute ischemicstroke

but only within . hours of symptom onset,; systemic fi-

brinolysis mayimprove theefficacyof treatmentfor CRAO. For

this reason, the aim of this analysis is to assemble the pub-

lished literature on systemic fibrinolysis in CRAO at the pa-

tient level and to compare theresults against the natural his-

tory of this illness to determine a time window of maximal

effectivenessof fibrinolyticinterventions foruse in future clini-

cal trials.

Table1. Patient-LevelTreatmentData

Source TherapyNo. ofPatients

Recovery, No.(%)

Conservative Treatment and Natural History Studies

Minton,24 1 937 No t reatment ( patie nts w ith a cet ylcholine c hlo rideinjection were excluded)

23 3 (13.0)

Henkes,25 1954 Acetazolamide, topical β-blockade 21 4 (19.0)

Ellis et al,26 1964 No treatment 24 3 (12.5)

Imamura,27 1968 No treatment 54 7 (13.0)

Karjalainen,28 1971 No treatment 49 7 (14.3)

Küchle and Richard,29

1979Pentoxifylline, corticosteroids 36 6 (16.7)

Augsburger andMagargal,31 1980

Ocularmassage, aspirin, acetazolamide, anterior chamberparacentesis

34 12 (35.3)

Dukeret al,32

1991 Ocular massage, anterior chamber paracentesis 33 4 (12.1)Schmidt et al,33 1992 Ocularmassage, pentoxifylline, anterior chamber

paracentesis41 2 (4.9)

Atebaraet al,34 1995 Anterior chamber paracentesis, carbon dioxide 89 5 (5.6)

Neubaueret al,35 2000 Acetazolamide, ocular massage, pentoxifylline 65 5 (7.7)

Frammeet al,36 2001 Ocularmassage, acetazolamide,anterior chamberparacentesis,aspirin, pentoxifylline

45 4 (8.9)

Muelleret al,7 2003 Ocular massage, anterior chamber paracentesis 71 5 (7.0)

Hayreh andZimmerman,30 2005

No treatment 189 38 (20.1)

Ahn etal,37 2013 Ocular massage, topical β-blockage, acetazolamide 44 2 (4.5)

Systemic Thrombolysis Studies

Rossmann,40 1966 IV streptokinase, 250 000 IU × 3 doses, plus heparin 9 4 (44.4)

Sautterand Rossmann,41

1971IV streptokinase 20 7 (35.0)

Boljka et al,42 1984 IV streptokinase, 1 000 000 IU total dose, plus heparin 26 7 (26.9)

Kamei et al,44 1985 IV urokinase 8 3 (37.5)

Yotsukura andAdachi-Usami,45 1993

IV urokinase,120 000-240000 IU,ocular massage,hyperbaric oxygen

15 4 (26.6)

Hagimura et al,46 1994 IVurokinaseinfusion for 7 d,some withhyperbaricoxygen

17 4 (23.5)

Rumeltet al,43 1999 IVstreptokinase, 750000IU,plus nitrates, mannitol,acetazolamide, anterior chamber paracentesis,corticosteroids, retrobulbar tolazoline hydrochloride

12 7 (58.3)

Kattahet al,38 2002 IV tPA, 0.9 mg/kg 12 3 (25.0)

Hattenbachet al,39

2008IV tPA, 50 mg 25 6 (24.0) Abbreviations: IV,intravenous; tPA,

tissue plasminogen activator.

Intravenous Fibrinolytic Therapy in Central Retinal Artery Occlusion Original Investigation Research

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Methods

LiteratureSearch

This analysis was performed in accordance with the Meta-

analysis of Observational Studies in Epidemiology (MOOSE)

guidelines. Theliterature searchstrategy wasnot limited by

year of publication or language. Datacollectionoccurred from

August through , . We systematically queried the

PubMed, Web of Science, and Scopus databases for the fol-

lowing variations of keywords: “retinal artery occlusion” OR

“retinal ischemia” AND “thrombolysis” OR “fibrinolysis” OR

“tissue plasminogen activator” OR “streptokinase” OR “uro-

kinase.” All studies reportingvisual outcomes afterCRAO (with

or withoutfibrinolytictherapy) werecollected.We alsoevalu-

ated the reference lists from the identified studies and rel-

evant review literature to identify additional relevant stud-

ies. Studies reporting fibrinolytic treatment in more than

patients wereconsidered for inclusionin thetreatment group

(case reports and smaller series were excluded to reduce the

risk for selection bias in favor of positive outcomes). Studies

reportingoutcomes withany other standard treatment or with

no treatment in a series of more than cases were included

in the conservative treatment group and the group receiving

no treatment (natural history group). Studies reporting out-

comes after treatment with hyperbaric oxygen, intra-arterial

fibrinolysis, and acetylcholine injection were not included;

however, if these studies reported on a control group, that

groupwas considered for inclusion.We did not include CRAO

related to a primary large-vesselvasculitis in this analysis be-

cause this condition is treated primarily with immunomodu-

latory medications. Branch retinal artery occlusionsand reti-

nal vein occlusions were excluded. Exclusion criteria also

includedinsufficientreporting of thedata;specifically, thetime

to treatment and pretreatmentand posttreatment visual acu-ity were required for the treatment group.

The visual recovery rate was the primary outcome

assessed in this analysis, which we defined as an initial

visual acuity of at least . logMAR or the Snellen equivalent

of / or worse that improved to . logMAR or less

(Snellen equivalent, / or better). Patients with visual

acuity better than . logMAR (Snellen equivalent, /)

on initial evaluation were excluded because they frequently

experience spontaneous visual recovery, likely as a result

of some degree of reperfusion or collateral blood supply.

Inclusion of these cases was likely to bias the results in

favor of fibrinolysis because many patients in the observa-

tional studies were first encountered at later time points. In

addition, this criterion emphasizes a recovery of functional

vision in patients meeting the legal definition of blindness

(in the United States) at the time of presentation. In the

natural history group, reporting of visual acuity at follow-up

(≥ hours after onset) was required, and the relevant sum-

mary statistics, specifically, the total number of patients

presenting with visual acuity of . logMAR or greater (Snel-

len equivalent, / or worse) and the percentage of

cases with spontaneous recovery of vision, were extracted

from the identified studies. For the intravenous or systemic

fibrinolysis studies, tissue plasminogen activator (tPA), uro-

kinase, and streptokinase were all considered appropriate

treatments. Patient-level data, including time from symp-

tom onset to treatment and pretreatment and posttreatment

visual acuity, were extracted. In those studies in which

these data were not available, the authors were contacted

directly to obtain these data. In most studies, visual recov-

ery was assessed at the end of the acute hospitalization or

shortly thereafter. In those studies explicitly stating the tim-

ing, follow-up ranged from day to a few weeks after fibri-

nolytic treatment, with most ranging from to days.

Exclusion criteria applied to studies in which the essential

data could not be obtained or were reported in insufficientdetail.

Table2. Characteristics of CRAOCohorts

Characteristic

Cohort Time to Treatment, h

Natural History(n = 396)

ConservativeTreatment(n = 419)

Total Fibrinolysis(n = 147)

0 to 4.5(n = 34)

>4.5 to 12.0(n = 48)

>12.0 to 24.0(n = (33)

>24.0(n = 34)

Female sex, No. (%) 170 (42.9) 134 (32.0) 60 (40.8) 4 (11.8) 29 (60.4) 13 (39.4) 19 (55.9)

Age, mean (SD), y 57.2 (13.0) 65.2 (14.3) 62.8 (12.2) 59.6 (14.4) 64.5 (11.8) 62.3 (12.4) 64.2 (11.8)

VAof LPor less(at firstevaluation), No. (%)

174 (43.9) 88 (21.0) 56 (38.1) 11 (32.4) 18 (37.5) 19 (57.6) 9 (26.5)

Agent used, No. (%)

Urokinase NA NA 41 (27.9) 4 (11.8) 10 (20.8) 10 (30.3) 19 (55.9)

Streptokinase NA NA 69 (46.9) 17 (50.0) 15 (31.2) 22 (66.7) 15 (44.1)

tPA NA NA 37 (25.2) 13 (38.2) 23 (47.9) 1 (3.0) 0

VA, mean (SD)a

Starting NA NA 12.1 (1.1) 12.0 (0.9) 12.1 (1.0) 12.4 (1.1) 11.7 (1.0)

Final NA NA 9.0 (4.3) 7.4 (4.4) 9.2 (3.9) 9.8 (4.3) 9.2 (4.3)

VA recoveredto at least20/100, No. (%)

70 (17.7) 31 (7.4) 47 (32.0) 17 (50.0) 13 (27.1) 8 (24.2) 9 (26.7)

Abbreviations: CRAO, central retinal artery occlusion;LP,light perception; NA,notapplicable;tPA, tissueplasminogen activator;VA, visualacuity.a Reportedas the number of standard logMAR increments belowthe equivalent

of 20/20visual acuity(0 indicates20/20;1, 20/25; 2, 20/30;3, 20/40;4,20/50; 5, 20/63;6, 20/80; 7, 20/100; 8, 20/125;9, 20/160;10, 20/200;11,countingfingers; 12,handmovement;13, LP;and 14, noLP).

Research Original Investigation Intravenous Fibrinolytic Therapy in Central Retinal Artery Occlusion

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StatisticalAnalysis

Data analysis occurred fromAugust through , . For the

fibrinolytic treatment group, we obtained patient-level data

forpretreatment andposttreatmentvisualacuityand timefromsymptom onset to treatment. Thedata were dichotomizedto

identify patients who recovered and those who did not; the

percentage with spontaneous visual recovery was reported

along with the binomial SD. The patients were divided into

those treated at . hours or earlier, longer than . to .

hours, longer than . to . hours, and longer than .

hours.The .-hour time point wasselected as an interval of

interest based on animal literature indicating that the retina

has a tolerance toischemia for a little more than hours and

that fibrinolysisis helpfulin ischemic strokewithin.hours.

The other time points dividethe remaining casesinto equiva-

lently poweredepochs.We calculated thevisual recoveryrate

for each group. For a comparison group, studies of the natu-

ral history of CRAO and conservative therapies were aggre-gated by meta-analysis using theMixsoftware(version.;Bio-

StatXL),and thedatawereweightedby theinverseof variance.

Heterogeneity was assessed with the Q statistic and I test.

Because of thepresenceof heterogeneity in the conservative

treatment group, thisgroup wasbelievedto be inadequate for

comparison, and only those studies reporting the natural his-

toryof thedisease (orminimal treatments) were usedfor com-

parison with intravenousfibrinolysis treatment. The hypoth-

esisthatthe probabilityof visual recoverywas relatedto delay

of treatment was assessed with the Kruskal-Wallis test ana-

Figure 1. ForestPlot forEstimatedRateof SpontaneousVisual Recovery

Natural historyAWeight,

%Source

Recovery Rate

(95% CI), %

7.31Minton,24 1937 13 (–1 to 27)

4.90Henkes,25 1954 19 (2 to 36)

17.24Imamura,27 1968 13 (4 to 23)

11.77Karjalainen,28 1971 18 (8 to 29)

7.90Ellis et al,26 1964 13 (–1 to 26)

9.33Küchle and Richard,29 1979 19 (7 to 32)

41.55Hayreh and Zimmerman,30 2005 21 (15 to 26)

Q = 4.3; P = .75; I2 = 0% (95% CI, 0%-67.6%)

Summary statistics 17.7 (13.9 to 21.4)

0 6050 704030

Recovery Rate (95% CI), %

2010–10

P


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lyzing treatment in each of the time windows and sponta-

neousrecoveryin thenaturalhistorygroup( groups).We then

compared the frequency of successful treatment at each in-

terval withthe frequency of spontaneous recovery in thenatu-

ral history analysis as a Bernoulli trial. We accepted α < .

as significant. Odds ratios, relative risk reduction, and num-

ber needed to treat are reported.

Results

VisualAcuityOutcome

Fourteen potentially relevant studies- were excluded be-

cause visual acuity data were not presented or were pre-

sentedin insufficientdetail toinclude in this analysis.Weiden-tified studies- thataddressedthe natural history of CRAO.

Most of these studies,-, used no treatment; study

treated with corticosteroids, and studies, treated with

topical intraocular pressure–lowering drops and/or acetazol-

amide. None of the treatments used have any demonstrated

effect on recovery of visual acuity. We found no statistically

significant heterogeneity in this analysis (Q = .; P = .;

I = %[% CI,%-.%]); patients wereincluded, and

patients(.%) had spontaneous visual recovery (%CI,

.%-.%).

Eight studies,- reported visual acuity outcomesin

patients after conservative therapies, including ocular mas-

sage,anteriorchamberparacentesis,and hemodilution. Theseinterventions frequently were used concurrently or in se-

quence, making it difficult to analyze their effect indepen-

dently of each other. In the studies using these more aggres-

sive nonfibrinolytic therapies, the recovery rate was

substantially lower than in the natural history control group

(of [.%; % CI,.%-.%] vs of [.%; %

CI, .%-.%]; P < .;numberneeded to harm,.[%

CI, .-.]). We found evidence of modest heterogeneity in

these studies (Q = .; P = .; I = . [% CI, %-

.%]) that was contributed by the earliest study in the

group, which behaved as an outlier. Exclusion of this study

from the analysis would further support the conclusion that

these treatments are harmful.

Of studies- we identified in which patients with

CRAO were treated with systemic fibrinolysis, we were able

to obtain patient-level data for (Table ).- Two of these

studies, used intravenous tPA; , streptokinase-; and

, urokinase.- This list represents an % capture of the

total number of patients in the published studies; data from

studies- that included patients could not be

obtained. Demographics for the included patients are

provided in Table . Age and starting visual acuity were simi-

lar in each group (no significant differences were deter-

mined by Kruskal-Wallis analysis). In this group of studies,

treated patients (.%; % CI, .%-.%) had visual

recovery. This recovery rate is significantly higher than that

for the natural history cohort or the conservative treatment

cohort ( P < . for each comparison; Figure ). We found no

significant between-study heterogeneity in this group of

studies (Q = .; P = .; I = % [% CI, %-.%]); inclu-

sion of the studies for which patient-level data were not

obtained did not introduce significant heterogeneity or alter

the conclusions of this analysis.

We found a significanteffectof timeto fibrinolyticadmin-

istration on visual recovery after CRAO ( P < .) (Figure ).

Systemic fibrinolysis within the first . hours after symp-

tom onset resulted in recovery of vision in of patients

(.%; % CI, .%-.%). This rate of spontaneous re-

covery is nearly times that in thenatural historycohort(odds

ratio, .[% CI, .-.]; P < .), witha .%absoluterisk

reduction and a number needed to treat of . (% CI, .-

.). We found no significant difference in the recovery rate

after fibrinolysis comparedwith the naturalhistorycohortfor

those patients treated in any of the epochs after . hours

( P = ., P = .,and P = .for >.to .,>. to., and>. hours, respectively). Two studies, reported long-

term visual acuity outcomes after fibrinolysis. Rumelt and

colleaguesobservedpatientsfor to yearsand foundthat

only of the successfully treated patients experienced sub-

sequent deterioration of their visual acuity owing to a cata-

ract. Kattah and colleagues observed patients for months

and found of patients with a response to fibrinolysis had

subsequent deterioration that was caused by glaucoma.Both

studies concludedthatimprovements in visual acuity weredu-

rable. Serious hemorrhagic events occurred in of pa-

tients (.%) of the total fibrinolysis cohort, for a number

needed to harm based on these data of . (% CI, .-

.). Theadverse effect profile of streptokinase is inferiortothatof tPA,particularly regardinghemorrhagic complications.

Among thepatientstreatedwith streptokinase, serioushem-

orrhagiccomplicationsoccurred ( of themwere fatal, includ-

ing fatal intracerebral hemorrhages and fatal hemorrhage

from theliver). No major hemorrhagesoccurredafteradmin-

istration of urokinase or tPA in this analysis.

Because most modern fibrinolytictherapy consists of tPA,

we performed a subgroup analysis of cases treated specifi-

cally with tPA. This analysis confirmed a comparable signifi-

cant benefit of early treatment compared with untreated pa-

Figure 2. Effect ofFibrinolysisbyTimeto Administration

80

70

60

50

40

30

20

10

0

V i s u

a l R e c o v e r y R a t e ,

% o

f P a t i e n t s

Time to Treatment, h

No. at risk

0-4.5

34

>4.5-12.0

48

>12.0-24.0

33

>24.0

34

Spontaneous (95% CI)

After fibrinolysis

Fibrinolytic treatmentwithin 4.5hours resulted in a significantlyhigher rateof visualrecovery (95% CI)comparedwiththe natural history cohort(17 of34patients [50.0%; 95%CI, 32.4%-67.6%] vs 70 of 396patients[17.7%; 95%CI,13.9%-21.4%]; P < .001). We foundno statisticalbenefit to treatmentbeyond4.5 hours afteronset. Errorbars indicate 95% CI.







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tientsin thewindow of. hoursor earlier, whichis notpresent

in the window of longer than . to hours; of patients

recovered if treated within . hoursafter onset of symptoms

( P < .); of ,after .to . hoursafteronset( P = .).

Discussion

Weexaminedthe effectivenessof systemic fibrinolytictherapy

in theacutetreatment of CRAO usingassembled, primarilyret-

rospective data in this meta-analysis. We obtained patient-

leveldata from patientswho receivedfibrinolytic therapy

and analyzed these data with a particular focus on defining a

timewindow in which fibrinolytictherapyis effective. Theef-

fective window appears to be within the first . hours after

symptom onset. A similar result was obtained from a sub-

analysis of only those patients treated with intravenous tPA.

Five major hemorrhages occurred in this series, including

treatment-related fatalities that all occurred in early study

that used streptokinaseinfusion,and the dosing usedin that

study wasnot clear. In theliteratureat large, case of a symp-

tomatic intracerebral hemorrhage has been reported in a pa-

tient with CRAO treated with intravenous tPA at the recom-

mended dose for ischemic stroke. Experience with tPA

infusion in stroke mimics suggeststhat,in the absence of ce-

rebral ischemic injury, intracerebral hemorrhage is a rare

complication. To our knowledge, no reports of intraocular

hemorrhage after fibrinolytic therapy exist (even when ante-

rior chamber paracentesis was performed concomitantly).

We found no convincing evidence fromthe literature that

anyconservativetreatmentmodality (specifically, ocularmas-

sage, hemodilution, and/or anterior chamber paracentesis) is

effective, andthe results fromthis meta-analysissuggest that

these modalities may be harmful. The recovery rate in pa-

tients treated in this fashion was less than half that of pa-tients receiving no treatment. Our conclusions on this topic

were limited bythe fact that most of thesestudiesreportedout-

comes of patients treated with multiple interventions; how-

ever,this multimodal treatment may reflect a typical clinical

approach to this disease that, based on this evidence, should

be discouraged.

Based ontheseresults,we believethata clinical trialof sys-

temic fibrinolysiswithin .hoursof CRAO is warranted. Be-

cause of the successful application of systemic fibrinolysis in

the setting of acute stroke and because of the similarities be-

tween CRAO andstroke, consideration of a similar treatment

in acute CRAOis logical. However, differences in the vascular

anatomy and metabolic characteristics of the retina preclude

direct extrapolation from the stroke literature. Fibrinolytic

drugs have been used to treat acute retinal vascular occlu-

sion in observational studies for more than decades; how-

ever, convincing randomized data demonstrating the effi-

cacyof thistreatmentstrategyare lacking. Thefirst large clinical

trial—theEAGLEstudy—examined intra-arterialdelivery oftPA

and was terminated owing to the futility of the experimental

treatment. All patients in that trial were treated from at least

.to . hoursaftersymptomonset,and this delayto treat-

ment may account for the negative results. The conservative

treatment group in the EAGLE trial also had better-than-

expectedoutcomes (visualacuity improving by lines in %

of untreated cases), which may have contributed also. Intra-

arterial delivery of fibrinolytics is a higher-morbidity inter-

vention and requires more time for drug delivery compared

with intravenous methods. Given this delay, this technique

does not appear to have much applicability in CRAO.

The majorstrengths of thisanalysisare the thoroughness

of the literature review, the lowlevels of heterogeneity in the

groups of studies, and the analysis of patient-level data. We

show that systemic fibrinolysis is significantly effective only

within thefirst. hoursof symptom onset.Thesedatashould

be interpreted cautiously in the clinical application of fibri-

nolytics because numerous limitations apply to the current

analysis,including the retrospectiveand nonrandomized na-

ture of the data and variability in specific treatment proce-

dures between andwithin the studies.However, the design of

a randomized controlled trial of tPA treatmentin acute CRAO

should take these data into account.

Conclusions

Systemic fibrinolysis for CRAO has not yet been evaluated in

an adequate clinical trial, although the results of this meta-

analysis are promising. Conservative treatments of CRAO are

futile and may be harmful. Therefore, a clinical trial of early

systemic fibrinolytic therapy for CRAO is warranted.

ARTICLE INFORMATION

Accepted for Publication: June1, 2015.

Published Online: August 10,2015.

doi:10.1001/jamaneurol.2015.1578 .Author Contributions: DrSchrag hadfull accesstoallof thedatain thestudy andtakes responsibilityfortheintegrity ofthe data andthe accuracy of thedata analysis.

Study concept and design: Schrag, Schindler. Acquisition, analysis, or interpretation of data: Allauthors.Draftingof the manuscript: Schrag, Youn,Schindler,Kirshner.Critical revision of the manuscript for important

intellectualcontent: Schrag, Schindler,Kirshner,Greer.

Statistical analysis: Schrag, Schindler. Administrative, technical, or material support:

Schrag, Schindler,Greer. Study supervision: Schindler,Kirshner, Greer.

Conflict of Interest Disclosures: None reported.

REFERENCES

1. HayrehSS,Zimmerman MB, KimuraA, SanonA.Central retinal artery occlusion:retinal survivaltime. ExpEyeRes. 2004;78(3):723-736.

2. FraserSG, AdamsW. Interventionsfor acutenon-arteritic central retinal artery occlusion.Cochrane Database SystRev . 2009;1(1):CD001989.

3. Schumacher M,Schmidt D,Jurklies B,et al;EAGLE-StudyGroup.Central retinal artery

occlusion:local intra-arterial fibrinolysisversusconservativetreatment, a multicenter randomizedtrial. Ophthalmology . 2010;117(7):1367-1375.e1.doi:10.1016/j.ophtha.2010.03.061.

4. National Instituteof Neurological DisordersandStroke rt-PA Stroke StudyGroup.Tissueplasminogenactivator foracute ischemic stroke.N EnglJ Med . 1995;333(24):1581-1587.

5. HackeW, KasteM, Bluhmki E, etal; ECASSInvestigators.Thrombolysiswith alteplase 3 to 4.5hoursafter acuteischemicstroke.NEngl JMed .2008;359(13):1317-1329.

6. StroupDF, BerlinJA, MortonSC, etal;Meta-analysis of Observational Studies inEpidemiology (MOOSE) Group. Meta-analysis of

Intravenous Fibrinolytic Therapy in Central Retinal Artery Occlusion Original Investigation Research

jamaneurology.com (Reprinted) JAMA Neurology October2015 Volume72,Number 10 1153



http://jama.jamanetwork.com/article.aspx?doi=10.1001/jamaneurol.2015.1578&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamaneurol.2015.1578http://jama.jamanetwork.com/article.aspx?doi=10.1001/jamaneurol.2015.1578&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamaneurol.2015.1578http://jama.jamanetwork.com/article.aspx?doi=10.1001/jamaneurol.2015.1578&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamaneurol.2015.1578http://www.ncbi.nlm.nih.gov/pubmed/15106952http://www.ncbi.nlm.nih.gov/pubmed/15106952http://www.ncbi.nlm.nih.gov/pubmed/15106952http://www.ncbi.nlm.nih.gov/pubmed/19160204http://www.ncbi.nlm.nih.gov/pubmed/19160204http://www.ncbi.nlm.nih.gov/pubmed/19160204http://dx.doi.org/10.1016/j.ophtha.2010.03.061http://dx.doi.org/10.1016/j.ophtha.2010.03.061http://www.ncbi.nlm.nih.gov/pubmed/7477192http://www.ncbi.nlm.nih.gov/pubmed/7477192http://www.ncbi.nlm.nih.gov/pubmed/7477192http://www.ncbi.nlm.nih.gov/pubmed/18815396http://www.ncbi.nlm.nih.gov/pubmed/18815396http://www.ncbi.nlm.nih.gov/pubmed/18815396http://www.ncbi.nlm.nih.gov/pubmed/18815396http://www.jamaneurology.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamaneurol.2015.1578http://www.jamaneurology.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamaneurol.2015.1578http://www.ncbi.nlm.nih.gov/pubmed/18815396http://www.ncbi.nlm.nih.gov/pubmed/18815396http://www.ncbi.nlm.nih.gov/pubmed/7477192http://dx.doi.org/10.1016/j.ophtha.2010.03.061http://www.ncbi.nlm.nih.gov/pubmed/19160204http://www.ncbi.nlm.nih.gov/pubmed/15106952http://jama.jamanetwork.com/article.aspx?doi=10.1001/jamaneurol.2015.1578&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamaneurol.2015.1578


7/7


Observational Studies in Epidemiology:a proposalfor reporting. JAMA. 2000;283(15):2008-2012.

7. Mueller AJ, Neubauer AS,SchallerU, KampikA;European Assessment Group for Lysis in the Eye.Evaluation of minimally invasivetherapiesandrationalefor a prospective randomizedtrial toevaluate selectiveintra-arteriallysis for clinicallycomplete central retinal artery occlusion. ArchOphthalmol . 2003;121(10):1377-1381.

8. Huedo-Medina TB, Sánchez-Meca J,Marío-Martínez F, Botella J. Assessingheterogeneityin meta-analysis: Q statisticor I2

index? Psychol Methods. 2006;11(2):193-206.

9. Papoulis A. Bernoulli Trials. Probability, RandomVariables, and Stochastic Processes. 2nd ed. NewYork,NY: McGraw-Hill; 1984:57-63.

10. Uhthoff W.Zu den arteriellenund venösenZirculationsstörungender Netzhaut. Ber

Zusammenkunft Dtsch Ophthalmol Ges Heidelberg.1925;45:63-76.

11. Benedict WL. Theclinical significanceof closureof theretinal vessels. J Med Assoc Ga. 1949;38(10):423-433.

12. MeythalerH. Onthe occlusions ofretinalvessels [in German].Klin MonblAugenheilkd . 1966;149(1):32-41.

13. vomHofeK, BrossogE. Onthe results of comparative clinical studies in arterial and venousvascular occlusionsof the retina [in German].KlinMonblAugenheilkd . 1967;150(1):16-26.

14. Gornig H, Verlohren G. Increase of vascularocclusionsin the fundusoculi [in German].DtschGesundheitsw . 1968;23(47):2232-2236.

15. Hikichi T, FujioN, TrempeCL. Thevitreous inretinal arterial occlusions.Retina. 1994;14(4):335-337.

16. O’DonnellBA, Mitchell P. Theclinical featuresand associations of retinal emboli. Aust N Z J Ophthalmol . 1992;20(1):11-17.

17. JaegerW, Schoenknecht L. Statisticalstudies on

arterial andvenous occlusionin theeyefundus [inGerman]. Albrecht Von Graefes Arch Ophthalmol .1955;156(6):566-576.

18. Liversedge LA, SmithVH. Neuromedical andophthalmicaspects of central retinal arteryocclusion. TransOphthalmol SocU K . 1962;82:571-588.

19. Magargal LE, Goldberg RE. Anteriorchamberparacentesis in themanagement of acutenonarteritic central retinal artery occlusion. SurgForum. 1977;28:518-521.

20. Beiran I, Goldenberg I, Adir Y, Tamir A,ShupakA, MillerB. Earlyhyperbaric oxygen therapy forretinal artery occlusion.Eur J Ophthalmol . 2001;11(4):345-350.

21. Schmidt DP, Schulte-Mönting J, SchumacherM.Prognosisof central retinal arteryocclusion: localintraarterial fibrinolysisversus conservativetreatment. AJNR Am J Neuroradiol . 2002;23(8):1301-1307.

22. Fieß A,Cal Ö,Kehrein S,HalstenbergS, Frisch I,Steinhorst UH. Anteriorchamberparacentesis after

central retinal artery occlusion:a tenable therapy?BMC Ophthalmol . 2014;14:28.doi:10.1186/1471-2415-14-28.

23. PayneIW,ReedH. Ocularpalsies followingretrobulbar injection of acetyl choline for retinalarterial occlusion. Br J Ophthalmol . 1954;38(1):46-48.

24. MintonJ. Clinicalstudy offifty-four cases of occlusionof thecentralartery of theretina andits

branches. ProcR Soc Med . 1937;30(3):285-300.

25. Henkes HE. Electroretinography in circulatorydisturbances of the retina, II: theelectroretinogramincasesof occlusionof thecentralretinal arteryorof its branches. AMA Arch Ophthalmol . 1954;51(1):42-53.

26. Ellis CJ, HamerDB, Hunt RW, etal. Medicalinvestigationof retinal vascular occlusion.BrMedJ .1964;2(5417):1093-1098.

27. Imamura T. Studies on retinal artery occlusion,I: statisticalobservations[in Japanese].NihonGankaGakkai Zasshi . 1968;72(8):1330-1343.

28. KarjalainenK. Occlusionof thecentral retinalartery and retinal branch arterioles:a clinical,tonographic and fluoresceinangiographic studyof 175 patients. Acta Ophthalmol Suppl . 1971;109:1-95.

29. KüchleHJ,RichardG. Therapy of arterialvascular occlusionsof retinal and opticnerve(author’stransl)[in German]. Ophthalmologica.1979;179(5):291-296.

30. Hayreh SS,ZimmermanMB. Central retinalartery occlusion:visual outcome. Am J Ophthalmol .2005;140(3):376-391.

31. Augsburger JJ,MagargalLE. Visualprognosisfollowingtreatment of acutecentralretinal arteryobstruction. Br J Ophthalmol . 1980;64(12):913-917.

32. DukerJS, Sivalingam A, BrownGC, ReberR.A prospective studyof acutecentralretinal arteryobstruction: the incidence of secondary ocularneovascularization. Arch Ophthalmol . 1991;109(3):339-342.

33. Schmidt D, SchumacherM, Wakhloo AK.Microcatheterurokinaseinfusionin central retinalartery occlusion. Am J Ophthalmol . 1992;113(4):429-434.

34. AtebaraNH, BrownGC, CaterJ. Efficacy of anteriorchamber paracentesis and Carbogen intreatingacute nonarteritic central retinal arteryocclusion. Ophthalmology . 1995;102(12):2029-2034.

35. Neubauer AS,Mueller AJ,Schriever S, GrüterichM,UlbigM, KampikA. Minimallyinvasive therapyforclinically complete central retinal arteryocclusion:results and meta-analysis of literature[inGerman]. Klin MonblAugenheilkd . 2000;217(1):30-36.

36. Framme C, Spiegel D,RoiderJ, et al.Centralretinal artery occlusion:importance of selective

intra-arterial fibrinolysis [in German]. Ophthalmologe .2001;98(8):725-730 .

37. Ahn SJ, KimJM, Hong JH,et al.Efficacyandsafety of intra-arterialthrombolysis in centralretinal artery occlusion. Invest Ophthalmol Vis Sci .2013;54(12):7746-7755.

38. KattahJC, WangDZ, ReddyC. Intravenousrecombinant tissue-type plasminogen activator

thrombolysis in treatmentof central retinal arteryocclusion. Arch Ophthalmol . 2002;120(9):1234-1236.

39. HattenbachLO, Kuhli-Hattenbach C, ScharrerI,BaatzH. Intravenous thrombolysis withlow-doserecombinant tissueplasminogen activatorin centralretinal artery occlusion. Am J Ophthalmol . 2008;146(5):700-706.

40. Rossmann H. Thethrombolytic therapy of vascular occlusionsof the retina [inGerman].Klin

MonblAugenheilkd . 1966;149(6):874-880.

41. Sautter H,RossmannH. Therapy ofvascularocclusivedisease of theretina withfibrinolysis [inGerman]. Angiologica. 1971;8(6):303-317.

42. Boljka M,PeternelP,Kolar G,VidensekJ.Thrombolytic therapy in central retinal vesselocclusion [in German]. Klin Monatsbl Augenheilkd .1984;185(11):395-396.

43. RumeltS, DorenboimY, Rehany U. Aggressivesystematictreatment forcentral retinal arteryocclusion. Am J Ophthalmol . 1999;128(6):733-738.

44. Kamei H, MatsuhashiH, Yoshimoto H. Therapyand visualprognosis in retinal artery occlusion.NipponGanka Kiyo. 1985;36:2279-2284.

45. Yotsukura J, Adachi-Usami E. Correlationof

electroretinographic changes withvisual prognosisin central retinal arteryocclusion. Ophthalmologica.1993;207(1):13-18.

46. HagimuraN, Kishi S,Iida T. Clinicalmanifestations and visualoutcomein central retinalarterial occlusion. Jpn J Clin Ophthalmol . 1994;48(4):715-719.

47. Semba M,Ohnishi T, Semba H,Fukushima M.Effect of combined therapy withnicotinicacid andurokinasein retinal artery occlusivedisease [inJapanese]. NipponGanka Kiyo. 1989;40(11):2431-2437.

48. Schinzel H,KernM, Kelbel C, WeilemannL,Benning H, Grehn F. Fibrinolytic therapy in acutecentral retinal artery occlusion [in German].Intensivmed Notfallmed . 1992;29(4):170-172.

49. von Mach MA,Güz A, Wiechelt J,PfeifferN,WeilemannLS. Systemicfibrinolytic therapy usingurokinasein central retinal artery occlusion:a casestudy[in German]. Dtsch Med Wochenschr . 2005;130(16):1002-1006.

50. ChenCS, Lee AW, Campbell B,et al.Efficacyof intravenous tissue-typeplasminogen activatorincentral retinal artery occlusion:report fromarandomized, controlled trial. Stroke . 2011;42(8):2229-2234.

51. Berkowitz SD, Granger CB,PieperKS, etal;GlobalUtilization of Streptokinaseand TissuePlasminogen Activatorfor Occluded CoronaryArteries (GUSTO)I Investigators.Incidenceandpredictorsof bleeding aftercontemporarythrombolytic therapy formyocardial infarction.

Circulation. 1997;95(11):2508-2516.52. ChernyshevOY, Martin-Schild S, Albright KC,etal. Safetyof tPA in stroke mimicsandneuroimaging-negative cerebral ischemia.Neurology .2010;74(17):1340-1345.



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/18718570http://www.ncbi.nlm.nih.gov/pubmed/18718570http://www.ncbi.nlm.nih.gov/pubmed/18718570http://www.ncbi.nlm.nih.gov/pubmed/18718570http://www.ncbi.nlm.nih.gov/pubmed/5987138http://www.ncbi.nlm.nih.gov/pubmed/5987138http://www.ncbi.nlm.nih.gov/pubmed/5987138http://www.ncbi.nlm.nih.gov/pubmed/5987138http://www.ncbi.nlm.nih.gov/pubmed/5157688http://www.ncbi.nlm.nih.gov/pubmed/5157688http://www.ncbi.nlm.nih.gov/pubmed/5157688http://www.ncbi.nlm.nih.gov/pubmed/10612510http://www.ncbi.nlm.nih.gov/pubmed/10612510http://www.ncbi.nlm.nih.gov/pubmed/10612510http://www.ncbi.nlm.nih.gov/pubmed/8278170http://www.ncbi.nlm.nih.gov/pubmed/8278170http://www.ncbi.nlm.nih.gov/pubmed/8278170http://www.ncbi.nlm.nih.gov/pubmed/8278170http://www.ncbi.nlm.nih.gov/pubmed/15830312http://www.ncbi.nlm.nih.gov/pubmed/15830312http://www.ncbi.nlm.nih.gov/pubmed/15830312http://www.ncbi.nlm.nih.gov/pubmed/15830312http://www.ncbi.nlm.nih.gov/pubmed/21757667http://www.ncbi.nlm.nih.gov/pubmed/21757667http://www.ncbi.nlm.nih.gov/pubmed/21757667http://www.ncbi.nlm.nih.gov/pubmed/21757667http://www.ncbi.nlm.nih.gov/pubmed/9184581http://www.ncbi.nlm.nih.gov/pubmed/9184581http://www.ncbi.nlm.nih.gov/pubmed/9184581http://www.ncbi.nlm.nih.gov/pubmed/20335564http://www.ncbi.nlm.nih.gov/pubmed/20335564http://www.ncbi.nlm.nih.gov/pubmed/20335564http://www.ncbi.nlm.nih.gov/pubmed/20335564http://www.jamaneurology.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamaneurol.2015.1578http://www.jamaneurology.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamaneurol.2015.1578http://www.ncbi.nlm.nih.gov/pubmed/20335564http://www.ncbi.nlm.nih.gov/pubmed/20335564http://www.ncbi.nlm.nih.gov/pubmed/9184581http://www.ncbi.nlm.nih.gov/pubmed/21757667http://www.ncbi.nlm.nih.gov/pubmed/21757667http://www.ncbi.nlm.nih.gov/pubmed/15830312http://www.ncbi.nlm.nih.gov/pubmed/15830312http://www.ncbi.nlm.nih.gov/pubmed/8278170http://www.ncbi.nlm.nih.gov/pubmed/8278170http://www.ncbi.nlm.nih.gov/pubmed/10612510http://www.ncbi.nlm.nih.gov/pubmed/5157688http://www.ncbi.nlm.nih.gov/pubmed/5987138http://www.ncbi.nlm.nih.gov/pubmed/5987138http://www.ncbi.nlm.nih.gov/pubmed/18718570http://www.ncbi.nlm.nih.gov/pubmed/18718570http://www.ncbi.nlm.nih.gov/pubmed/12215107http://www.ncbi.nlm.nih.gov/pubmed/24176901http://www.ncbi.nlm.nih.gov/pubmed/24176901http://www.ncbi.nlm.nih.gov/pubmed/11552411http://www.ncbi.nlm.nih.gov/pubmed/11552411http://www.ncbi.nlm.nih.gov/pubmed/10949814http://www.ncbi.nlm.nih.gov/pubmed/10949814http://www.ncbi.nlm.nih.gov/pubmed/9098313http://www.ncbi.nlm.nih.gov/pubmed/1558118http://www.ncbi.nlm.nih.gov/pubmed/1558118http://www.ncbi.nlm.nih.gov/pubmed/1706177http://www.ncbi.nlm.nih.gov/pubmed/1706177http://www.ncbi.nlm.nih.gov/pubmed/7448144http://www.ncbi.nlm.nih.gov/pubmed/16138997http://www.ncbi.nlm.nih.gov/pubmed/16138997http://www.ncbi.nlm.nih.gov/pubmed/545196http://www.ncbi.nlm.nih.gov/pubmed/545196http://www.ncbi.nlm.nih.gov/pubmed/4334005http://www.ncbi.nlm.nih.gov/pubmed/5751047http://www.ncbi.nlm.nih.gov/pubmed/5751047http://www.ncbi.nlm.nih.gov/pubmed/20790334http://www.ncbi.nlm.nih.gov/pubmed/20790334http://www.ncbi.nlm.nih.gov/pubmed/13103884http://www.ncbi.nlm.nih.gov/pubmed/13103884http://www.ncbi.nlm.nih.gov/pubmed/19990974http://www.ncbi.nlm.nih.gov/pubmed/13115619http://www.ncbi.nlm.nih.gov/pubmed/13115619http://dx.doi.org/10.1186/1471-2415-14-28http://dx.doi.org/10.1186/1471-2415-14-28http://www.ncbi.nlm.nih.gov/pubmed/12223369http://www.ncbi.nlm.nih.gov/pubmed/12223369http://www.ncbi.nlm.nih.gov/pubmed/11820305http://www.ncbi.nlm.nih.gov/pubmed/11820305http://www.ncbi.nlm.nih.gov/pubmed/617526http://www.ncbi.nlm.nih.gov/pubmed/617526http://www.ncbi.nlm.nih.gov/pubmed/13931064http://www.ncbi.nlm.nih.gov/pubmed/13931064http://www.ncbi.nlm.nih.gov/pubmed/13302089http://www.ncbi.nlm.nih.gov/pubmed/13302089http://www.ncbi.nlm.nih.gov/pubmed/1599661http://www.ncbi.nlm.nih.gov/pubmed/1599661http://www.ncbi.nlm.nih.gov/pubmed/7817026http://www.ncbi.nlm.nih.gov/pubmed/7817026http://www.ncbi.nlm.nih.gov/pubmed/5732682http://www.ncbi.nlm.nih.gov/pubmed/5732682http://www.ncbi.nlm.nih.gov/pubmed/5598216http://www.ncbi.nlm.nih.gov/pubmed/5598216http://www.ncbi.nlm.nih.gov/pubmed/5966438http://www.ncbi.nlm.nih.gov/pubmed/5966438http://www.ncbi.nlm.nih.gov/pubmed/18141837http://www.ncbi.nlm.nih.gov/pubmed/18141837http://www.ncbi.nlm.nih.gov/pubmed/16784338http://www.ncbi.nlm.nih.gov/pubmed/14557172http://www.ncbi.nlm.nih.gov/pubmed/14557172http://www.ncbi.nlm.nih.gov/pubmed/10789670

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