Rules of Evidence and Clinical Recommendations on the Use of Antithrombotic Agents

D.L. Sackett M.D.

hat rules committees for the clinical the thoroughly trials tion the of useless potential

of evidence meet

ought to generate

to apply

when

expert

recommendations

double-blind, case series

randomized
or unblinded,

trials than in uncontrolled open comparisons with series reports and reports not for of patients; with controls with be enthumisinterthe

management of patients? Should only validated results of randomized clinical to avoid or minimize therapy? patients the applicaor harmful benefits to Or, to maximize (including those

contemporaneous hence, the maxim: tend to have

or historical Therapeutic

be admissible

no enthusiasm,

siasm tend to have no controls. The foregoing discussion should preted large who as constituting body have a mandate

possible from unproved remedies), ought a synthesis of the experiences of seasoned clinicians form the basis for such Ample recommendations? precedent exists for the latter approach even

discarding

of uncontrolled observations by clinicians used these agents in an effort to halt the and complications of thromboembolism. of the disorders under consideration here, control trials have never been (and, axand the only of the recomclinical obserit is impor-

when attempts the following that cians 1. forms will the tend

are made to replace it. 3 reasons, the nonexperimental recalled treatment experiences efficacy: responses are to overestimate

However, for evidence clinilikely when follow5 docuin the far than

progression For many randomized

of seasoned more

Favorable

guably, never could be) carried out, information base for generating some mendations comes from uncontrolled vations. What tant, this whenever does mean, possible, however, to base involving controlled

to be recognized and their patients comply up appointments. mented instances groups favorable

remembered with treatments there compliant

by clinicians and keep are already patients exhibited survival)

is that firm risk when

However, in which

recommendato patients) investigations recommen-

placebo
more

of randomized trials outcomes (including

tions (and especially those on the results of rigorously and to be much more

circumspect

their noncompliant companions.2 Because high compliance is therefore a marker for better outcomes, even when treatment is useless, our uncontrolled clinical experiences often will cause us to conclude that compliant therapy. (eg, blood transient pressure when they patients must have been receiving eflicacious

dations rest only on the results of uncontrolled clinical observations. This approach was adopted by the conference participants and led to the definition and adoption of both Levels of Evidence and Grades of Recommendations.
LEVELS OF EVIDENCE

2. Unusual patterns of symptoms ischemic attacks) or signs (eg, high levels) and extreme laboratory test are reassessed even a short time later, toward the more usual, normal result. universal tendency for any treatment (regardless in the interim 3. Routine

The marizing

participants what was

in

this

undertaking, about the

when causes,

sumclinical

results,

known

tend to return Because of this the mean, is initiated and

regression toward of its efficacy) that

course, and management of a given clinical entity, specified the level of evidence that was being used in each case, according to the following classification:

Level
(a) and

will appear efficacious. clinical practice is never their way. shown, clinicians know As a result, both for example, by mock of patients

I: Randomized low false-negative

false-positive

trials

with low false-positive (13) errors (high power)

is meant a positive

blind:

By low

(a) error

both patients and treatment is under effect pectoris ligation8)

success

when active the placebo that angina

trial from now

that

demonstrated

a statistically treatment. randomized statistically and death

significant

benefit

(which

has

experimental been several very risk large, of stroke

For example, there have trials in which aspirin significant among (high reductions patients power) no effect the had any
Therapy

can be relieved and the desire

can cause

internal mammary and clinicians for

efficacy.

produced in the

with is

For the preceding

both parties to overestimate reasons, the consensus

approach

transient ischemic attacks. By low false-negative meant a negative trial of therapy, possibility very narrow

(13) error that

based upon uncontrolled clinical experience risks precipitating the widespread application of treatments that are useless or even harmful. These same treatments are much less likely to be judged efficacious in
2S

demonstrated

yet was large enough of a clinically important 95% confidence limits

2nd ACCP Conference

to exclude benefit (ie, that excluded

on Antithrombotic

Downloaded From: https://publications.chestnet.org/ on 08/13/2013

clinically

important

improvement the recently active drugs was confidence halve with

from

the

test

treat-

Table!-

ment). For example, ized trial of platelet concluded that this disorder. sulfinpyrazone that death sulfinpyrazone and myocardial

completed in unstable not

randomangina for this

Level

The Relation Grades

Level of Evidence
randomized

Between

Levels

of Evidence

and

of Recommendations

Grade
trials

of Recommendation Grade
A

sulfinpyrazone The 95% effect excluded could

efficacious limits on possibility risk

I: Large

with

any practical the

clearcut error)

results

(and low risk of

of cardiac
Level H: Small with uncertain moderate Level Level Level only III: IV: randomized results risk trials (and of error) Grade B

infarction. high false-positive (13) errors (low power) (a) error is meant a trial trend that is not statistically 6 trials of aspirin positive aspirin. power) is that therapy numbers of of a 95% therin (low but generated favoring concluded of small

Level II: (a) and/or

By with high

Randomized trials high false-negative

false-positive positive

to high

Nonrandomized, controls historical case-series Grade C Nonrandomized,

an interesting

contemporaneous controls V: No controls,

significant. following statistically By meant was

For

example,

5 of the trends that because

myocardial nonsignificant

infarction

high false-negative a negative trial not efficacious, yet

(13) error

extremely prognosis
THE

useful but can

information only hint

OF

about

clinical

course

and

patients clinically confidence apy). For completed treatment

limits on

could not exclude the real possibility important benefit (ie, had very wide limits on the effect of experimental example, thrombotic is ineffective,
the treatment

at efficacy.
RECOMMENDATIONS

GRADING

several

trials

of anticoagulants

Finally, timate therapy

Conference recommendations into 3 grades,

participants on the depending use

classified on These (Table and the

their level

ulof of

stroke have concluded when, in fact, the

effect they observed

that such confidence

ranged

of antithrombotic 3 grades 1): prefrrably are: aspirin (2

from virtually eliminating and death to doubling the If holds meta-analysis the promise

subsequent risk of these generally multiple, I overview, concurrent

deterioration outcomes. accepted, it small Level cohort patients agents who comdid

evidence used recommendations Grade more,

to generate them. were as follows

becomes of converting

A: Supported by at least one, Level I randomized trial(s). of grade A recommendations

Examples

II trials into a single, Level Level III: Nonrandomized parisons and did
In this

in transient ischemic attacks (2 statistically positive trials); aspirin in unstable angina statistically significant positive lants in deep vein thrombosis positive trials); and (1 statistically one Level

significant pectoris anticoagusignificant II random-

between contemporaneous not receive antithrombotic

case, the outcomes

of patients

who

receive

trial).
B: Supported trial. B recommendations are: aspirin infarction (5 of 6 trials showed trends); (several only by and trials Level anticoagulants with Ill, positive l1 or V in by at least

(and

complied with not

with) those

antithrombotic

agents

would patients

be

Grade ized

compared who did indication, same are usually

of contemporaneous

(through refusal, noncompliance, contralocal practice, oversight, etc) receive these The in play biases here. historical patients and former cohort comparwho did receive patients (from the who who did not received described in the Introduction

Examples of grade following myocardial nonsignificant myocardial trends). Grade evidence. C: positive infarction Supported

drugs.

Level IV: Nonrandomized isons between current antithrombotic agents same institution In this case, the

or from the outcomes

literature) of patients

Examples of grade agulants for prosthetic

C recommendations heart valves; and

are: anticoanticoagulants

antithrombotics (as a result of a local treatment policy) would be compared with those of patients treated in an earlier era or at another institution (when and where different treatment policies prevailed). To the biases those presented that result in the from Introduction must comparisons be added over inappropriate without reader of patients. controls is simply Such

in atrial fibrillation. It is hoped that advances in our understanding of the mechanisms of these disorders will be matched by more Level I evidence on their prevention and treatment; greater future
Reprint L8N 3Z5

such

advances

will of grade

be

reflected

in

an

everin

time and space. Level V: Case series In this case, the the fate of a group

proportion reports.
requests:

A recommendations

informed series may

about contain

and Biostatistics,

Dr. Sackett, McMaster

Department

University,

of Clinical Epidemiology Hamilton, Ontario, Canada

CHEST

/ 95 / 2 / FEBRuARY,

1989

/ Supplement

3S

Downloaded From: https://publications.chestnet.org/ on 08/13/2013

REFERENCES 1 National ences. 2 Coronary to treatment Drug WL, 26:21 Harper loss, 1-18 Goldberg. patients. Drug Arch and Gen sociotherapy Psychiatry in the aftercare 1973; 28:54-64 Coronary 3 Asher 1973; on weight Institutes 1977-1978; Drug and of Health 1:1-43 Project Project. HW. hunger, Research of N EngI Effect and feeling Group. cholesterol Influence on 1980; chorionic of adherence mortality in the response Consensus Development Confer-

5 Fuller

R, Roth

H,

Long

S. Compliance Dis 1983;

with 36: 161-70

disulfram

treatment

of alcoholism.

Chronic

6 Pizzo PA, Robichaud KJ, Edwards BK, Schumaker C, Kramer BS, Johnson A. Oral antibiotic prophylaxis in patients with cancer; a double-blind randomized placebo-controlled trial. J Pediatr
1983; 7 Sackett Boston: 8 Cobb An blind 102:125-33 DL, Little, LA, evaluation technique. Haynes Brown, CI, N EngI RB, 1985:36, Tugwell 39 DH, 1959; Merendino ligation 260:1115-18 KA, by Bruce BA. a doubleP Clinical epidemiology.

Med

303:1038-41 gonadotropin Am

of human

of well-being.

Clin

Nutr

Thomas

Dillard

4 Hogarty GE, of schizophrenic

of internal-mammary-artery

Med

4S

2nd ACCP

Conference

on Antithrombotlc

Therapy

Downloaded From: https://publications.chestnet.org/ on 08/13/2013