IS A CONTROLLED TRIAL OF LONG TERM ORAL (1)

the two _groups as noted above for the whole series. A difference in exclusion criteria would

_potentially

have had a

profound

effect on the relative remission rates of the two

groups.

DISCUSSION

We believe this

_patient

series to be

_{representative}

of the full clinical spectrum

of AML,

and have shown that if all

_patients

are taken into _account, the clinical course _may be less

successful than

_previously

_{thought. 2-4}

A

_large

number of

_patients

_(43/272)

were not

_given

chemotherapy.

In most _cases, this was because the

attending

physician

judged

the

_patient

to be

_unlikely

to withstand

chemotherapy.

These

_patients

are never included in

treatment series and _yet a discussion of treatment results and

prognosis

with new

patients

should include this information.

31

_patients

were started on

chemotherapy

but did not

complete

a

single

course of treatment,

usually

because of infectious

_{complications leading}

to

_early

death. Treatment series will often exclude such

_patients

as

"inevaluable",

but

they

are better

regarded

as treatment failures.

Many

treatment series _report an _average

patient

_age of 45 to

50

_{years,’ 2-14}

whereas the mean _age of all AML

patients

and the mean _{age in} our

_series,

is

60.15

_{Protocols may exclude}

patients

over

_{50, 60,}

or 70

years,12,16,17

or these

patients

_may

not be referred to treatment centres. Patients with

_preceding

myelodysplastic

syndromes,

and

_patients

in whom AML

develops secondary

to

_{cytotoxic chemotherapy}

have been shown to

_respond

_poorly

to

_chemotherapy

for

leukaemia.6

Patients with poor

prognostic

variables have been

_segregated

in _separate

series.7,8,18

It is

_likely,

_therefore,

that these

patients’

are also

_generally

excluded from recent

chemotherapy

series. If we exclude

_patients

aged

70 and over,

patients

with

_{preceding myelodysplastic syndromes,}

and

patients

with

_{previous chemotherapy, analysis}

shows a

_high

complete

remission rate

_(85-307o)

as

reported

in other

series.2-4

Reports

of recent

_improvements

in

_chemotherapy

for AML _{may reflect inadvertent exclusions and} refinements in

leukaemia classification rather than true

_improvement

in

treatment

results.190ur

new treatment

_regimen

led to an

improvement

in

_complete

remission rate but no

significant

difference in overall median

_survival,

when all

_patients

are taken into account. If

_only

the second series were

_subject

to

the exclusions we have

discussed,

the apparent

_improvement

could have been considerable. The remission rate for all

patients

in the first series

_{(35%) might}

then be

_compared

with the remission rate for

_patients

with various exclusions in the second series

_{(60 - 90%).}

Results of treatment trials in AML that show an overall

improvement

in results should include an

analysis

of

patients

who are untreated or

_partially

_treated,

and the

_proportion

of

patients

with adverse

_prognostic

indicators.

This work was _{supported by} the National Cancer Institute of Canada and Grant CA31761-04A2 from the National Cancer Institute, USA, and the William J. Matheson Foundation.

Correspondence should be addressed to Dr Michael A. Baker, Oncology

Clinic, Toronto General _Hospital, 657 _University Avenue, Toronto, Ontario M5G 1L7, Canada.

REFERENCES

1. Bloomfield CD. Treatment of adult acute nonlymphocytic leukemia-1980 Ann Int Med 1980; 93: 133-34.

consolidation _therapy in adult acute _{nonlymphocytic} leukemia. Blood 1984, 63: 843-47.

6. Estey EH, Keating MJ, McCredie KB, Bodey GP, Freireich _EJ. Causes of initial

remission induction failure in acute _myelogenous leukemia. Blood 1982; 60: 309

7. Preisler _{HD, Early} AP, Raza A, et al. _{Therapy of secondary} acute nonlymphocytic

leukemia with cytarabine. N Engl J Med 1983; 308: 21.

8. Capizzi RL, Poole M, Cooper MR, et al. Treatment of poor risk acute leukemia with

sequential high dose ARA-C and asparaginase. Blood 1984; 63: 694-700. 9. Harousseau JL, Castaigne S, Milpied N, Marty M, Degos L Treatment of acute

non-lymphoblastic leukaemia in _{elderly patients.} Lancet 1984; ii: 288

10. Yates J, Wallace J, Ellison RR, Holland _{JF Cytosine} arabinoside _(NSC-63878) and daunorubicin _{(NSC-83142) therapy} in acute _{nonlymphocytic} leukemia. Cancer Chem _Rep 1973; 57: 485-88.

11. Baker MA, Taub RN, Carter WH, and the Toronto Leukemia _{Study Group} Immunotherapy for remission maintenance in acute _myeloblastic leukemia Cancer Immunol Immunother 1982; 13: 85-88

12. Sauter _{C, Fopp M,} Imbach _P, et al Acute _myelogenous leukaemia: maintenance

chemotherapy after early consolidation treatment does not _prolong survival Lancet

1984; i: 379-82.

13. Buchner T, Urbanitz D, Fischer J, et al. Long-term remission in acute _myelogenous

leukaemia Lancet 1984; i: 571.

14. Champlin R, Gale RP, Elashoff R, et al. Prolonged survival in acute _myelogenous

leukaemia without maintenance _{chemotherapy.} Lancet 1984, i: 894-96 15 Wintrobe MM, Lee GR, Boggs DR, et al, eds. Classification, pathogenesis and _etiology

of _neoplastic disease of the _{hematopoietic system. In Clinical hematology}

Philadelphia Lea and Febiger, 1981: 1455-58.

16. Weinstein HJ, Mayer RJ, Rosenthal DS, Camitta BM, Coral FS, Nathan DG, Frei E Treatment of acute _myelogenous leukemia in children and adults N Engl J Med

1980, 303: 473-78.

17. Cassileth PA, Begg CB, Bennett JM, et al A randomized study of the _efficacy of

consolidation therapy in adult acute _{nonlymphocytic} leukemia. Blood 1984; 63:

843-47.

18. _{Keating MJ,} McCredie _{KB, Benjamin RS,} et al. Treatment _{of patients} over _{50 years of}

age with acute _myelogenous leukemia with a combination of rubidazone and cytosine arabinoside, vincristine and prednisone (ROAP) Blood 1981, 58: 584

19. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new _{diagnostic techniques} as a source _{of misleading} statistics for survival in

cancer. N _Engl J Med 1985; 312: 1604-08

20 The Toronto Leukemia Study Group. Survival in acute _myeloblastic leukemia is not

prolonged by remission maintenance or early reinduction _chemotherapy Blood

1985; 66 _(suppl): 210a.

Trial

_Design

IS A CONTROLLED TRIAL OF LONG-TERM

ORAL ANTICOAGULANTS IN PATIENTS WITH

STROKE AND NON-RHEUMATIC ATRIAL

Walton

_Hospital,

_Liverpool;

_{Radcliffe Infirmary, Oxford;}

and Northern General

_Hospital,

_Sheffield

Summary

A controlled randomised trial

_large

_enough

to assess the value of

_{anticoagulating}

stroke

patients

in atrial fibrillation would be difficult to conduct in

the UK and the results would be

_applicable

to

_only

a _small

proportion

of stroke

_patients.

It would be more worthwhile to

organise

a trial that also assessed the value of other treatments that are

simpler

and

applicable

to all stroke

_patients.

A trial

that assessed the value of

_aspirin

and beta-blockers

_against

control in all stroke

_patients

would not cost much more than

one restricted to

_comparing

_{anticoagulants against}

control in

patients

with stroke and atrial fibrillation but would

_provide

information of more relevance to _{the management}

_{of patients}

with stroke in the UK.

INTRODUCTION

MANY stroke

_patients

in atrial fibrillation

_(AF)

are

_given

TABLE I-POSSIBLE RANDOMISED TRIAL DESIGN TO INCLUDE ALL

STROKE PATIENTS _(AF AND SINUS _RHYTHM)

BB=betablocker. AC= oral anticoagulant.

To assess various anti-haemostatic _therapies: X versus Y versus Z. To assess beta-blockade: 1 versus 2.

anticoagulant

versus control

_ought

to be conducted.

However,

there are reasons

why

a _{very different trial}

might

be

better. The alternative trial would include not

_just

those in AF but all stroke

_patients;

it would be a

comparison

of

anticoagulants

versus control versus

_aspirin;

and

_finally

half of each of the three _groups would be

_{given beta-blockers,}

to

discover whether these agents were of _any additional value

(table I).

The

_design

of this trial was based on the

_following

general

considerations;

that the _type and number of stroke

patients

in AF

_likely

to enter the first _type of

_study

_{may be}

limited;

that the outcome for

_patients

with AF is not much different from that for those in sinus

_rhythm

and that most

stroke

_patients

die not of stroke but of heart

_disease,

so

treatments that

_might

reduce heart disease need to be

_studied;

that

_{anticoagulants}

_{may reduce the incidence} of heart disease and occlusive stroke but increase the incidence of

haemorrhagic

stroke;

that

_aspirin

_{and beta-blockers may be} as effective as

_{anticoagulants}

but are easier to

_give

and less

_toxic;

and

_finally

that there are _many more stroke

patients

in sinus

rhythm

than in

_AF,

which makes the former much easier to

study

and of much _greater

_public

health

_importance.

We conclude

_{by asking}

whether a

_simpler

trial

_{(paradoxically,}

without the two

_{anticoagulant subgroups) might}

be even

better in a _country, such as Great

Britain,

where _computer

tomography (CT)

is often not

_readily

available for the detection

_{of haemorrhagic}

stroke

_(in

which

_{anticoagulants}

are

contraindicated).

The evidence reviewed derives from many

sources,

including

the Oxfordshire

Community

Stroke

Project

(OCSP),’

in which 512 consecutive cases of first-ever stroke were

investigated .

WHAT IS A TYPICAL STROKE PATIENT IN AF LIKE?

The sort of stroke

_patient

in whom the

_question

of

anticoagulation typically

arises

_might

be an

_elderly

woman

with a mild

right hemiparesis,

hypertension,

a left carotid

bruit,

and atrial fibrillation but no evidence of rheumatic

valvular disease. The decision to

_{anticoagulate}

should

_ideally

be based on: whether the stroke was due to cerebral infarction or

_primary

intracerebral

_{haemorrhage (this}

_requires

a CT scan of the

brain);

if the stroke was due to infarction whether it was a result of

_hypertensive

small vessel disease within the

brain,

embolism from an atheromatous

plaque

in the internal carotid _artery, or embolism from the

_fibrillating

left

atrium;

and whether it is wise to

_subject

an

_{elderly hypertensive}

patient

to the risks and inconvenience of

_{anticoagulation.}

WHAT IS THE EFFECT OF AF ON RISK OF DEATH AND RECURRENT STROKE IN STROKE PATIENTS?

Although

AF not associated with rheumatic heart disease

(NRAF)

may increase the risk of death in the first 30

days

after a

stroke,

it has a less marked effect on

mortality

Fig 1-Probability of survival _{(Kaplan-Meier} survival curve) among 346 _patients who survived at least 30 _days after a first cerebral

infarction.

Data from the Oxfordshire Community Stroke Project.

TABLE II-RISK OF DEATH OR RECURRENT STROKE IN PATIENTS WITH STROKE AND ATRIAL FIBRILLATION

RHD = cases ofAF associated with RHD; NRHD = cases ofAF not associated with RHD; NK = not known.

Fig 2-Probability of _remaining free of recurrent stroke among 346

patients who survived at least 30 _days after a first cerebral

infarction.

Data from the Oxfordshire _Community Stroke Project.

thereafter.

_However,

it is the

_30-day

survivors who would be

most

_likely

to be entered into a

long-term

trial of

anticoagulants (table

II and

_{fig 1).}

In the

_long

term NRAF

seems to have little effect on the risk of recurrent stroke

_(table

II and

_fig

_2).

The

_possibility

that

_patients

with stroke and NRAF _may be at _{greater risk} of

_early

recurrence

(within

the first

_month)

than

_patients

in sinus

_rhythm3-’

has not been

confirmed;6,7

the OCSP data so far show that the 6 recurrent

strokes in OCSP

_patients

with AF have all occurred more than 1 month after the first stroke.

WHAT IS THE EFFECT OF RHEUMATIC HEART DISEASE

(RHD)

ON RISK OF RECURRENT STROKE?

In AF

_patients

who have not had a

stroke,

the _presence of RHD increases the relative risk of first-ever stroke

approximately

threefold,

from 5 - 6 to

17. 6.8 However,

there

are no reliable data on how much RHD influences the

frequency

of recurrent stroke in

_patients

with

AF,

though

the

risk is often assumed to be much

_higher

with than without RHD. In the OCSP

_only

5/68

_(7%)

of the cases of first-ever

stroke in AF had RHD.

_Therefore,

even if it were

accepted

that those with RHD should be

_{anticoagulated,}

the treatment

policy

for stroke and AF in the 90% or so without RHD

might

still _{be open} to debate

_(but

_{this dilemma may} not arise in the

parts of world where the

_prevalence

of RHD is

_high).

WHAT IS THE EFFECT OF ANTICOAGULANTS ON RISK OF RECURRENT STROKE?

The

_only

randomised controlled trial of

_{anticoagulants}

in

patients

with stroke attributed to embolism from the heart

was small

₍₂₈

_patients)

and did not state the criteria for

diagnosis

of embolic

stroke,

the number of

_patients

with

_AF,

or the number with

RHD.9

There have been extensive reviews of non-randomised studies of

_{anticoagulants}

in

patients

with stroke that was

presumed

to be due to embolism from the

heart,5,10-12

and some of the reviews have come out

very

strongly

in favour of the use of

anticoagulants. But,

non-randomised studies do not in

_general

_yield

reliable data and when historical controls have been

used,

claims such as "...

in studies of

_{anticoagulation}

... in

patients

with cerebral

embolism ... there has been a 65 to 90% reduction in the number

ofembolic accidents"’2

should be

_interpreted

with

caution. In

addition,

many of the studies were done before CT

_scanning

was available and most included a

high

proportion

of cases with

RHD,

so their relevance to the

treatment of strokes in the UK in the _1980s, when RHD is

relatively

uncommon, is debatable.

A

_rough

idea of the

_likely

reduction in risk of stroke that

anticoagulation might

confer on

_{elderly people}

_{may be}

obtained from a

_study

of the use of

anticoagulants

after

myocardial

infarction in

_{patients aged}

over

60.’

This

study

was

large

and randomised and

attempted

to determine

by

CT scan and/or necropsy whether strokes that did occur

were ischaemic or

_{haemorrhagic.}

There were 4 cases of

CT-proved

cerebral infarction _among the 493

_patients

allocated

placebo

and

_only

_{1 among} the 493 allocated

_{anticoagulants (a}

risk reduction

_{of 70%).}

However,

there were 7 cases

(6

fatal)

of definite intracranial

_{haemorrhage (ICH)}

in the treated group and

only

1 in the control group.

Thus,

if cases of

definite cerebral infarction and definite ICH were

counted,

anticoagulants

caused a 60% net increase in the risk of stroke. The numbers of cases were _very small and the confidence

intervals

_wide,

so no firm conclusions can be drawn.

Nevertheless,

the

_findings

show the

_importance

of

_balancing

any reduction in the risk of cerebral infarction

against

any

increased risk of ICH in studies of stroke

_prevention.

WHAT IS THE EFFECT OF ANTICOAGULANTS ON RISK OF INTRACRANIAL HAEMORRHAGE?

Despite

the

_high

relative risk of ICH in

_{anticoagulated.}

patients,

the absolute number of

_patients

with ICH is still small.

_{Unfortunately,}

ICH _may nevertheless be the

commonest fatal

_complication

of

_{anticoagulant}

_{therapy. IS}

However,

its

_frequency

in

_patients

with well-controlled

prothrombin

times is still not known.

_Widespread,

inadequately

controlled use of

anticoagulants

in the 1960s may well have caused an

appreciable

increase in the

frequency

of ICH in

_Rochester,

Minnesota.16

In

_Leiden,17

where

_{anticoagulant}

_therapy

is centralised and _very

_closely

supervised, anticoagulants

increased the risk of ICH ten-fold

in

_people

over 50. A similar increase in risk occurred in

over-60s

_given

oral

_{anticoagulants}

after

_myocardial

infarction.14

The risks of ICH in

_patients

who have

_already

had a stroke

are rather different. For stroke due to

_ICH,

_{anticoagulants}

are

obviously strongly

contraindicated,

so

early

CT

scanning

to

rule out ICH before

_starting

_{anticoagulant}

treatment for _any

type of stroke is

mandatory. 18-20

However,

a cerebral infarction may be followed

by

spontaneous

haemorrhage

into

the infarcted area, and

anticoagulants

may exacerbate this

tendency

(even

if

_prothrombin

_activity

remains within an

acceptable

therapeutic

range). 111,11,21-2’

The risk of a

"pale"

cerebral infarct

_becoming

a

_{"haemorrhagic"}

infarct is

_highest

in

_patients

with

_large

infarcts or

_hypertension

and,

not

surprisingly,

in

_{patients given}

excessive doses of

anticoagulants. 21-21

The difficulties of

_controlling

anticoagulant

therapy

in stroke

_patients

with AF are

compounded by

the _age of most of the

_patients.

In the OCSP

57/68

_(84%)

of the

_patients

with first strokes in AF were

aged

70 or over and 24/68

_(35%)

were

aged

80 or over.

Although

age did not affect the relative risk of ICH due to

anticoagulants

in the Leiden

_study,l

the absolute risk may

rise _very

_steeply

with

_age.15,26-28

Moreover,

supervision

of

anticoagulants

in

_elderly

_patients

may be difficult:

they

may

be on several other

drugs,

so that interactions _may occur,

drug compliance

may be poor

(especially

after a

stroke);

and

they

may have

difficulty

in

attending

an

_{anticoagulant}

clinic.

Hypertension,

which

_greatly

increased the risk of ICH for

patients

with stroke and

AF;

for

_example,

54% of the OCSP series were

definitely hypertensive (at

least two blood

pressures greater than 160/90 mm

_Hg

recorded before the

stroke),

and in

_Kelley’s

_study29

78% of

_patients

with stroke and AF were

already

on

antihypertensive

drugs

at the time of

admission.

IS A RANDOMISED CONTROLLED TRIAL NEEDED?

As discussed

above,

after oral

_{anticoagulation}

the net

reduction in risk of recurrent

stroke-and,

more

_importantly,

of

_disabling

and/or fatal stroke-could be modest in

_patients

with NRAF. The risk of ICH _may be

_particularly

_high

since

many such

patients

are

elderly

and/or

hypertensive.

A

randomised trial is therefore _necessary to assess the balance of risks and benefits

_{of anticoagulant}

treatment in

_patients

with stroke and non-RHD AF.7,3O A similar

_{study might}

also be

appropriate

for the small

_minority

of

_fibrillating

stroke

patients

who do have

_{RHD, though}

few clinicians would consider such a trial ethical.

WHAT PROPORTION OF STROKE PATIENTS ARE SUITABLE FOR ANTICOAGULATION?

The OCSP data

_{(fig 3)}

_suggest that

_only

13/68

_(19%)

cases

of first stroke with AF were suitable for

anticoagulant

Fig 3-Number of first strokes in AF suitable for anticoagulant therapy in the OCSP.

*Includes five cases ofAF associated with RHD.

tNo CT scan or _{necropsy performed.}

$Some patients had more than one contraindication. _{Hypetension=two _} BP>160/90 mm _Hg recorded _before stroke.

§Severe stroke=hemiplegia, aphasia, and/or coma, survived >72 h; very disabled before stroke=needs assistance to walk and to attend to own _body and/or bedbound.

TABLE

III-LIKELY

NUMBER OF PATIENTS WITH CT-PROVEN ISCHAEMIC STROKE AND NON-RHEUMATIC ATRIAL FIBRILLATION

AVAILABLE FOR CLINICAL TRIAL OF ANTICOAGULANTS Number available in _England and Wales

First strokes in _England and Wales each _year* =96 000

ofwhoml3-3%inAF =12770

of whom 16-2% have non-RHD AF and "suitable for

anticoagulant therapy" = ₂₁₀₀

of whom 50% _might enter a _trialt = ₁₀₅₀

Number avazlable zn _{average datrict general hospital}

(servmg about 250 _OOO/yr)

Number of strokes per year =500

of whom 50% admitted to _hospital =250

of whom 13.3% m AF = ₃₃

of whom 16-2% have non-RHD AF and "suitable for

anticoagulant therapy" = ₅

of whom 50% might enter a trial = ₃

*From OCSP.1

t Previous multicentre trials suggest that about 50% of the _{patients eligible} to enter the trial are not entered for a _variety of reasons _(patient refusal, follow-up

likely to be difficult, &c.).

therapy,

a

_proportion

similar to that

_reported

from

Scandinavia:31 however,

2 of these cases had RHD

_(and

1 of these was

already

on

_{anticoagulants).}

Thus

_only

11/512

_(2%,

95% confidence limits 0 - 8-3’

_2%)

of all first strokes would

have been

_eligible

for a trial

of anticoagulation

in NRAF and

stroke. Such a

study

would not be of direct relevance to 98%

of strokes.

_Nonetheless,

2% of all first strokes is

_equivalent

to

about 2000 cases in

England

and Wales a _year. In

practice,

only

a small

_proportion

of these

_might

enter a randomised

trial

_{(table III).}

Would a trial in

fibrillating

stroke

patients

thus

be feasible?

WHAT SIZE OF SAMPLE IS _REQUIRED FOR A TRIAL OF ANTICOAGULANTS IN STROKE WITH NRAF?

If anticoagulants

can reduce the

frequency

of stroke and/or death

_by

about

30%,

then about

1500

patients

would have to

be randomised and followed _up for a few years if there is to be

a reasonable chance

(90%)

of

getting

a

conventionally

significant

result

_{(p<O’ 05).32}

It would

_probably

be

practicable

to enter

_only

_inpatients,

and our

experience

(table

III)

suggests that a

_{hospital might}

be able to enter

_only

about 2 or 3

_patients

_per

_year,

so well over 100

_{hospitals might}

be

required.

Furthermore,

since all

_patients

would

_require

a CT scan before randomisation to exclude

_ICH,

_only

the limited

number of

_hospitals

in the UK with

_rapid

access to a CT scanner could

_participate,

so it would

probably

be

impossible

to recruit the numbers that

_might

be needed for an

adequate

study.

However,

if the true risk reduction is much better than

one-third,

then much smaller numbers of

_patients

would

suffice;

conversely

if attention was restricted to fatal or

disabling

strokes,

far

_larger

numbers

_might

be

_required.

IS A TRIAL OF ANTICOAGULANTS IN NRAF WORTHWHILE?

A trial that had to recruit

_subjects

_{from many} centres would be difficult to

_organise,

would be

_expensive,

and would

require

considerable effort to ensure strict adherence to the

protocol (especially

with _respect to

_prothrombin

measure-ment for control of

_therapy).

Furthermore,

if the results

would be

_applicable

to

_only

about 2% of all first

_strokes,

from

a

_public

health

_viewpoint

at _least, the value of a trial of

anticoagulants

restricted to stroke

patients

with NRAF seems

less worthwhile than at first.

SHOULD THE TRIAL INCLUDE ALL PATIENTS WITH ISCHAEMIC STROKE?

Since the

_long-term

outcome after ischaemic stroke seems to be similar whether

_patients

are in AF or sinus

rhythm

(table

II)

and since the value

_{of anticoagulants}

in either _{type of}

patient

has not been

_reliably

_{established,33}

there could be a case for

_testing

_{anticoagulants}

in all

_patients

with ischaemic stroke.

_However,

we think that most clinicians would not

have as _{much enthusiasm for such} a trial. Indeed _many

_might

be disturbed at _{the prospect, if} the trial were to be

_positive,

of thousands

of elderly

stroke

_{patients being}

_{given long-term}

anticoagulants.

Furthermore,

the number of CT scans that

would have to be done _may be an

impossible

burden for

Britain’s

_already

stretched CT

_scanning

facilities.’9

ARE THERE OTHER TREATMENTS THAT ARE _SIMPLER, MORE WIDELY APPLICABLE, AND LIKELY TO CONFER USEFUL

BENEFIT?

Death after transient ischaemic attack

_(TIA)

and stroke is

more often due to ischaemic heart disease than to recurrent

stroke.34-36

_Aspirin,

taken

_daily

for months or _{years after}

myocardial

infarction,

reduces the risk of death

_by

about 15% and of further

_myocardial

infarction

_by

about

25%.

Beta-blockers reduce the

_mortality

after

_myocardial

infarction

_by

about

25%.38

_Furthermore,

there is some

suggestion

that

aspirin given

after TIA and mild ischaemic stroke reduces the risk of

_subsequent

death and recurrent

stroke;39

this effect is

being

assessed

_by

the UK TIA

_aspirin

_study

and

_by

a collaborative

_analysis

of

_published

trials.

_Apart

from

simplicity

and wide

_{applicability}

these two _{agents have the}

advantage

that a CT scan _may not _{be necessary before} start of

treatment to exclude ICH-a

_simple

clinical

_scoring

_system

might

be

_{adequate. 21}

WHAT IS THE DESIGN OF THE IDEAL TRIAL?

The

_simplest

trial that would answer most of the

important

questions

(ie,

are

anticoagulants

and

aspirin

each

effective,

and, if so,

which is the more

_effective?)

would be to allocate all stroke

_{patients (AF}

and sinus

_rhythm

_subgroups

can still be

analysed separately)

randomly

to one of three treatments

(placebo, aspirin,

or oral

_{anticoagulants).}

This trial would

require

an 11%

larger sample

than a trial of

_placebo

vs

anticoagulants.

A factorial

_design

would allow beta-blockers

to be tested as well without further

_increasing

the

_sample

size

(table I).

Such a trial is

likely

to be no more

_expensive

in terms

of money or effort than one of

_{anticoagulants}

versus

placebo

but would

_provide

more answers.

CONCLUSIONS

A trial of

_long-term

oral

_{anticoagulants}

in

_patients

with ischaemic stroke and NRAF or in all ischaemic stroke would

perhaps

be done more

_easily

in countries

_(such

as the Netherlands or the

USA)

where a

high

proportion

of strokes

are admitted to

_hospitals

with CT scanners. In the

_UK,

it would be more worthwhile to concentrate collaborative efforts

_(and

limited

_resources)

on the reliable assessment of

simpler,

more

widely practicable

treatments for

_secondary

stroke

_prevention

which

_might

be

_applicable

to all

_patients

with ischaemic

_stroke;

_aspirin

and beta-blockers are two such

agents which we believe could-and should be-tested.

Data from the Oxfordshire _Community Stroke Project formed the basis for this paper and we would therefore like to thank all those who collaborated with

us in that _study. The Oxfordshire _Community Stroke _Project is funded _by the MRC _{with additional support} from the _Chest, Heart and Stroke Association.

Correspondence should be addressed to P. S., Department of Neurology,

Walton _Hospital, Rice Lane, Liverpool L9 lAE.

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