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2S 2n d ACCP Con fe ren ce on A ntith rom bo tic Therapy

R u les o f E v iden ce and C lin ica lR ecomm enda tio ns on the U se o fA n tith rom bo tic A gen tsD .L . Sa cke tt M .D .

ha t ru les o f ev idence o ugh t to app ly w hen ex pe rtcomm ittee s m ee t to g en era te recomm enda tion s

fo r the clin ica l m anagem en t o f p atien ts ? Shou ld on lyth e tho ro ugh ly va lida ted resu lts o f random ized c lin icaltr ia ls be adm iss ib le to av o id o r m in im ize the ap p lica -tio n o f use le ss o r ha rm fu l the rapy? O r, to m ax im izeth e p o ten tia l bene fits to pa tien ts ( inc lud in g tho sep ossib le from unp ro ved rem ed ie s) , oug h t a sy n thesiso f the ex pe riences o f seaso ned c lin ic ians fo rm the basisfo r su ch recom menda tions?

Am ple p reced en t ex is ts fo r the latte r ap proach evenw hen a ttem pts are m ade to rep lace it. How ever , fo rth e fo llow ing 3 reason s, the non ex pe rim en tal ev idenceth at fo rm s th e reca lled exp eriences o f seaso ned clin i-c ians w ill tend to ove res tim a te e fficacy :

1 . F av orab le trea tm en t respon ses a re m ore like lyto be recog n ized an d rem em bered b y clin icians w henth eir pa tien ts com ply w ith treatm en ts an d keep fo llow -up ap po in tm en ts . H ow eve r, th ere a re a lready 5 do cu -m en ted instances in w hich com plian t pa tien ts in theplacebo group s o f rand om ized tr ia ls ex h ib ited fa rm o re favo rab le o u tcom es (inc lu d ing su rv iva l) thanthe ir non com plian t com pan ion s.2 B ecause h ig h com -p liance is th ere fo re a m arke r fo r be tte r ou tcom es,even w hen trea tm en t is use le ss , o u r un co n tro lledc lin ica l ex pe riences o ften w ill cau se us to conc lud etha t com plian t pa tien ts m u st h av e been rece iv inge flicacio us the rap y .

2 . U nu sua l pa tterns o f sym ptom s (eg , tran sien tisch em ic a ttack s) o r sign s (eg , h ig h b lo od pres su relev els ) an d ex trem e labora to ry tes t re su lts , w h en th eyare rea sse ssed even a short tim e la ter , ten d to re tu rntow ard th e m ore u sua l, no rm al re su lt. B ecau se o f th isun iv ersa l tend ency fo r reg re ssion tow ard the m ean ,an y trea tm en t (rega rd les s o f its efficacy ) tha t is in itia tedin the in te rim w ill ap pear e ff icac io us.

3 . R ou tine c lin ical p rac tice is n eve r b lind : an dbo th pa tien ts and th e ir c lin ic ian s kn ow when ac tivetreatm en t is und er w ay . A s a re su lt, bo th the p laceboe ffec t (w h ich h as sh ow n , fo r exam p le , tha t ang in ap ec to r is can b e re liev ed b y m ock in terna l m amm arylig atio n8) an d th e desire o f p a tien ts and c lin ic ian s fo rsuccess can cause bo th partie s to overes tim ate e fficacy .

For th e p reced in g reasons , th e co nsensu s ap proachbased upon uncon tro lled c lin ical expe rien ce risksp recip itatin g the w id esp read app lica tio n of trea tm en tstha t a re usele ss o r even h arm fu l. T hese sam e trea t-m en ts a re m uch le ss like ly to be jud ged e ff icac iou s in

d oub le-b lin d , rand om ized tria ls than in unco n tro lledcase se ries o r unb linded , o pen com pariso ns w ithco n tem po raneou s o r h isto rica l se r ies o f p atien ts ;h ence, th e m ax im : Th e rapeu tic reports w ith con tro lstend to have no en th usia sm , and repo rts w ith en thu -sia sm ten d to have no con tro ls .

T he fo rego in g d iscus sion sh ou ld no t be m isin ter-p re ted as cons titu ting a m and ate fo r d is ca rd ing thela rge b ody o f uncon tro lled o bse rv a tio ns by clin iciansw ho have used these agen ts in an effo rt to h alt thep rog re ssion an d com p lica tio ns o f th rom boem bolism .Fo r m any o f th e d iso rd ers u nde r con side ratio n h ere ,random ized con tro l tria ls h av e n eve r been (and , ax -guab ly , neve r cou ld b e) ca rried o u t, an d the o n lyin fo rm atio n base fo r gene ra ting som e of th e recom -m enda tion s com es from un con tro lled clin ical o bse r-vat ions.

W hat th is d oes m ean , h ow ev er , is th a t it is im por-tan t, w h en ev er pos sib le , to b ase f irm recom m end a-tions (and esp ec ia lly tho se invo lv ing risk to pa tien ts)on the re su lts o f r igo rous ly con tro lled inv es tiga tionsand to b e m uch m ore c ircum spec t w hen recom m en-da tion s re st on ly o n the re su lts o f u ncon tro lled clin ica lobserva tion s. Th is app ro ach w as ad op ted by the co n-ference p artic ipan ts and led to the de fin ition andadop tion of bo th L eve ls o f E v idence an d G rades o fRecommend a t i o n s .

LEVELS O F EVID ENCE

T he pa rtic ipan ts in th is u nde rtak ing , w hen sum -m ariz ing w hat w as known ab ou t the causes, c lin ica lcou rse , an d m an agem en t o f a g iven c lin ica l en tity ,spec ified the lev el o f ev id en ce tha t w as b ein g used ineach case , acco rd ing to the fo llow in g c la ss ifica tio n :Leve l I: R an dom ized tr ia ls w ith lo w false-posi t ive(a ) and low fa lse -nega tiv e (13 ) er rors (h igh pow er)

By low fa lse -p ositive (a ) e rro r is m ean t a pos itivetria l th a t dem onstrated a s tatis tic a lly sign ifican t bene fitf rom expe rim en ta l trea tm en t. F o r exam p le , the re h av enow been seve ra l rand om ized tria ls in w h ich asp irinp rodu ced ve ry la rge , s ta tis tica lly sig n if ican t redu c tio nsin the risk o f strok e an d dea th am ong p atien ts w ithtrans ien t ischem ic attacks.

B y low fa lse -neg ativ e (13 ) e rro r (h ig h p ow er) ism ean t a nega tive tria l th a t dem onstra ted no effec to f the rapy , ye t w as la rg e enough to ex clu de thepo ssib ility o f a c lin ica lly im portan t bene fit ( ie , ha dve ry na rrow 95% confidence lim its th at exc lud ed an y

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CHEST / 95 / 2 / FEBRuARY, 1989 / Supp lem en t 3S

c lin ica lly im po rtan t im p ro vem en t from th e te st trea t-m en t) . F o r ex am ple , th e recen tly com ple ted ran dom -ized tr ial o f p la tele t activ e d rugs in un stab le ang inacon clu ded tha t su lfin py razone w as n o t e ff icac ious fo rth is d iso rde r. Th e 9 5% con fid en ce lim its o n th issu lf inp yrazon e effec t ex clu ded an y practica l p ossib ilityth at su lfin pyrazo ne cou ld ha lve the risk o f ca rd iacd ea th and m yocard ia l in fa rc tion .L eve l II : R an dom ized tr ia ls w ith h ig h fa lse -positiv e(a ) a nd /o r h igh fa lse -nega tiv e (13 ) e rro rs (low pow er)

By h igh fa lse -pos itive (a ) e rro r is m ean t a t r ialw ith an in te res ting pos itive trend tha t is no t statisticallysign ifican t. F o r ex am ple , 5 o f th e 6 tr ials o f a sp irinfo llow ing m yo card ia l in farc tion g en era ted positiv e b u tsta tis tic ally no nsign ifican t trends fav orin g asp ir in .

B y h igh fa lse -n eg a tive (13 ) e rro r (low pow er) ism ean t a nega tive tria l tha t co nc luded tha t th e rapyw as no t efficac ious, ye t because o f sm a ll num bers o fp atien ts cou ld no t exc lud e the real p ossib ility o f ac lin ica lly im po rtan t bene fit ( ie , h ad v ery w ide 95%con fid en ce lim its on th e effec t o f ex pe rim en tal th e r-apy ). F o r ex am ple , s ev era l tr ia ls o f an ticoagu lan ts incom ple ted th rom bo tic s trok e have conc lud ed tha t su chtrea tm en t is ine ffec tive , w hen , in fact, th e confidencelim its o n the trea tm en t e ffec t they ob served ran gedfrom v irtua lly elim ina ting sub sequen t de ter io ra tio nand d ea th to d oub ling the risk o f these o u tcom es.

If m eta -an aly sis b ecom es gene rally accep ted , itho lds the p rom ise o f con ve rtin g m ultip le , sm a ll L ev elII tria ls in to a sin g le , L eve l I ov erv iew ,L eve l III : N onrand om ized concur ren t coh ort com -pa rison s be tw een con tem poraneou s p a tien ts w ho d idan d d id no t rece ive an tith rom bo tic a gen ts

In th is case , the ou tcom es of pa tien ts w ho rece ive(an d com plied w ith ) an tith rom bo tic agen ts w ou ld becom pared w ith th ose o f con tem poraneous pa tien tsw ho d id no t ( th roug h re fu sa l, no ncom pliance, co n tra -ind ica tion , lo ca l p rac tice , ov ersigh t, e tc) rece ive thesesam e d ru gs. Th e b ia se s desc r ibed in th e In trod uc tiona re usua lly in p lay he re.L eve l IV : N onrand om ized h is to rica l coh ort com pa r-ison s be tw een cu rren t pa tien ts w ho d id rece ivean tith rom bo tic agen ts and fo rm er pa tien ts ( from th esam e institu tio n o r from th e lite ra tu re ) w ho d id no t

In th is case , the ou tcom es of pa tien ts w ho rece iv edan tith rom bo tic s (a s a re su lt o f a l oca l trea tm en t po licy )w ou ld be com pared w ith th ose o f p atien ts treated inan ea rlie r e ra o r a t ano the r in stitu tion (w hen andw here d iffe ren t trea tm en t p o lic ies p reva iled ). T o th eb ia se s p resen ted in th e In tro duc tion m u st be add edthose th at re su lt f rom in ap propria te com pariso ns ov ertim e an d space.L evel V : C a se se rie s w ithou t con tro ls

In th is ca se , the reade r is sim p ly in fo rm ed abou tthe fa te o f a g rou p of p atien ts . S uch se rie s m ay con ta in

Tab le!- The R e la tio n B etw een L eve ls o f E vidence an dGrades of Recommenda t ions

L eve l o f E vidence G ra de o f R ec om m en da tio nL eve l I : La rge random ized tria ls with

c lea rcu t resu lts (and low risk ofe r ro r )

G rade A

L ev el H : Sm all ran dom iz ed tria lsw ith uncerta in resu lts (a ndm ode rate to h igh r isk of e rro r)

G rad e B

L evel I II: N onrand om ize d,c on tem poraneou s contro ls

Level IV : N onrand om ized , h is to r ica lcon tro ls

Level V : N o con tro ls, case-serie son ly

G rad e C

ex trem e ly u sefu l in fo rm atio n abou t c lin ica l cou rse an dprog nos is bu t can on ly h in t at efficacy .

TH E GRAD ING OF RECOMM ENDATION SF in ally , C onference pa rtic ipan ts cla ssif ied th eir u l-

tim a te recomm enda tions on the use o f an tith rom bo ticthe rap y in to 3 grades, depend ing o n the lev e l o fev idence u sed to g ene ra te them . T hese 3 grad es o frecom m enda tion s w ere as fo llow s (T ab le 1 ):G rade A : Sup ported by a t leas t one , and pre frra blym ore , L eve l I rand om ized tr ia l(s) .

E xam p les o f g rade A recomm enda tions a re : a sp ir inin tran sien t ischem ic attacks (2 s ta tis tic a lly sign ifican tpo sitive tria ls) ; asp irin in uns tab le ang in a pec to r is (2statis tica lly sign if ican t po sitive tr ia ls); and an ticoag u-lan ts in deep ve in th rom bosis (1 sta tis tica lly sig n ifican tposi t ive t r ia l) .G rade B : Sup por ted b y a t least one L eve l II rand om -ized tr ia l.

E xam p les o f g rad e B recomm enda tions a re: a sp ir info llow ing m yoca rd ial in farc tion (5 o f 6 tr ia ls sh ow ednonsign ifican t pos itive trends ); an d an ticoagu lan ts inm yo ca rd ia l in fa rc tion (sev e ra l tria ls w ith p ositiv etrends) .G rade C : S upp orted on ly by L eve l Ill, l1 o r Vev idence .

E xam p les o f g rad e C recomm enda tions a re: an tico -agu lan ts fo r p ro sthe tic hea rt va lves; an d an tico agu lan tsin a tr ial f ib rilla tion .

It is h op ed tha t advances in our u nde rstan d ing ofthe m ech an ism s o f th ese d iso rd ers w ill b e m a tch ed bym o re Leve l I ev id en ce o n the ir p reven tio n and treat-m en t; such adv ances w ill be ref lected in an ev er-g reate r p rop ortion of g rad e A recom m end atio ns infu tu re reports .Rep r in t r equ ests: D r. Sac ket t, D epar tm en t of C lin ica l E pid em io lo gyan d B ios ta t istics, M cM aster Univers i ty , H am ilton , O nta rio , Cana d aL8N 3Z 5



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4S 2n d ACCP Con fe rence on A ntith ro mb otlc T he ra py

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4 H og arty G E , G old be rg . D rug and soc io th erapy in th e afte rca reof sch izo phren ic p atien ts. A rch G en Psy ch iatry 19 73; 28 :54 -64

5 F uller R, Ro th H , Long S . C om plianc e w ith d isu lfram tre atm en to f a lc o ho li sm . J C hronic D is 19 83; 36 : 1 61-70

6 P izzo PA , R ob ichaud K J, E dw ards BK , Schum ak er C , Krame rB S, J oh ns on A . O ra l an t ib io tic p rop hylax is in pat ien ts w ith c anc er;a d o ub le -b li nd ran dom iz ed placebo-con tro lled tria l. J Pediatr1 98 3; 1 02 :1 25 -3 3

7 Sacket t D L , H ayn es R B , Tugw ell P C lin ica l e p id em io logy .B oston : L itt le , B row n , 1 985 :36 , 3 9

8 Cobb LA , Thom as C I, Dil la rd DH , M erend ino K A , B ru ce BA .A n evaluation o f in tern al-m amm ary -artery ligation by a double -b lin d tech n iq ue. N EngI J M ed 1959; 2 60 :11 15-18


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Articulo Qx Cabeza