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1286 JACC Vo l. 25, No. 6May 1995:1286-92

I n c i d e n c e a n d F o l lo w U p o f B r a u n w a l d S u b g r o u p s i n U n s t a b l eA n g i n a P e c t o r i sA D D Y J . M . V A N M I L T E N B U R G - v A N Z I J L , M D , P H D , * M A A R T E N L . S I M O O N S , M D , P H D , F A C C , *R I N U S J . V E E R H O E K , M D , ? P A T R I C K M . M . B O S S U Y T , M S c , P H D *:I :Rotterdam and Amsterdam, The Netherlands

Object ives This s tudy was pe rfor me d to e s tabl i sh the pr ogn os i so f p a t i e n t s w i t h u n s t a b l e a n g i n a w i t h i n t h e s u b g r o u p s o f t h eBraunwald c lass if icat ion.

B a c k g r o u n d A m o n g m a n y c l a s s if i c a ti o n s o f u n s t a b l e a n g i n a ,the Braunwald c lass if icat ion is frequently used. However , theinc ide nc e and r i sk for e ac h subgr oup in c l in ic a l pr ac t ic e have no tbe e n e s tabl i she d .M e th o d s Pr ospe ct ive data for 417 c onse c ut ive pat ie nt s admit -t e d for suspe c te d uns table angina we r e analyz e d . Pat ie nt s we r eclass if ied acco rdin g to Braunw aid cr iter ia an d fol lowed up for 6m onth s. Survival , infarct .free survival and infarct-free survivalw i thout inte r ve nt ion ar e r e por te d for e ac h c las s .

Resu l ts Afte r in-hospi ta l obse r vat ion the f inal d iagnos i s wasac ute myoc ar d ia l in far c tion in 26 pat ie nt s (6 ) , nonc o r onar yc he s t pain in 109 (26 ) and def in it e uns table angina in 282 (68 ) .Recurrence of chest pa in was s ignif icantly different for the differ-ent severity c las ses (28 , 45 an d 64 for c lasse s I [acce leratedangina[ , I I [ subac ute angina at r e s t ] and I I I [ac ute angina atrest] , respect ive ly) but not for c l inical c ircum stance s (49 and

53 for c las se s B [primar y uns table angina] and C [pos t infar c-t ion uns tab le an gina] , r e spe c tive ly) . S ix-m onth a nd infarc t -f r eesurvival (96 and 88 , respect ive ly) were not s ignif icantly differ-ent between severity c lasse s but were signif icantly different (p =0 .01) be twe en c las se s B (97 and 89 ) and C (89 and 80 ) .Infarc t -f r ee sur vival w i thout inte r ve nt ion w as be s t for c las s I I(72 ) , in te r me diate for c las s I (53 ) and wor s t for c las s I I I(35 ) . In mul t ivar iate analys i s , e lde r ly age , male ge nde r ,hype r te ns ion , c las s C and m axima l ( intr ave nous ) the r apy we r einde pe nde nt pr e dic tor s for de ath; e lde r ly age and c las s C forinfarct-free survival; and m ale gender , c las s III , c lass C, electro-c ar diogr aphic c hange s and maximal the r apy we r e as soc iate d w i thinfarct-free survival without intervention.

Con c l u s i o n s Br aunwald c las s i f i c at ion i s an appr op r iate instr u-m ent to pred ict outc om e. Risk strat if icat ion by these cr iter iaprovides a tool for patient se lect ion in c l inical tr ials and fore valuat ion of t r e atme nt s t rate gie s .

J Am Coil Cardiol 1995;25:1286-92)

T h e c l i n i c a l s y n d r o m e u n s t a b l e a n g i n a p e c t o r i s e n c o m p a s s e s av a r i e t y o f c l in i c al p r e s e n t a t i o n s o f t r a n s i e n t e p i s o d e s o f m y o -c a r d i a l is c h e m i a . T h e s e e p i s o d e s a r c c a u s e d b y o b s t r u c t i o n o fc o r o n a r y f l o w b y d if f e r e n t p a t h o p h y s i o l o g i c m e c h a n i s m s , i n -c l u d i n g i n t r a c o r o n a r y a t h e r o m a t o u s p l a q u e r u p t u r e , p l a t e l e ta g g r e g a t i o n , t h r o m b u s f o r m a t i o n a n d i n c r e a s e d v a s o m o t o rt o n e ( 1 , 2 ) . O t h e r t e r m s t h a t h a v e b e e n u s e d t o d e s c r i b e t h es y n d r o m e , s u c h a s i m p e n d i n g m y o c a r d i a l i n f a r c t i o n , p r e i n f a r c -t i o n a n g i n a , a c u t e c o r o n a r y i n s u f f ic i e n cy o r i n t e r m e d i a t e c o r -o n a r y s y n d r o m e ( 3 ) , i n d i c a t e c o n c e r n f o r p r o g r e s s i o n t o m y o -c a r d i a l i n f a r c t i o n , w h i c h h a s b e e n r e p o r t e d t o o c c u r i n 7 % t o1 6 % o f p a t i e n t s ( 4 - 6 ) . T h e r i sk in a g i v e n p a t i e n t d e p e n d s o nt h e a c t u a l p a t h o p h y s i o l o g y a n d c l i n i c a l p r e s e n t a t i o n ( 6 - 1 3 ) .

From the *T horaxcenterand Depa rtment of Public Health Services. Centerfor Clinical Decision Sciences, Erasm us Universityand tS int Franciscus Gast-huis, Ro tterdam; and :~Department of Clinical Epidemiologyand Biostatistics,Academic Hospital, Am sterdam, The N etherlands. This study was supported bya grant from the Netherlands Health Research Promotion Programme SGO),Gravenhage and Erasmu s University. Rotterdam , The N etherlands.Manuscript received May 31, 1994: revised manuscript received Octo ber 3,1994, accep ted Jan ua~ 4, 1995.Address for correspondence: Dr. Ma arten L. Simoons,Thora xcenter Bd 434,University Hospital Rotterdam Dijkzigt Dr. M olewaterplein40, P.O. Box 1738,3000 DR Rotterdam , The Netherlands.

T o r e c o g n i z e g r o u p s o f p a t i e n t s w i t h d i f f e r e n t l e v e l s o f r is k , ac l a s s if i c a ti o n o f u n s t a b l e a n g i n a w a s d e s c r i b e d b y B r a u n w a l d( 1 4 ). H o w e v e r , t h e p r e c i s e r i s k o f s u b g r o u p s a c c o r d i n g t o t h isc l a s s if i c a ti o n h a s n o t b e e n e s t a b l i s h e d . I n f a c t , fe w d a t a a r ea v a i l a b l e o n t h e p r o g n o s i s o f a w i d e s p e c t r u m o f p a t i e n t s w i t h

u n s t a b l e a n g i n a b e c a u s e m o s t r e p o r t s a d d r e s s s p e c i fi c s e -l e c t e d s u b g r o u p s ( 8 , 1 2 , 1 5 - 1 8 ) , w h i c h m a k e s c o m p a r i s o n b e -t w e e n s t u d i e s d i f f i c u l t .

T o e s t a b l i s h t h e i n c i d e n c e a n d p r o g n o s i s o f t h e v a r i o u ss u b g r o u p s o f u n s t a b l e a n g i n a a s d e f i n e d i n t h e B r a u n w a l dc l a s s i f i c a t i o n , w e a n a l y z e d 4 1 7 c o n s e c u t i v e p a t i e n t s w h o w e r ea d m i t t e d f o r c h e s t p a i n o f s u s p e c t e d i s c h e m i c o r ig i n , w i t h o u ts i g ns o f a c u t e i n f a r c t i o n o r o t h e r d i s e a s e s a t t h e t i m e o fa d m i s s i o n . T h e d i a g n o s t i c a n d t h e r a p e u t i c p r o c e d u r e s u s e d i nv a r i o u s s u b g r o u p s w e r e r e c o r d e d a s w e l l a s t h e i n c i d e n c e o fe v e n t s b o t h i n h o s p i t a l a n d d u r i n g 6 m o n t h s o f f o ll o w - u p ,i n c l u d in g d e v e l o p m e n t o f m y o c a r d i a l i n f a r c t io n , m o r t a l i t y a n dt h e n e e d f o r r e v a s c u l a r i z a t i o n p r o c e d u r e s .

M e t h o d sP a t i e n t s e l e c t i o n a n d d e f i n i t i o n s . A p r o s p e c t i v e r e g i s t r y

w a s m a i n t a i n e d i n t w o h o s p i t a l s i n R o t t e r d a m , T h e N e t h e r - 1995 by the Am erica n Co llege of Cardit~lt~g~. 0735-1097/95/$9.500735-1097(95)00009-S

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JACC Vol. 25 No. 6 VAN MILTEN BURG -vAN ZIJ L ET AL. 287May 1995:1286-92 PROGN OSIS OF UNSTABLE ANG INA SUBGR OUPS

lands, du ring a 7-mo nth period in 1988 and 1989. All pat ientsprimari ly admit ted for suspected un s table angina, accord ing tothe a t tending physic ian, were included in the regis try. Theinitial diagnosis, suspec ted uns tab le angina , was m ade im m edi -ate ly on admission on th e bas is of a his tory of ches t pain a t res tor a t minimal exert ion, probably of ischemic origin, withoute lec t roca rd iograph ic (ECG ) s igns o f acu te in fa rc tion o r s ignsof other causes of ches t pain, such as dissect ing aneurysm orarrhythmia. ST -T wave changes were not re quired f or inclu-s ion. Secondary referra ls from other hospi ta ls for furthertreatment were excluded.A f i n a l diagnosis was es tabl ished us ing subsequ ent inform a-t ion acquired du ring admiss ion, including the oc curre nce orabsence o f new ep i sodes o f ches t pa in , ECG changes o relevated serum enzyme levels . The major diagnost ic groupswer e acute myo cardial infarct ion, defini te uns table angina andextraco ronary or nonspecif ic disease (oth er) (1,19). Th e f inaldiagnosis, de f in i te uns tab le a ngina , was based on the eva lua t ionof sym ptom s and on the do cum en ta t ion o f ECG changes ( seeData col lect ion) during in-hospi ta l observat ion or exercisetesting. Myocard ia l in farc t ion was de f ined a s the o ccur rence o fserum c reat ine kinase levels above twice the local upp er l imito f norm a l . The t im e of onse t o f in fa rc t ion was de te rm inedfrom analys is of his tory and ECG and enzyme changes .P a t i en ts who deve loped recur ren t ang ina l pa in ->24 h a f t e rmyocardial infarct ion were c lass if ied as having pos t infarct ionangina.

All pat ients we re c lass ified a t admiss ion, and for pat ientswith definite unstable angina, a final classification was appliedat the t ime when the decis ion for defini te therap y was mad e(corona ry in te rven t ion or con t inua t ion on m edica l the rapy) ,according to the c l inical aspects as defined by Braunw ald forclassification of unstable angina (14):Severity . New onse t o f s eve re o r acce le ra ted ang ina wi thou tpain a t res t c lass I =- accelerated ang ina) angina a t res t but no twi th in the p receed ing 48 h c lass H = subacute angina a t res t)or an gina a t re s t within 48 h c l a s s I l l = acute angina a t res t) .Clin ica l c i rcumstances . Uns tab le ang ina s econdary to anextracardiac condit ion c lass A = second ary uns table angina),ang ina deve loped in the absence o f ex t raca rd iac condi t ionc lass B = pr im ary uns tab le ang ina ) o r deve loped shor t ly a f te racute myocardial infarct ion c lass C = po st infarct ion uns tableangina). Pat ients with c lass A unstable an gina were ex cluded atadmission.

Elec trocard iographic changes . Electrocardiographic changeswere scored as present or absent.

Medica l t rea tment in tens i ty . N o n e o r o n e o f t h e m a j o rant ianginal drugs, ni t ra tes , beta-ad renergic and calcium chan-nel blocking age nts (minimal thera py); more th an on e of thesedrugs (extens ive oral therap y); or use of ant ianginal therapy,including intravenous ni t ra tes (maximal therapy).

D a t a c o l l e c ti o n Th e data were prosp ect ively col lected withpart icular a t tent ion to various decis ion moments during apat ient ' s hospi ta l s tay. Demographic data , his tory and charac-teris tics o f presentat ion w ere reco rded at admission. A log waskept of new pain episodes , new infarct ions or death and of

diagnost ic and therapeut ic measures , such as ECGs, exercisete s t s , m edica t ion and in te rven t ions . The ECGs were codedwith respect to the prese nce or absence o f Q waves , s igns of leftven t r i cu la r hype r t rophy o r in t raven t ri cu la r conduc t ion d is tu r -bances (20). The ST segment was scored as ST elevat ion ordepress io n _>0.1 mV or T wave invers ion, o r both. Th e EC Gchanges were de f ined a s add i t iona l S T e leva t ion /depres s ion->0.1 mV or T w ave deviat ion _>0.1 mV versus that o n thebasel ine ECG, without pain.

Fol low-up data . Fol low-up data after discharge were ac-quired by review of the c l inical records or through a s impleques t ionna i re s en t to the gene ra l p rac t i tione r . F o l low-up da tacou ld be ob ta ined fo r 407 pa t ien t s (97%) . Th e occur rence o fnew pain episodes , myocardial infarct ion, death or any coro-nary intervent ion (coronary angioplas ty or bypass) was re-corded unt i l 6 months after admiss ion. Combined end pointsare prese nted in terms of survival withou t myocardial infarc-t ion and survival witho ut infarct ion or revascularizat ion.

Stat i s t i ca l ana lys i s P a t ien t g roups were com p ared wi th aStude nt t tes t for cont inu ous variables and a chi-square tes t fordiscrete variables. Th e probabil i ty of survival, survival withoutinfarct ion and survival without infarct ion or revascularizat ionwas e s t im a ted us ing the Kaplan-Meie r m e thod . Di f fe rencesbetwe en curves were analyzed with log-rank tests . A s tepwisepropor t iona l haza rds m ode l was used to s e lec t p red ic to rs o f(even t-free) survival , specif ical ly to re la te the v arious Bra un-wald classes to prognosis. T he following variables w ere consid-ered: age, gender, his tory of myocardial infarct ion, hyperten-sion, Braun wald classes I to III (severity) an d B and C (clinicalc i rcum s tances ) , ECG changes and in tensi ty o f m edica l t rea t -ment . Two-level variables were coded as indicator variables ,assuming 1 i f the p rop erty a t issue was presen t an d 0 otherwise .Three-lev el variables were cod ed with two separa te indicato rvariables.

R e s u l t sB a s e l i n e c h a r a c t e r i st i c s A tota l of 417 pat ients were ad-

mit ted for observat ion for suspected uns table angina. Thisini t ia l diagnosis was supported by an abnormal repolarizat ionpa t t e rn on adm is sion or by dynam ic EC G changes dur ing orshort ly after pain in 214 pat ients . In 203 pat ien ts the diagnosisof suspected uns table angina was based on his tory a lone.Dem ograph ics , his toric data and the c lass ificat ion of uns tableangina a t admiss ion are presented in Table 1. There was nodifference in age b etween pat ients with a f inal diagnosis ofuns table angina, myocardial infarct ion or ches t pain of othercauses . Pat ients with uns table an gina mo re ofte n had a his toryof docum ented coro na ry a r t e ry d is ease. Acute ang ina a t re s t(c lass III) was present in the m ajori ty of pat ients (n = 309)(74%). In con t ra s t , on ly four pa t ien t s were adm i t t ed w i thou tpain in the last 48 b be fore adm ission (class II). Patients with afinal diagnosis of ches t pain of other causes bad fewer ECGchanges and less intensive medical treatm ent be fore admission.

Among the 109 other pat ients (26%) with a f inal diagnosisof ches t pain of other causes , in 25 pat ients an extracoronary

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1 2 8 8 V AN M I L T E N B U R G - v A t , Z I J L E T A L . J A C C V o l . 2 5 , N o . 6P R O G N O S I S O F U N S T A B L E A N G I N A S U B G R O U P S M a y 1 99 5:1 28 6- 92

Table 1. Character istics of 417 Study Patients in Relation to Final DiagnosisF i n a l D i a g n o s i sI n i t ia l D i a g n o s i s

o f S u s p e c te d A M I U A P O t h e rU A P ( n - 4 1 7 ) ( n = 2 6 ) ( n = 2 8 2 ) ( n = 1 0 9 )

D e m o g r a p h i c sA ge (yr) 62 _+ 13 62 _+ 13 62 _+ 12 61 -+ 14M al e ge nd er 276 (64 ) 20 (77 ) 181 (64 ) 66 (61 )

H i s t o r yHy per t ens i on 152 (36 ) 10 (38 ) 102 (36 ) 40 (37 )Di a bet e s me l l i t u s 49 12 ) 2 (8 ) 37 (13 ) 10 (9 )H y p e r c h o l e s t e r o l e m i a 5 9 ( 1 4) 4 ( 1 5) 4 7 ( 1 7 ) 8 ( 7 )C u r r en t sm ok i ng 142 (34 ) 8 (31 ) 100 (35 ) 34 (31 )Fam i l y h i s t o ry o f C A D 151 (36 ) 4 (15 ) 113 (40 ) 34 (31 )*M yoca rd i a l i n f ar c t i on 193 (46 ) 10 (38 ) 142 (50 ) 41 (38 )PT C A 51 (12 ) 1 (4 ) 45 (16 ) 5 (5 )*C A B G 63 (15 ) 2 (8 ) 51 (18 ) 10 (9 )*

Severi ty 'C l ass 1 104 (25 ) 3 (12 ) 78 (28 ) 23 (21 )C l a s s I I 4 ( 1 ) - - 4 ( 1 ) - -C l ass I I I 309 (74 ) 23 (88 ) 200 (71 ) 86 (79 )C l i n i c a l c i r c u m s t a n c e sC la s s A . . . .C l ass B 382 (92 ) 26 (100 ) 248 (88 ) 108 (99 )C l ass C 35 (8 ) - - 34 (12 ) 1 (1 )*

E C G a b n o r m a l i t i e sNo 203 (49 ) 7 (27 ) 110 (39 ) 86 (79 )Ye s 214 (51) 19 (73) 172 (61) 23 (21)*

I n t e n s it y o f t r e a t m e n t b e f o r e a d m i s s io nM i n i ma l 303 (73 ) 18 (69 ) 189 (67 ) 96 (88 )Ex t e ns i ve o r a l 114 (27 ) 8 (31 ) 93 (33 ) 13 (12 )*

* p < 0 . 05 f o r c o m p a r i s o n a m o n g t h e th r e e p a t i e n t g ro u p s . D a t a p r e s e n t e d a r e m e a n _+ S D o r n u m b e r ( ) o f p a ti e n t s. A M I - a c u t e m y o c a r d ia l in f a r c ti o n ; C A B G =c o r o n a r y a r t e r y b y p a s s g r a f t in g ; C l a s s A = s e c o n d a r y u n s t a b l e a n g i n a ; C la s s B = p r i m a r y u n s t a b l e a n g i n a ; C l a s s C = p o s t i n f a r c t i o n a n g i n a ; C l a s s I = a c c e l e r a t e d a n g i n a ;C l a s s I I = s u b a c u t e a n g i n a a t r e s t ; C l a s s I I I = a c u t e a n g i n a a t r e s t ; E C G = e l e c t r o c a r d i o g r a p h i c ; E x t e n s i v e o r a l = m o r e t h a n o n e a n t i a n g i n a l d r u g ( s e e M e t h o d s f o rd e t a i l s ); F a m i l y h i s to r y o f C A D = c a r d i a c d e a t h b y i n f a r c t i o n a t > 6 0 y e a r s o l d in f ir s t - o r s e c o n d - d e g r e e r e l a ti v e [ C A D = c o r o n a r y a r t e r y d i s e a s e ] ;H y p e r c h o l e s t e r o l e m i a = s e r u m c h o l e s t e ro l > 6 . 5 m m o l , qi te r o r c u r r e n t tr e a t m e n t ; H y p e r t e n s i o n - b l o o d p r e s s u r e > 1 6 0 /9 0 m m H g o r c u r r e n t tr e a t m e n t ; M i n i m a l =n o n e o r o n e o f t h e m a j o r a n t i a n g i n a l d r u g s , n it r a t e s , b e t a - b l o c k e r s a n d c a l c i u m c h a n n e l b l o c k e r s ; P T C A = p e r e u t a n e o u s t r a n s l u m i n a l c o r o n a r y a n g i o p l a s ty ; U A P =u n s t a b l e a n g i n a p e c t o r i s .

cause was found: ga l lb ladder and l iver d isease ( in 2) , gas tro-in tes t ina l problems ( in 4) , musculoske le ta l pa in ( in 2) , hyper -tens ion ( in 4) , hear t f a i lure ( in 6) , va lvula r d isease ( in 2) ,a r rhythmias ( in 3) , ca rd iomyopathy ( in 1) and per icard i t is(in 1).

C l i n i c a l c o u r s e d u r i n g h o s p i t a l s t a y Patients w ith defi-nite unstable angina. I n 2 8 2 p a t i e n t s ( 6 8 % ) , 2 1 0 o f wh o m( 7 4 %) s h o we d n e w ECG c h a n g e s , a d e f in i t e d ia g n o s i s o fu n s ta b le a n g ina w a s ma d e b e tw e e n a d mis s io n a n d th e d e c i s io nb e tw e e n c o r o n a r y in te rv e n t io n a n d c o n t in u a t io n o f me d ic a lth e r a p y . I n - h o s p i ta l me d ic a l t r e a tme n t wa s s t a r t e d wi th in t ra -venous n i t r a tes in 164 pa t ien ts (58%) , with ex tens ive ora lth e r a p y ( m o r e th a n o n e a n t ia n g in a l d r u g ) in 7 3 p a t i e n t s ( 2 6 % )and minimal thera py (none or one an t iangina l drug) in 45pa t ien ts (16% ) . The in i tia l and f inal c lass if icat ions o f thesep a t i e n t s a r e p r e s e n te d in Ta b le 2 . A l th o u g h a f e w p a t i e n t s inc la s s I B a t a d mis s io n p r o g r e s s e d to c l a s s I I I B d u r in g th eh o s p i t a l p e r io d , h a l f o f th e p a t i e n t s ( n = 8 8 ) w i th a c u teuns tab le angina a t admiss ion (c lasses I I IB and I I IC) s tab i l izeda n d b e c a m e s u b a c u te u n s ta b le an g ina ( c la s se s II B a n d I IC) .

Ha l f o f th e p a t i e n t s ( n = 1 3 7 ) h a d r e c u r r e n t p a in d u r in gin-hospi tal observ a t ion , usua l ly (80% ) with in 48 h a f te r admis -s io n . Re c u r r e n t i s c h e mia a f t e r a d mis s io n wa s mo r e f r e q u e n t inpa t ien ts with acute angina a t r es t ( c lass I I I ) compared withthose in c lass I o r I I (p = 0 .0001) (Fig . 1) . There was nos ignif icant d if fe rence in recur rent ischemia be tween pa t ien tswith pr imary (c lass B) and pos t infa rc t ion angina (c lass C) . Inf ac t , t h e s t r o n g e s t p r e d ic to r o f r e c u r r e n t i s c h e mia wa s th e t imein te r v a l s in c e th e p r e v io u s e p i s o d e . Th e p r o b a b i l i ty o f d e v e l -o p me n t o f r e c u r r e n t c h e s t p a in r a p id ly d e c r e a s e d d u r in g th ef ir s t days a f te r a previous ep isode (Fig . 2) . Af te r a pa in- f reep e r io d o f 4 8 h , th e p r o b a b i l i ty o f d e v e lo p in g n e w c h e s t p a ind e c r e a s e d to

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J A C C W o l . 2 5 , N o . 6 VAN M I L T E N B U R G - v A N Z I J L E T A L . 289M a y 1 99 5: 12 86 -9 2 P R O G N O S I S O F U N S T A B L E A N G I N A S U B G R O U P S

Table 2. Classificationat Adm ission and Af ter In-Hospital Observation for 282 P atients With Definite Unstable AnginaPostobse rva t ion

A d m i s s i o n I B I C l I B I I C I I I B I I I C T o t a l ( % )IB 50 l 7 0 13 2 73 (26)IC 0 4 0 1 0 0 5 (2)liB {l 0 4 0 0 0 4 (I)IIC li 0 0 0 0 0 0 (0)IIIB (1 0 73 3 89 6 171 (61)III C 0 0 0 12 0 17 29 (10)Tota l 50 (18) 5 (2) 84 (30) 16 (6) 102 (36) 25 (9) 282 (100)

D a t a p r e s e n t e d a r e n u m b e r ( ) o f p a t i e n t s . C l a s s if i c a t io n o f s e v e r i t y ( c l a s s e s 1 t o l I l ) a n d c l in i ca l c i r c u m s t a n c e s ( c l a s s e s B a n d C ) a t a d m i s s i o n a n d a t t h e t i m et h a t t h e d e c i s i o n f o r fi n a l t r e a t m e n t i s m a d e ( P o s t o b s e r v a t i o n ) . D e f i n i t i o n s o f c l a s s i fi c a t io n c a t e g o r i e s a s i n T a b l e I .

phy and angioplasty or bypass were m ade m ost frequent ly inpatients with recurre nt chest pain at rest (class III) an d only in10% to 15% o f patients with clas s II angina. Patien ts withaccelerated angina (class I) were scheduled for interventionstwice as often as class II patients. Th e freq uency of in-hospitaldecisions f or interventions was significantly high er for postin-farction angina (class C).

Six-month follow-up. Survival, survival without infarction,and infarct-free surviv al with out intervention are shown asKaplan-M eier curves for the 6-month follow-up period for thedifferent subgroups of severity and clinical circumstances (Fig.3). Surv ival and infarct-free survival were b oth highe r inpat ients wi th pr imary unstable angina (c lass B) com pared wi ththat in postinfarction patients (class C, p = 0.01 and p = 0.1,respectively). Th ese e nd points were not significantly differentfor the three severity subgroups. For both Braunwald classes 1to III and B and C, there was a distinct difference when theoutc om e of infarct-free survival witho ut intervention was con-sidered (p = 0.0001 and p = 0.01, respectively).

For a l l three outcomes, the adjusted r isk ra t io for thedifferent classes was estimated, using proportional hazardsmultivariate analysis (Table 4). For bo th m ortality and infarc-tion, the risk difference betw een classes B and C was confirmedafter correct ion for oth er covaria tes. Elderly age, male gender ,hypertension, postin farct angina (class C) a nd maximal anti-anginal therapy were indep end ent predictors of mortality.Survival without infarction was impaired for elderly patientsand p atients with postinfarc t angina (class C). All four catego-ries described in the Braunwald classification were indicators

for a highe r risk of mortality, infarction or revascularization:acute a ngina at rest (class III), postinfarctio n angina (class C),presence of ECG changes and use of maximal antianginaltherap y (two or mo re antianginal drugs) in addition to the riskfactor of male gender .

Eigh t of 109 patien ts with a final diagnosis of chest pain ofoth er causes developed myocardial infarction (two), died(four) or underwent coronary angioplasty (one) or bypasssurgery (two) within 6 months after admission. Four of theseeight patients were discharged with atypical chest pain, andfour had a history of heart fa i lure ( two), arrhythm ia (one) ormyocardial infarction (one).

i s c u s s i o nThe classification of unstable angina as defined by Braun-

wald (14) was appl ied to a g roup o f 417 pat ients adm it ted forchest pain suspected o f being unstab le angina pectoris. Theselection of pat ients imm ediate ly a t admission ensured that thewhole spectrum of unstable angina was included in this regis-try. This is in contrast with most other studies on unstableangina, where only selected patients were included, restrictedby age (12,21), absence of recent myocardial infarction orbypass surgery (7,9,12,22), dur ation o f pain episodes (9,22,23)or by presence of i schemic signs on the EC G (7,23,24) . In m oststudies, patients were selected 24 to 48 h afte r admission, wh enmyocardial infarction had been ruled out by serial enzymeanalysis, which also excludes most patients with a final diag-nosis of chest pain of other causes. In contrast, the only

Figure l. Frequency of recu rrent ischemiafor the various subgroups. Left, Severityclasses: accelerated ang ina (I) , suba cute an- ~ ~0gina at rest (II) and acute angina at rest ~(Ill). Right,Primary.unstable (B) and postin-farction (C) ang ina.

lit ...................... 6445

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1 2 9 0 V AN M I L T E N B U R G - v A t ~ Z I J L E T A L . J A C C V o l . 2 5, N o . 6P R O G N O S I S O F U N S T A B L E A N G I N A S U B G R O U P S M a y 1 9 95 : 12 8 6- 92

probabili ty

0.90.80.70.60 . 5 ~ - ' - ,0.4 , . % ~0.30.2 'O.l

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Figu re 2. Probability of d evelopment of recu rrent pain afteradmission (solid line), development of a second pain episodeafter a first recurrence l on g -d as h ed l in e ) and developmentofa th ird episode after a secon d episode short-dashed l ine) .

exclusion criterion in the pre sent stu dy was evidence of otherdisease assu med to be causing the chest pain, such as aneu rysmdissecans, and referral from other hospitals for further treat-ment of pat ients in whom a complete diagnost ic workup hadalready been performed.

For practical reasons, the tentative diagnosis of unstableangina should be m ade a t the t ime of hospita l admission. Apatient with chest pain severe enough to warrant hospitaladmission will be classified at admission as having suspectedunstable angina when symptoms and s igns are such thattransien t myocardial ischemia is believed to be the underlyingcause. The pa tient will be m onito red to d etect possible life-threatening arrhy thmias from recurrent ischemia or evolvingmyocardial infarction. O ften tre atm ent will be started withbeta-blockers, n itrates , aspirin or heparin. S ubsequen t infor-mation acquired during admission, such as the occurrence orabsence of new episodes of chest pain, ECG changes orelevated serum enzyme levels , wi l l contr ibute to a f i n l diag-nosis that can be e ither a cute my ocard ial infarction, unstableangina, noncardiac disease or nonspecific chest pain (1,19).

Final diagnosis. The diagnosis of unstable angina wasconfirmed in 68 of patients, whereas in 26 the complaintswere a t t r ibuted to causes other than coronary insuff ic iencyafter observation. This propo rt ion is low com pared with Du n-

can e t al . (25) , who reported that 60 did not sa t is fy thecri teria for uns table angina in an outpat ient s tudy of 616 menwho were ref erred fo r chest pain by gen eral practitioners. Thisdifference suggests that a considerable prop ortion o f patien tswith ches t pain from other causes m ay be f i l tered beforeadmission. At the other end of the spectrum, myocardialinfarct ion had a l ready occurred in 9 of a l l adm it ted pat ients ,which became apparent from subsequent serum enzyme as-says. Similarly, in the HINT study (23), myocardial infarctionhad occurred a t the t ime of random izat ion in 8 of patientswith prolonged ches t pain and co ncom itant EC G changes .

C l i n i c a l c o u r s e a n d u n d e r l y i n g p a t h o p h y s i o l o g y . Dur ingthe hospi ta l s tay, pat ients moved from one c lass to another .For example , 12 pat ients appeared to have, in addi t ion to the34 patients who actually had, postinfaretion angina (class C)recognized as such on admission. By contrast, 88 patients whopresented with class III symptoms were in class II afterobservation, indicating that th e unstab le period ha d stabilized.This il lustrates the dynamic aspects of unstable angina as anintermediate condi t ion between chronic s table angina andacute myocardial infarction (5,26 ) and corresponds to thedyna mic changes within the co rona ry arteries described inrelation to unstable co rona ry disease (1,19,27). Th e similarityof occurrence of subsequent pain episodes over t ime may

Tab le 3 . Events and Interventions During the Hospital Period by ClassClass Total A M I/D ea th Ang iograph y* PTCA/CABG*

S e v e r i t yI 55 2 ( 4) 22 ( 40) 19 ( 35)I I 100 4 ( 4) 15 ( 15) 10 ( 10)I I I 127 14 ( l l ) t 100 ( 79) * :~ 71 ( 56) :~

C l i n ic a l c i r c u m s t a n c e sB 236 13 ( 6) 104 ( 44) 77 ( 33)C 46 7 (46) i 33 (72)*:] : 23 (50)+

T o t a l 2 8 2 2 0 1 3 7 1 0 0* I n c l u d i n g b o t h e m e r g e n c y a n d e l e c ti v e p r o c e d u r e s , t p < 0 . 0 5 , :~ p < 0 . 0 1 , fo r c o m p a r i s o n o f s u b g r o u p s . D a t a

p r e s e n t e d a r e n u m b e r ( % ) o f p a t i e n ts . D e f i n it i o n o f c l as s if i c at i o n c at e g o r i e s a n d a b b r e v i a t io n s a s i n T a b l e 1 .

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JAC C Vol . 25 , No. 6 ,'AN MILTENBURG-vAN ZIJL ET AL. 12 91M ay 1 9 95 :1 2 86 -92 P R O G N O S IS O F U N S T A B L E A N G IN A S U B G R O U P S

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cor r espond to r epea ted f o r m a t ion and r ecover y o f an unstab leplaque, resul t ing in a layered thromb us (28) , Fur t herm ore, thecl inical decrease of f requency of symptoms over t ime cor re-sponds to the d ec r ease o f ang iographic p r esence o f in t r acor o-nary thrombus over t ime (29) .

E v e n t s a n d i n t e r v e n t i o n s . For pat ien ts with def ini te unsta-ble angina, the ra te of death or infarct ion was 4.3 dur ing thein-hospita l per iod and 9.6 a t 6-month fol low-up. This re la-t ively good prognosis com pares favorably with oth er repor ts

Table 4. Mu ltivariate Analysis: Indepen dent Predictors ofLong-Term Outcom e (6 m onths) in 282 Patients With UnstableAngina PectorisR at eRat io 95% CI

MortalityAg e >7 0 yr 14.5 3.5-61Male gend er 3 .7 0 .9-14 .8Hypertens ion 3 .5 1 .0-12Cla ss C 8.{I 2.2-28Maximal antian ginal thera py 3.2 1.0-10.4

Death or infarctionAge >70 yr 2 .1 1 .1-4 .1Class C 2 .1 1 .0-4 .6

Death , in farction o r in te~ 'en t ionMale gender 2 .7 1 .8-4 .1Class I11 3.0 2.1-4 .3Class C 1.6 1.0-2.4ECG changes present 1 .8 1 .2-2 .8Maximal (IV) antiang inal thera py 2.1 1.5-3.1

CI = confidence interval; EC G = electrocardiographic: IV = intraven ous.Def init ions of classification c atego ries as in Table 1.

F i g u r e 3 . Six-month ollow-upoutcomes: survival (solid ines), infarct-free survival (long-dashed lines ) and infarct-free survival withou tintervention (short-dashed lines) for the various subgroups, p =probability.

(12,13,23,30,31) and m ay be re la ted to the intens ive medicaltherapy and high intervention ra te . Af ter hospita l admiss ion,78 of a l l pat ients received ei the r oral or intravenou s ni tra tes ,58 received beta-blockers , 33 received calc ium antago-nis ts , and 78 of the pat ients were init ia l ly t reated with e i theraspir in or hepar in. In addit ion to medical therapy, 35 ofpat ients with a f inal diagnosis of angina pector is underwentrevascular izat ion, most of them dur ing the h ospita l per iod.Similar revascular izat ion ra tes af ter extens ive medical t reat-ment were repor ted by Theroux et a l . (30) and Cairns e t a l .( 32) , wher eas o the rs r epor ted lower num b er s o f 4 and 18within the f irst 3 to 8 months (11,33).

C l a s s i f i c a t i o n system. The classif ication system proposedby Braunw ald ap peare d to b e ap prop r ia te for r isk s tra ti ficat ionin c l inical pract ice . The subgroups of the four categor ies- -severity, clinical circumstances, EC G ch ange s and intensity oft r ea tm ent - - w er e a ll r e la ted to d i f f e r en t p r ognoses. How ever ,for the severity category, prognosis was best for class II ,intermediate for class I and worst for class III (Fig. 3) .Appar en t ly , absence o f pain f o r >4 8 h i s a be t t e r ind ica tor f o rou tcom e than the occur r ence o f pa in a t ex e r t ion or a t r e st . I fa pat ient is pain f ree for >48 h, the probabil i ty of new episodesi s

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12 92 w,s MILTENBURG-vaN ZIJL ET AL. JACC Vol . 25, No. 6P RO G N O S I S O F U N S T A BL E A N G I N A S U BG RO U P S M a y 1995 :1286-92

pr ognos i s o f pa ti en t s wi thou t pa in ove r the p r ev ious 48 h m aybe re f lected in the low nu mb er of c lass I I pat ients a t admiss ion.

Conclus ions . The c lass if icat ion proposed by Braunwaldcan be used easily in clinical practice and is a helpful tool topredict outcome. For c lass if icat ion of sever i ty, the pain- f reeper iod is a bet ter r isk indicator than the dis t inct ion betweenaccelerated angina and angina a t res t . In general , uns tableangina has a re la t ively good prognosis under the cur rentmanagement s tra tegy.

Survival withou t infarct ion var ies betw een 80 and 91among the various classes, with the best prognosis in classes I ,I I and B an d the w ors t prognosis in c lasses I I I and C. Betw een35 and 72 of the pa t ien t s have an uncom pl ica ted cour sewith medical therap y alone, with the bes t outc om e for c lass 1Iand the wors t for c lasses I I I and C . The dif ferent outcom e ratesfor the individual classes are con firm ed by mu ltivariate analysisand p rov ide a useful too l for r isk stratification in patie ntsselected for c l inical t r ia ls an d ev aluat ion of t rea tme nt s tra te-gies.

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