antithrombotic in acute - bmj

Journal of Neurology, Neurosurgery, and Psychiatry 1993;56:17-25

Antithrombotic therapy in acute ischaemicstroke: an overview of the completed randomisedtrials

P A G Sandercock, A G M van den Belt, R I Undley, J Slattery

AbstractA formal statistical overview of all trulyrandomised trials was undertaken todetermine whether antithrombotic ther-apy is effective and safe in the earlytreatment of patients with acute stroke.There were 15 completed randomisedcontrolled trials of the value of earlyantithrombotic treatment in patients withacute stroke. The regimes tested in acutepresumed or confirmed ischaemic strokewere: heparin, 10 trials with 1047 patients:oral anticoagulants, one trial with 51patients: antiplatelet therapy, three trialswith 103 patients. Heparin was tested inone trial with 46 patients with acute haem-orrhagic stroke. Outcome measures weredeep venous thrombosis (confirmed by125 Sscanning or venography), pulmonaryembolism, death from all causes, haemor-rhagic transformation of cerebral infarc-tion, level of disability in survivors. Inpatients with acute ischaemic stroke, allo-cation to heparin was associated with ahighly significant 81% (SD 8, 2p < 0-00001)reduction in deep venous thrombosisdetected by I"25 fibrinogen scanning orvenogram. Only three trials systemat-ically identified pulmonary emboli, whichoccurred in 61106 (5.7%) allocated controlvs 31132 (2.3%) allocated heparin, a non-significant 58% reduction (SD 45'7, 2p >0*1). There were relatively few deaths inthe trials in patients with presumedischaemic stroke: 94/485 (19.4%) amongpatients allocated to the control group vs791497 (15-9%/6) among patients who wereallocated heparin. The observed 18% (SD16) reduction in the odds of death was notstatistically significant. The least biasedestimate of the effect of treatment onhaemorrhagic transformation ofthe cere-bral infarct (HTI) comes from trialswhere all patients were scanned at the endof treatment, irrespective of clinical dete-rioration; using this analysis, haemor-rhagic transformation occurred in 7/102(6-9%Y.) control vs 8/106 (7.5%) treated, anon-significant 12% increase (SD 56, 2p> 0-1). These data cannot exclude thepossibility that heparin substantiallyincreases the risk of HTI. No data ondisability in survivors could be obtained.Early heparin treatment might be asso-ciated with substantial reductions in deepvenous thrombosis (and probably alsopulmonary embolism) and possibly a onefifth reduction in mortality (equivalent to

the avoidance of 20-40 early deaths perthousand patients treated). However, thedata were wholly inadequate on safety,particularly on the risk of haemorrhagictransformation of the infarct and on thehazards of heparin therapy in patientswith known intracerebral haemorrhage.The trials of oral anticoagulants (15deaths among 57 patients) and antiplatelettherapy (two deaths among 103 patients)were too small to be informative. Muchlarger randomised trials-comparingaspirin, heparin and the combination ofboth drugs against control-in patientswith acute ischaemic stroke are justified(and several are now planned or under-way).

(J Neurol Neurosurg Psychiatry 1993;56:17-25)

Each year, there are about 1-5 million newstrokes per year in the USA and in theEuropean Community. 1-3 Eighty five per centof strokes are ischaemic,3 so over the nextdecade, there will be some 12-8 millionpatients with acute ischaemic stroke, for whomantithrombotic treatment might be considered.Of these patients, about 15 million will bedead within two weeks of their stroke. Manywill survive, but be dependent on other peoplefor help with activities of daily living. Aspirinand heparin are simple, practicable anti-thrombotic regimes which could be givento almost every patient with acute ischaemicstroke. If these two treatments were proven tobe effective and safe, the potential scale of theiruse is enormous.

Antithrombotic drugs yield substantial clin-ical benefits in the early treatment of unstableangina and acute myocardial infarction.-4-0For example, in acute myocardial infarction,one month's oral aspirin reduces early mortal-ity by one fifth4 and one or two weeks' heparincan reduce one month mortality by about onetenth.5 11 If the widespread early use of thesetreatments in patients with acute ischaemicstroke (cerebral infarction) were associatedwith similar benefits, perhaps 300 000 earlydeaths would be avoided over the next decadein Europe and USA. In addition to improvingsurvival, early antithrombotic treatment withaspirin or heparin, by reducing the volume ofinfarcted cerebral tissue, avoiding early recur-rence of thromboembolic stroke and reducingvenous thromboembolic complications mightreduce neurological disability in surviv-ors 12-14

Department ofClinicalNeurosciences,Western GeneralHospital, EdinburghEH4 2XU, UKP A G SandercockR I lindleyJ SlatteryAMC, Department ofNeurology, HZZV,Meibergdreef 9,Amsterdam, TheNetherlandsA G M van den BeltCorrespondence to:Dr SandercockReceived 26 February 1992and in revised form2 June 1992.Accepted 12 June 1992

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Sandercock, van den Belt, Lindley, Slattery

This paper is a formal statistical overview ofall the randomised trials of antithrombotictreatment in patients with acute ischaemicstroke. Our aim was to determine whetherthere is clear evidence that treatment is bene-ficial and, if not, whether a very large scale trialis justifiable.15-17

MethodsWe sought to identify all truly randomisedtrials of early treatment with antithromboticagents in patients with acute stroke. Thus trialsin which allocation to treatment or controlgroup was not truly randomised (that is,alternating, or based on date of birth orhospital number) were not included, sinceforeknowledge of treatment allocation mightlead to biased treatment allocation. Trialswhich randomised patients more than sevendays after onset of the stroke, and trials inpatients with only transient ischaemic attackswere excluded, because this review was con-fined to early treatment of acute stroke. Theanticoagulant agents considered were: stan-dard unfractionated heparin, low molecularweight (LMW) heparin, and oral anticoagu-lants. We sought trials of the antiplateletagents: aspirin, ticlopidine, sulphinpyrazone,suloctidil, dipyridamole, indobufen, flurbipro-fen and the combination of aspirin and dipy-ridamole. Relevant randomised trials wereidentified by computer aided search (MED-LINE), by conversation with colleagues (par-ticularly those who had coordinated suchstudies), by scrutiny of the reference lists oftrials and review articles, by inquiry of variousmanufacturers of anticoagulants and bysearching the trials register held by the Anti-platelet Trialists' Collaboration (APT)."7 Weaimed to extract from each trial the number ofpatients originally allocated to each treatmentgroup, and in each treatment group, thenumber of patients: a) with objective evidenceof the occurrence of deep venous thrombosis(DVT) detected by systematic 125-I-fibrino-gen scanning or systematic radiograph contrastvenography during the scheduled treatmentperiod; b) with at least one confirmed pulmo-nary embolus; c) who died from any causeduring the scheduled follow up period (gen-erally longer than the scheduled period of drugtreatment); d) who died from any cause duringthe scheduled treatment period; e) with haem-orrhagic transformation confirmed by routineCT scanning; f) with recurrent stroke by theend of the scheduled study follow up period; g)who were dead or dependent on help fromother people in activities of daily living at 6months after the stroke. Data on the number ofpatients with each outcome event, by allocatedtreated group, irrespective of compliance, andwhether or not the patient was subsequentlyconsidered ineligible or otherwise excludedfrom treatment or follow up were sought toallow an "intention to treat" analysis.

If these data were not available in publica-tions, further data were sought by correspond-ence with the authors. Data on whether CTscanning was performed before randomisationwere also sought.

Statistical analysisThe statistical overview was performed by thestandard method described by Yusuf andPeto.'"'8 For each trial, the number of sub-jects in whom a particular adverse event wasobserved in the treatment group (0) is con-trasted with the number that, if treatmentreally had no effect, would have been expected(E) on the basis of the overall experience in thetreatment and control groups combined. Iftreatment were effective, the grand total (GT)should be negative. If, however, treatmentwere wholly without effect, the GT woulddiffer only randomly from zero (with variancetotal [VT] equal to the sum of the individualvariances in the separate 0 - E values, and withthe standard deviation [SD] equal to thesquare root of the total variance). Formalstatistical tests assessing whether treatment iswithout effect involve the calculation of Z, thenumber of standard deviations by which theGT differs from zero (Z = GT/SD), andcomparison of Z with tables of the standardnormal distribution. (Thus, for example, afavourable result with Z = - 1-96 suggests a Pvalue of about 0-05.) (All P values are two-sided.) An estimate of the typical percentagereduction in the odds (R) of an adverse eventoccurring among treated patients comparedwith controls can be calculated with use of theapproximate formula R = 100 - 100 expected(Z/SD), with 95% confidence limits 100-100expected (Z/SD + 1 96/SD), and the standarddeviation of R may be estimated by -R/Z.Tests for heterogeneity of the effects of treat-ment between several different trials (or cate-gories of trial) can also be performed. For eachtrial in which the variance, V, of 0 - E is notzero, the quantity (O - E)2/V can be calcu-lated, and all such quantities, one per trial,added up. Subtraction of (GT)2/(VT) fromthis total provides an approximate chi-squaretest statistic, with one fewer degree of freedomthan the number of such trials. An overview ofmany trial results assumes not that the realeffects of treatment are all exactly the same sizein the different trials but merely that most or allof the real effects probably point in the samegeneral direction.

ResultsTwenty one trials were identified (tables 1 and2). Six trials are either planned or are still inprogress and results are not expected to beavailable for some time. This review is of theremaining fifteen 19-33 completed trials.

Trials of heparin and oral anticoagulant drugs inacute strokeWe have identified 11 controlled trials ofanticoagulant drugs in patients with acuteischaemic stroke which compared anticoagu-lant effects with control. The agents were:standard heparin (six trials), LMW heparin(four trials), oral anticoagulants (one trial).One trial in patients with haemorrhagic strokecompared standard heparin with control.Details of the regimes are in the tables. Thescheduled period of acute antithrombotic

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Antithrombotic drugs in acute ischaemic stroke

Table 1 Randomised trials of heparin or oral anticoagulants in acute stroke

Start of CT scan Scheduledtreatment before Scheduled duration ofwithin (hrs) trial duration of clinical

Study Number of of stroke entry treatment follow up Active ControlAuthor/trial name patients onset (%) (days) (months/days) treatment treatment Route Dose Dose interval

Acute presumed ischaemic stroke: completed trialsStandard Heparin TrialsDuke'9 225 48 100 7 12 months Heparin P iv adjusted' cont infCESG20 45 48 100 10 14 days Heparin N iv adjustedb cont infMcCarthy2l 305 48 0 14 3 months Heparin N sc 5000U 8 hrsMcCarthy22 32 48 0 14 1 month Heparin N sc 5000U 8 hrsCzechanowski23 107 120 0 14 14 days H-DHE P sc 5000U+0 5mg 12 hrsDuke24 65 48 81' 7 12 months Heparin P sc 5000U 8 hrsLMWHeparin TrialsTurpie2' 75 168 100 14 3 months LMWH P sc 75OaXaU 12 hrsPrins26 60 72 100 14 14 days LMWH P sc 2500aXaU 12 hrsSandset27 103 72 100 14 1 month LMWH P sc 3000-5500aXaU 24 hrsElias28 30 48 100' 14 14 days LMWH N sc 15,OOOaXaU 24 hrsOral AnticoagulantsMarshall29 51 72 0 21 6 months Phen N o adjusted' 24 hrs

+24 hrs HAcute Presumed Ischaemic Stroke: planned/in progressTOAST 1300d 24 100 7 3 months LMWH P sc Adjusted' 24 hrsUK ORG10172 180d 120 100 8-10 12 weeks LMWH P sc 75OaXaU 12 hrs

or 125OaXaU 24 hrsInternational 20 ooOd 48 1 OOh 14 6 months Heparin N sc 5000U 12 hrsStroke Trialf Heparin N sc 12 500U 12 hrs

Heparin+ N sc 5000U 12 hrsAspirin f o/pr 300mg 24 hrsHeparin+ tN sc 12 500U 12 hrsAspirin f o/pr 300mg 24 hrsAspirin N o/pr 300mg 24 hrs

Kay 200d 48 100 7 12 months LMWH P sc 7500aXaU 12 hrsAcute Haemorrhagic Stroke: completed trialDickman30 46 4 days 100 6 ns H N sc 5000U 8 hrs

H: standard heparin; H-DHE: standard heparin + Dihydroergotamine; LMWH: low molecular weight heparin; Phen: Phenindione; aXaU: anti-factor Xa units; P:placebo; N: No treatment; iv: intravenous; cont inf£ continuous infusion; sc: subcutaneous; ns: not stated.'Adjusted dose to keep partial thromboplastin time 50-70 secondsbAdjusted dose to keep partial thromboplastin ratio 1 5-2-5x pretreatment level.'Adjusted dose to keep prothrombin ratio 2-3x controldPlanned numbers of patients'Treatment of acute stroke trial (TOAST). Adjusted dose therapy9This trial has a 3x2 factorial design'Percentage with CT scan within 48 hours of trial entryhCT scan not mandatory before randomisation, but should be obtained quickly thereafter if possible.

Table 2 Randomised trials of antiplatelet agents in acute ischaemic stroke

Start of Scheduledtreatment Scheduled duration ofwithin (hrs) duration of clinical

Study Number of of stroke treatment follow up Active ControlAuthorltrial name patients onset (days) (monthsldays) treatment treatment Route Dose Dose interval

Completed TrialsUtsumi3' 29 ns ns N/A Ticl P o 300mg nsJoseph32 44 240 ns N/A Asp+dip N o ± 330mg Asp ns

± 180mg DipCiuffetti33 30 12 21 N/A Ticl P o 250mg 12 hrsPlannedlIn ProgressBritton 300- ns ns ns Aspirin P o 325mg 24 hrsMAST Italyb 1500' 6 10 6 months Aspirin N o/or A 350mg 24 hrs

iv f 100mgStr iv 1-5MU One dose only

International Stroke Trial 20 000 See table 1 for detailsNational Study, China 20 ooOd 48 100 35 days Aspirin P o 325mg 24 hrs

Ticl: Ticlopidine; Dip: Dipyridamole; P: Placebo; N: No treatment; o: oral; iv: intravenous; ns: not stated; N/A: not available; Str: Streptokinase' Planned number of patientsb Patients are allocated to one of four treatment groups in a 2 x 2 factorial design: placebo, aspirin, streptokinase, and aspirin and streptokinase.

treatment ranged from six to 21 days (mean 12days). The scheduled period of clinical followup varied from 1-12 months. Six trials rou-tinely performed CT in all patients beforerandomisation,1920 25-28 one trial performedCT in most patients,24 three trials performedCT in almost none2-2' and one trial wasundertaken before CT scanning was intro-duced.29

a) Effect of heparin on deep venous thrombosisTwo trials did not report data on deep venousthrombosis (DVT).'9 29 Nine trials, all com-paring heparin with placebo or open control,systematically sought to determine the effect oftreatment on the occurrence of (DVT) detec-ted by systematic I125 fibrinogen scanning or

systematic radiographic contrast venography;eight trials were in patients with ischaemicstroke2'1-28 and one was in patients with haem-orrhagic stroke.30 In trials of heparin in ischae-mic and haemorrhagic stroke, treatment wasassociated with a highly significant 79% (SD 8)2p < 0-00001 reduction in the odds of con-firmed DVT in the scheduled treatment period(fig 1).There was no clear evidence that reductions

in confirmed DVT were importantly differentbetween: patients with ischaemic stroke andpatients with haemorrhagic stroke; patientswith adjusted dose intravenous heparin, lowdose subcutaneous heparin or LMW heparin;when DVT was detected by venography andI125 fibrinogen scanning (fig 1).

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Figure I Apparent effecton deep venous thrombosisdetected by systematic I125fibrinogen scanning or bysystematic venography intrials among patients withischaemic stroke and onetrial in haemorrhagicstroke. The stratified ratioof the odds of an event inthe treatment group to thatin the control group it isplotted for each trial (blacksquare: area proportionalto the amount ofinformation contributed);with its 99% confidenceinterval (horizontal line).The presence of a blacksquare to the left of thesolid vertical line suggestsbenefit (but this benefit issignificant at the level of2p < 0 01) only if theentire confidence interval isto the left of the solidvertical line. An overviewof aUl of the trial results(and its 95% confidencelimit) is represented by ablack diamond besidewhich is the reduction inthe overall incidence inthose trials.

Heparin in acute strokeHEPARIN versus CONTROL: deep vein thromb6sis

Trialsanalysed

Events/PatientsHeparin Control

OddsStratified Odds Ratio and CL reduction

(O-E) Variance (Heparin : Control) (sd)

ACUTE PRESUMED ISCHAEMIC STROKE:

DETECTION METHOD: 1'25 fibrinogen leg scanMcCarthy21 32/144 117/161 -38-3 19-19McCarthy2 2/16 12/16 -5-0 2-0 *--Czechanowski23 11/54 23/53 -6-2 5-9 j- -Duke24 0/35 3/30 -1-6 0-7

* Subtotal: Standard heparln 45/249 155/260 -51-1 27.7

Turpie25 2/50 7/25 -4-0 1-8-*-jPnS26 6/30 15/30 -4-5 3-5 -Elias-8 0/15 12/15 -6-0 1-9

* Subtotal: LMW Heparln 8/95 34/70 -14*5 7-1 <>

* Total: Heparin 1125 trials 53/344 189/330 -65.6 34-8 a

DETECTION METHOD: venography

Sand27 15/52 17/51 -1 2 5*6

* Total: lschaemic stroke trials 68/398 206/381 -66-8 403 <

ACUTE HAEMORRHAGIC STROKE:

Dickmann3 8/23 10/23 -1 0 28

* Total: All trials 76/419 216/404 -67 8 43 1

,. .

~> 81% (8)

a *__

0.0 05 1*0 I 5 2-0Heparin | Heparinbetter worse

Treatment effect 2P < 0 00001

Figure 2 Apparent effecton pulmonary embolism.For explanation of symbolsand conventions, see legendto fig 1.

Trialsanalysd

Heparin In acute ischaemic strokeHEPARIN versus CONTROL: pulmonary embolism

Events/PatlentsHeparin Control

OddsStratified Odds Ratio and CL reduction

(O-E) Variance (Heparln: Control (sd)

3/132 6/106 -1*9 21

0.0 0-5 1.0 5 20

Heparin Heparinbetter worse

Treatment effect 2P > 0-1; NS

84% (9)

87% (16)

85% (8)

79% (8). . I

Prins26Sandset27Turpie25

Total

1/302/520/50

2/30 -0-5 0 72/512/25

0.0 1.0-1-3 0-4

58% (46)__~~~~~~~~~~~

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Antithrombotic drugs in acute ischaemic stroke

Figure 3 Apparent effecton mortality of heparin orwarfarin on trials inpatients with ischaemic orhaemorrhagic stroke. Forexplanation of symbols andconventions, see legend tofig 1.

Heparin or oral anticoagulants In acute strokeTREATMENT versus CONTROL: death from all causes

Trialsanalysd

Events/PatIetsTreatment Control

Stratifed Odds Ratio and CL(O-E) Variance (Treatment: Control

ACUTE PRESUMED ISCHAEMIC STROKE:

HEPARIN TRIALSDuke19CESG20McCarthy21McCarthy22CzechanowskiDuke24

* Subtotal: Standard heparln

TurSPrins26Sandset27Elias2

* Subtotal: LMW Heparin

* Total: Heparin trils

17/112 8/113 4-6

0/24 3/21 -1-6

31/144 53/161 -8-7

3/16 5/16 -1-0

7/54 12/53 -2-6

(data not available)

58/350 81/364

4/50 5/259/30 4/305/52 1/513/15 3/15

-9-3

-2-0

2-5

2-00-0

5-6

0-7 -

15-2

1-5

3-9

27-0

1 -8

2-6

1-4

1-2

21/147 13/121 2-5 7-0

79/497 94/485 -6*8 34-0

ORAL ANTICOAGULANT TRIAL

Marshall- 8/26

* Total: lschaemlc stroke trfials 87/523

7/25 0-4 2-7

ACUTE HAEMORRHAGIC STROKE:

Dickman30 5/23

* Total: All trials 92/546 105/533 -6-0 38-6

0.0 0-5 1.0 1.5 2-0

Treatment Treatmentbetter worse

Treatment effect 2p > 0.1; NS

b) Effect of heparin on pulmonary embolismThe data on pulmonary embolism (fatal ornon-fatal) are given in fig 2. The 58% reduc-tion in pulmonary embolism, though sub-stantial, is not conventionally significant.

c) Effect of heparin or warfarin on death fromall causes by the end of study periodAllocation to treatment with any type ofanticoagulant therapy in acute ischaemic or

haemorrhagic stroke was associated with anon-significant 14% reduction in the odds ofdeath (SD 15, 2p > 0 1) from all causes by theend of scheduled follow up period9'30 (fig 3).Because of the relatively few deaths, the 95%confidence intervals were wide and includedthe possibilities that treatment could be asso-ciated with a reduction of perhaps one third orwith an increase of about one sixth in the odds

of death. Analysis of the heparin trials in acuteischaemic stroke 19-28 showed that treatmentwas associated with a non-significant 18%reduction (SD 16, 2p > 0 1) in the odds ofdeath by the end of scheduled follow up period(fig 3). The trial in haemorrhagic stroke30showed a non-significant 31% increase in theodds of death (SD 84, 2p > 0 1, NS). Theseresults are shown in fig 3. Mortality resultswere not significantly different in trials whereheparin was given to patients with CT-con-firmed cerebral infarction and in trials whereheparin was given without CT. However, thedata were wholly inadequate to determine theeffect on mortality of a policy of "hepariniza-tion without CT".A separate analysis of the numbers of deaths

from all causes during the scheduled treatmentperiod was reported in eight trials.19 20 23 25-29

Oddsreduction

(sd)

29% (16)

-42% (45)

18% (16)

::0. 16% (15)101/510 -6*5 36 7

4/23 0-5 1-9

14% (15)

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Figure 4 Apparent effectof heparin onhaemorrhagictransformation of theinfarct. For explanation ofsymbols and conventions,see legend to fig 1.

Heparin In acute Ischaemic strokeHEPARIN versus CONTROL: haemorrhagic transformation of the infarct

Trialsanalysd

Events/PatientsHeparin Control

Stratified(O-E) Variance

Odds Ratio and CL(Heparin: Control

Detection: CT scan only after clinical worsningDuke19 0/112 0/113TurpiePrins26Sandset27CESG20

1/50 0/251/30 0/302/52 1/510/24

Total

0-3 0-20-5 0-30-5 0-7

0/21

4/268 1/240

Detection: Systematic CT scan at end of treatmentCESG20 0/24 2/21Prins26 4/30 2/30Sandset27 4/52 3/51

Total 8/106 7/102

The numbers of deaths were small; 28/333allocated control vs 32/363 allocated anti-coagulants. There was a non-significant 10%increase in the odds of death (SD 29, 2p > 0 1,

NS) with a very wide confidence interval;consistent with either evidence of a beneficialeffect, a harmful effect or no effect at all. Dataon cause specific mortality in each treatmentgroup, on recurrent stroke and on disability atsix months were not available from the pub-lished reports or from the trialists' personalrecords.

1-3 1-2

-1-1 0-5

1-0 1-40-5 1-6

04 3-5 :-12% (57)

0-0 0-5 1.0 1-5 2-0Heparin Heparinbetter worse

Treatment effect 2P > 0-1; NS

showed that treatment was associated with a12% increase in HTI (SD 56, 2p > 0O1, NS)(fig 4).

Trials of antiplatelet agents in acute strokeOf the six trials of antiplatelet therapy inpatients with acute ischaemic stroke, the threelargest have not been completed. Two of thecompleted trials did not systematically recorddata on clinical events 31 32 (they studied labo-ratory coagulation factors only) and the thirdwas too small to be informative.33

d) Effect of heparin on haemorrhagictransformation of the cerebral infarctA relatively unbiased assessment of the effectof antithrombotic treatment on the occurrenceof haemorrhagic transformation of the infarct(HTI) would come from studies where allsurviving patients have a CT scan at the end ofthe scheduled treatment period, irrespective ofany clinical deterioration. The least biasedassessment would be of the effect of treatmenton the composite event "HTI detected onroutine CT scanning at the end ofthe scheduledtreatment period or fatal-haemorrhagic strokeduring the scheduled treatment period" (notrials had this as a prespecified analysis). Fivetrials'9 20 25-27 reported data on HTI detectedby CT scan: CT scan was performed becauseof clinical deterioration and the results of thesetrials showed that treatment was associatedwith a 198% excess of HTI (SD 165%, 2p> O l, NS) (fig 4). Analysis restricted to"haemorrhagic transformation on routinescans performed at the end of the scheduledtreatment period or fatal haemorrhagic stroke"

DiscussionCurrent use of antithrombotic drugs in acutestrokeThere is considerable variation in the use ofantithrombotic drugs (aspirin or heparin) totreat patients with acute ischaemic stroke.34 Ina survey of the current treatment of patientswith ischaemic stroke, 83% ofUS neurologistsreported that they had used heparin in suchpatients over the previous year.34 However,only 6% of the physicians felt that, based ontheir understanding of the literature, heparinhad clearly been shown to be effective in thetreatment of patients with acute cerebralinfarction. Furthermore, 59% thought it hadnot been shown to be effective.34 Despite theseapparently conflicting opinions, approximately22% of patients with ischaemic stroke seen byUSA neurologists in the survey were givenheparin within the first 24 hours of stroke.34 Inthe Stroke Data Bank,35 36 a multicentre pro-ject which prospectively collected data onpatients with stroke admitted to academichospitals in the USA, 538 of 1273 patients

Oddsreduction

(sd)

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23Antithrombotic drugs in acute ischaemic stroke

Deep vein thrombosis, pulmonary embolism, death andhaemorrhagic transformation of the infarct in

randomised trials of heparin in acute ischaemic stroke.

Proportonal reduction: 81 % (8)2p <0-00001

Event prevented per 1000: 369 (98)

Percentageof patientsaffected

(after adjustmentfor unevenlyrandomised

trials)

68 206396 36117.2% 54-1S

58 % (46)NS

34 (a6)

18 % (16)NS

35 (142)

ConE Heparin

6106

Outcome Deep Pulmonary Deathmeaare: vein embolism

thromboele

Figure 5 Absolute rates of DV7I pulmonary embolism, death and haemorrhagictransformation of the infarct in patients with presumed or confirmed cerebral infarction.Figures in brackets are standard deviations.

with cerebral infarction (42%) were giveheparin during their admission to hospitaThus in the USA, heparin is used, but withoia clear consensus on whether it is effectivenot; clinical practice in other western countriis probably similar. Similar variations in t1use of aspirin in the acute treatment of strolhave been found in a survey of physicians iYorkshire, UK (Bamford J, personal commi

nication).

Heparin in acute myocardial infarctionAs the underlying pathophysiology of acu

cerebral infarction and acute myocardiinfarction have many features in common, ituseful to review the effects of heparin in acu

myocardial infarction. A formal reviewtwenty four trials of heparin in patients with a

acute myocardial infarction by MacMahonal37 provided clear evidence of benefit; alloction to heparin was associated with a sinificant 10% reduction in mortality. In thetrials, heparin significantly reduced reinfartion by one fifth and stroke by one half. TIheparin regimes tested in about 90%patients involved doses of 20 000 IU or mo

daily, given subcutaneously in about half tdpatients. An overview of two large trials pullished after McMahon's review (ISIS-3 ar

GISSI-2) showed that, when subcutaneoiheparin is given to patients with acute my

cardial infarction who have already receivaspirin and a fibrinolytic drug, the benefitsadding heparin may be rather more modest.

Heparin or warfarin in acute stroke; are theyeffective?There has been no formal overview of t]studies in acute stroke which we have iden

fied. Previous reviews have either been infor-mal, with no statistical estimation of typicaltreatment effects,39-41 or did not use acceptedstatistical methods42 or pooled data from trialsof acute treatment with trials of long-termsecondary prevention.42 In the present over-view in patients with acute, presumed ischae-mic stroke, allocation to heparin therapy wasassociated with a highly significant 81% reduc-tion in the odds of DVT. Proportional reduc-tions in DVT were similar with standardheparin, LMW heparin, fixed low-doseregimes and adjusted full-dose regimes.Reductions were similar in patients with acuteCT confirmed ischaemic stroke, with pre-sumed ischaemic stroke and with acute haem-orrhagic stroke. Heparin had similar effects onDVT in stroke patients as in patients experi-encing different types of surgery'3 and inpatients with acute MI.37 In the presentoverview, the reductions in the absolute risk ofDVT were substantial: heparin therapy

' reduced DVT from 57% among controls to15% among treated patients. There were insuf-ficient events in the present overview to deter-

| mine whether the reduction in DVT wouldet lead to a reduction in pulmonary embolism

(PE) in stroke patients. However, the observed58% reduction in PE with heparin prophylaxisfor stroke patients was similar to the results ofheparin prophylaxis in surgical patients (47%reduction in PE)"3 and in patients with acute

En MI (54% reduction in PE).37 The reduction inal. non-fatal pulmonary embolism with heparinut (5 7% reduced to 2-3%) would suggest thator routine heparin thromboprophylaxis forLes patients with acute stroke might avoid three or.

ie four hundred DVTs and perhaps 30-40 pul-ke monary emboli for every thousand patientsin treated (fig 5). Should therefore all patientsu- with ischaemic (or, indeed, haemorrhagic)

stroke now be given heparin routinely toprevent DVT (and probably pulmonary embo-lism)? Our conclusion is that they should not

te because of lack of good data on safety.ialis Is heparin safe in acute stroke?te There is considerable uncertainty about theof effect of therapy on the risk of death; therapyan was associated with an 18% reduction in theet odds of death (equivalent to the avoidance ofa- perhaps 20 to 40 deaths per 1000 patientsig- treated), but the upper 95% confidence inter-se val was compatible with heparin leading to anrc- increase in the odds ofdeath by one sixth. Thushe the present data cannot exclude the possibilityof that routine heparin therapy might cause an)re excess of perhaps 40 deaths for every 1000he patients treated. The second reason is that thekb- data were wholly inadequate to assess the effectnd of heparin on the risk of disabling or fatalus haemorrhagic transformation of cerebral0 infarction.o eioof Heparin dosage38 There is also uncertainty about the optimum

dose of heparin. Whilst low dose subcutaneousheparin is effective in the prevention of venousthromboembolism,'3 higher dose subcutane-

:he ous heparin regimes, such as 12 500 units 12ti- hourly, are more effective in the prevention of

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thrombi in the arterial circulation, as assessedby the effects on left ventricular thrombusformation in acute myocardial infarction.9 1OInhibition of formation or propagation ofthrombi in cerebral arteries holds the promiseof preventing stroke progression, and possiblyeven reducing cerebral infarct size, with a

reduction in the subsequent neurologicalimpairment and disability. However, severalstudies have suggested a higher risk of bleedingcomplications with the higher dose heparinregimes.'0 " A study by Turpie directly com-

pared 12 500 units of heparin subcutaneouslytwice a day. with 5000 units subcutaneously inpatients with acute myocardial infarction,9 therisk of serious bleeding in the two treatmentgroups was very similar (1/112 for high doseheparin, 1/109 for low dose heparin). Whilstthe observed effect (a 3% reduction in seriousbleeds) was not conventionally significant,confidence intervals were very wide andincluded the possibility that the higher dosewas associated with a 15-fold excess of seriousbleeds. These data are wholly inadequate toassess any excess bleeding risk associated withthe higher heparin dose. In acute ischaemicstroke, when haemorrhagic transformation or

frank intracerebral bleeding can often be fatalor disabling, a randomised trial is clearlyneeded, not just to determine whether heparinis effective, but also to determine the relativesafety and efficacy of the two doses: thebalance of risks and benefits may be quitedifferent for different doses.

Antiplatelet therapy in acute ischaemic strokeIf a policy of routine early aspirin therapy was

shown to be equally effective and safe in thetreatment of acute cerebral infarction as it is inthe treatment of acute myocardial infarction,4such a policy might lead to the avoidance ofperhaps 20 to 40 deaths for every thousandacute ischaemic stroke patients treated. Wide-spread use of immediate aspirin therapy forpatients with acute ischaemic stroke in theUSA and the European Community mighttherefore avoid several thousand early deathsfrom stroke each year; perhaps 300 000 deathsover the next decade. If aspirin were to be usedon this scale, it would need to be supported byparticularly reliable evidence of safety andefficacy from large trials. No such trials exist.Whilst heparin is promising, aspirin is equally,or perhaps even more promising as an anti-thrombotic regime, as it is even cheaper andsimpler to administer than fixed-dose subcuta-neous heparin.

Design considerations for trials capable ofconfirming or refuting the effects ofantithrombotic therapy in acute ischaemic strokesuggested by present reviewFirstly, the trial should be large: ISIS-2 was

able to provide particularly clear evidence on

the efficacy and safety of two widely practica-ble treatments for acute myocardial infarctionbecause of its size: 1820 deaths occurred in therandomised 17 187 patients.4The results werestatistically reliable and allowed the analysis ofclinically important subgroups, thus it was

possible to determine whether or not treatmentwas effective, but also for whom treatment wasmost likely to be effective. For example,stratified analyses clearly demonstrated thatincreasing delay in the start of fibrinolytictherapy was associated with progressive reduc-tion in efficacy. The strength of evidenceprovided by the trial persuaded many clini-cians to change their clinical practice and soboth aspirin and streptokinase are now part ofthe routine care of patients with acute MI.43The use of a 2 x 2 factorial design allowedeach agent (aspirin and streptokinase) to becompared separately, and in combination,against control with the same sample size thatwould be required to compare one agentagainst control; the factorial design is statis-tically efficient and allows "two questions to beanswered for the price of one". The trial wasextremely simple in design, involving cliniciansin little extra work, and thus enabled busyclinicians in district general hospitals to collab-orate in the trial. The treatment was tested ona scale appropriate to its future use (ie inmillions of patients with acute myocardialinfarction worldwide). Similar, large, simpletrials of aspirin and subcutaneous heparinwhich recruit the number of patients appro-priate to the likely scale of their future use(millions of stroke patients worldwide) are nowneeded. In this context, trials which enroll afew tens of thousands of patients with acuteischaemic stroke seem appropriate. For exam-ple, a study which recruited just 20 000patients with acute ischaemic stroke (that is,about half the size of ISIS-3), in which twoweek mortality was 12% in patients allocatedcontrol and 10% in patients allocated heparincould provide reliable evidence on the mortal-ity effects: if an 18% (SD4) reduction in theodds of death were observed, it would behighly statistically significant and the 95%confidence intervals would be fairly precise(11-25% reduction). Perhaps more impor-tantly, reliable analyses of medically importantsubgroups would also be possible (for example,whether benefit was substantially different in:patients started on treatment within six hoursof onset, compared with those started later, inpatients with cerebral infarction due to majorcerebral vessel occlusion, compared with smallvessel lacunar strokes, in patients aged over 75compared with younger patients). Such analy-ses would give useful guidance to clinicians onwhether treatment is particularly beneficial (orparticularly hazardous) in certain categories ofpatient.

Trials in acute ischaemic stroke must alsomeasure outcome in terms of survival free ofsevere disability (as in the Italian haemodilu-tion trial44) to ensure that treatment does notincrease the proportion of patients surviving ina disabled state. No data on survival free ofsevere disability were available for the presentreview. Several trials conforming to theserequirements are now planned or in progress(tables 1 and 2).

ConclusionFor patients with acute ischaemic stroke there

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25Antithrombotic drugs in acute ischaemic stroke

is therefore uncertainty about the balance ofrisks (disabling or fatal haemorrhagic trans-formation of cerebral infarcts and otherbleeds) and potential benefits (reductions incerebral infarct size, reduction in DVT andpulmonary embolism, all contributing toreduced early mortality and reduced disabilityin long-term survivors) from early antith-rombotic therapy with either heparin or aspi-rin. On present evidence therefore a policy ofroutine antithrombotic therapy in the acutephase of stroke cannot be justified until theresults of current large trials are available.

This report could not have been compiled without thecoUaboration of the trialists who undertook these trials and, inseveral instances, provided extra data to enable appropriateanalyses to be performed. Dr P A G Sandercock and Mr JSlattery are supported by a grant from the Medical ResearchCouncil. Dr R I Lindley is supported in part by grants fromTheClinical Trials Service Unit, Oxford, Lilly Pharmaceuticals andthe Stroke Association. The authors gratefully acknowledge theassistance of the Clinical Secretariat of the AntiplateletTrialists'Collaboration in identifying all truly randomised trials ofantiplatelet therapy in the early treatment of acute ischaemicstroke. The figures were produced by Jon Godwin and PamelaBell in the Clinical Trials Service Unit, Oxford.

The Intemational Stroke Trial (co-principal investigators DrPeter Sandercock and Professor Charles Warlow) will begin inearly 1993. Anyone who would like to collaborate in the trialshould write to Dr Peter Sandercock, Neurosciences TrialsUnit, Western General Hospital, Edinburgh EH4 2XU,UK (telephone UK(44)-(0)31-343-6639, Fax UK(44)-(0)31-332-5150).

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