O riginal R esearch

Annals of Internal Medicine

Effectiveness of an Early Versus a Conservative Invasive Treatment

Strategy in Acute Coronary Syndromes
A Nationwide Cohort Study
Kim Wadt Hansen, MD; Rikke Sorensen, MD; Mette Madsen, MSc; Jan Kyst Madsen, DMSc; Jan Skov Jensen, DMSc;
Lene Mia von Kappelgaard, MScPH; Poul Erik Mortensen, MD; Theis Lange, MSc; and Soren Galatius, DMSc
Background: Randomized clinical trials have found that early
invasive strategies reduce mortality, myocardial infarction (Ml),
and rehospitalization compared with a conservative invasive ap
proach in acute coronary syndromes (ACSs), but the effective
ness of such strategies in real-world settings is unknown.
Objective: To investigate adverse cardiovascular outcomes of
an early versus a conservative invasive strategy in a national co
hort of patients with ACSs.
Design: Retrospective cohort study.

(cumulative incidence, 5.9% vs. 7.6%; adjusted hazard ratio [HR],

0.75 [95% Cl, 0.66 to 0.84]; P < 0.001). Similar results were
found for rehospitalization for Ml (cumulative incidence, 3.4% vs.
5.0%; adjusted odds ratio, 0.67 [Cl, 0.58 to 0.77]; P < 0.001) and
all-cause death (cumulative incidence, 7.3% vs. 10.6%; adjusted
HR, 0.65 [Cl, 0.59 to 0.72]; P < 0.001).
Limitation: Potential residual confounding due to lack of core
clinical variables.

Setting: Administrative health care data on hospitalizations, pro

cedures, and outcomes abstracted from the Danish national reg
istries and covering all acute invasive procedures in patients pre
senting with an ACS.

Conclusion: In this real-world cohort of patients with a first hos

pitalization for an ACS, the use of an early invasive treatment
strategy was associated with a lower risk for cardiac death and
rehospitalization for Ml compared with a conservative invasive
approach.

Patients: 19 704 propensity score-matched patients hospital

ized with a first ACS between 1 January 2005 and 31 December

Primary Funding Source: Department of Cardiology, Univer

sity Hospital Gentofte.

2011.
Measurements: Risk for cardiac death or rehospitalization for
Ml within 60 days of hospitalization.

Ann Intern Med. 2015;163:737-746. doi:10.7326/M15-0303 www.annals.org

For author affiliations, see end o f text.

Results: Compared with a conservative approach, early invasive

strategies were associated with a lower risk for cardiac death

This article was published online first at www.annals.org on 27 October

espite significant advances in treatm ent and pre

vention (1), ischemic heart d isease-including
acute coronary syndrom es (ACSs)still ranks first in
glo ba l m ortality statistics (2). Clinical trials have estab
lished that an early invasive approach is a cost-effective
strategy fo r reducing rates o f death, m yocardial infarc
tio n (Ml), and rehospitalization (3, 4), although the ef
fe ct seems highly d e p e n d e n t on the clinical setting (5).
Thus, em pirical evidence docum enting a sim ilar benefit
with w idespread use is lacking.
Unlike random ized clinical trials, national registries
include unselected patients, thus enabling an assess
m ent o f trea tm en t effects in a real-w orld setting (6, 7).
In Denmark, all citizens are covered by a pub lic national
health care system, and in 2009, the Danish Health and
M edicines A u th ority im plem ented national com pulsory
fast-track protocols stating th a t all patients hospitalized
with a clinically stable non-ST-segm ent elevation ACS
(NSTE-ACS) should have diagnostic coronary a ng io gra
phy w ithin 72 hours o f adm ission. A lthough the prim ary
aim was to reduce w ait tim es and ensure uniform trea t
m ent o f patients with subacute coronary syndromes,
the p rotocols also p rovided im petus fo r a natural ex
perim e nt exam ining the p rognostic effects o f early in
vasive strategies outside a random ized setting. We
investigated the effectiveness o f an early versus conser

vative invasive treatm ent strategy on short-term ad

verse cardiac outcom es in a national co ho rt o f patients
with ACSs.

2015.

M ethods
D esig n O verview
W e conducted a retrospective cohort study o f all
patients hospitalized fo r a first ACS from 1 January
2005 th ro ug h 31 D ecem ber 2011 in Denmark. Patientand hospital-level data were collected from the na
tional Danish registries, which hold inform ation on all
5.6 m illion inhabitants. We studied th e effects o f an
early invasive trea tm en t strategy on adverse cardiac
outcom es in a real-world setting. An early invasive
treatm ent strategy was defined as diagnostic coronary
a ngiography w ithin 72 hours o f the index hospitaliza
tion, assuming cardiac catheterization w ith intent to
perform revascularization if app ro priate on the basis of

See also:
Celebrating the ACP Centennial: From the Annals
A rch ive ......................................................................798
Editorial c o m m e n t...................................................799
2015 American College of Physicians 737

O riginal R esearch
EDITORS'NOTES________________________________________
Context

In clinical trials, an early invasive strategy for acute coro

nary syndromes (ACSs) is associated with better out
comes than a conservative approach, but whether this
is true in everyday practice is unclear.
Contribution

Using national health care data from Denmark, investi

gators compared outcomes for patients with an ACS
who had a diagnostic coronary angiography within
72 hours with those who had coronary angiography
more than 3 days later or not at all.
Caution

Information on important clinical findings (such as elec

trocardiographic results) was unavailable.
Implication

An early invasive strategy for ACSs was associated with

reduced risk for cardiac death and rehospitalization for
myocardial infarction compared with the conservative
approach.

coronary anatom y (8). Adverse cardiac outcom es were

defined as cardiac death or rehospitalization fo r Ml. Pa
tients were fo llo w ed fo r 60 days from the date o f the
index hospitalization or until death or em igration,
w hichever came first. W e a dopted this follow -up to dis
entangle potential effects o f secondary preventive
m edication on outcomes.
The study was approved by the Danish Data Pro
tection Agency (no. 2007-41-1406; internal reference:
GEH-2013-021) and conducted in accordance with cur
rent rules o f ethics and legislature. Register-based stud
ies do not require approval from an ethics com m ittee in
Denmark.

Setting
The national setup fo r invasive m anagem ent o f pa
tients presenting with an ACS is highly centralized, with
5 invasive heart centers located in densely populated
urban areas and 8 sm aller hospital units perform ing all
acute and subacute cardiac procedures, respectively.
Invasive heart centers are high-volum e hospitals with
facilities fo r cardiac catheterization, percutaneous coro
nary intervention (PCI), and coronary artery bypass
g rafting (CABG). A lthough the smaller hospital units
prim arily perform subacute cardiac catheterizations,
one unit initiated PCI treatm ent o f stabilized patients
with ACSs with low-risk lesions during the study. Emer
gency m edical services perform extensive prehospital
tria g in g using e lectrocardiographic telem edicine, thus
ensuring that patients presenting with ST-segment ele
vation Ml (STEMI) are transported directly to the near
est invasive heart center. Patients with NSTE-ACSs are
a dm itted to the nearest hospital fo r noninvasive phar
m acologic therapy and transferred fo r further invasive
738 Annals of Internal Medicine Vol. 163 No. 10 17 November 2015

Effectiveness of Early Invasive Treatment Strategies in ACS

assessment at an invasive heart center. They are then
returned to th e ir local hospital fo r cardiac rehabilitation
or additional treatm ent.

Data Sources
W e perform ed individual-level linkage o f data from
5 registries by using the unique personal civil registra
tion num ber given to all Danish citizens at birth or im
m igration. W e identified the study co ho rt from the Dan
ish National Patient Register (9). All hospitals are
required to rep ort inform ation on each hospitalization,
including 1 prim ary discharge diagnosis and, if a p p ro
priate, 1 or more secondary diagnoses coded accord
ing to the International Classification o f Diseases, Eight
Revision, until 1994 and International Classification of
Diseases, 10th Revision (ICD-10) thereafter. The p ri
mary diagnosis is assigned by the treating physician at
discharge and describes the prim ary reason fo r inhospital diagnostic investigation and treatm ent; sec
ondary diagnoses describe additional com orbidity. We
obtained inform ation on cardiac catheterizations, PCIs,
and CABG from the Danish Heart Registry, a clinical
register with m andatory reporting o f data on the tim e,
type, and findings o f all cardiac procedures perform ed
since 2000 (10). The Danish Register o f M edicinal Prod
uct Statistics holds inform ation on all redeem ed drug
prescriptions (grouped according to Anatom ical Ther
apeutic Chemical classification) since 1995. Because
the Danish health care system provides partial reim
bursem ent fo r drug expenses, accurate registration by
pharmacies o f inform ation on all redeem ed prescrip
tions, including dispensing date, drug, quantity, and
strength, is required (11). Deaths and related causes
were obtained from the Danish Register o f Causes of
Death (12). Finally, patient-level data on d em ographic
and socioeconom ic characteristics were p rovided by
Statistics Denmark.

Case Definition
Cases o f ACS were identified by using prim ary d i
agnoses o f Ml (ICD-10 codes 121 to 121.9) and unstable
angina pectoris (UAP) (ICD-10 code I20.0). The d ia g n o
sis o f Ml has been validated, w ith a sensitivity and pos
itive predictive value exceeding 93% and 91%, respec
tively (13). The diagnosis o f UAP has been validated
only by using a strict d efinition requiring e lectrocardio
graphic changes in addition to classic sym ptom s, with a
positive predictive value around 42% (14).

Study Cohort
All patients adm itted to a Danish hospital with
acute Ml (AMI) or UAP were e lig ib le fo r inclusion. We
excluded patients with a p rio r hospitalization fo r an
ACS after 1978 to corroborate the validity o f the d ia g
noses. Patients discharged on the day o f admission
were excluded to ensure sufficient tim e fo r p ro p e r in
vestigations, including e lectrocardiographic m o n ito r
ing and sequential measurements o f cardiac troponins,
to m inimize misclassification due to invalid ACS reco rd
ings. W e restricted the study cohort to patients aged 30
to 90 years under the assum ption that those younger
than 30 years tended to have an underlying cause
www.annals.org

O riginal R esearch

Effectiveness of Early Invasive Treatment Strategies in ACS

o t h e r th a n a th e r o s c le r o s is a n d m o s t o f th o s e o ld e r th a n
9 0 y e a r s w e r e t o o f r a i l t o h a v e in v a s iv e p r o c e d u r e s .

We

used

a v e r s io n

o f th e

O n ta r io

AMI

m o r t a lit y

p r e d ic t iv e r u le m o d if ie d t o t h e IC D - 1 0 s y s te m t o id e n
t if y c a r d ia c a n d n o n c a r d ia c c o m o r b id it ie s (1 7 , 1 8 ). A d

In vasive S tra teg ies

d it io n a l c h r o n ic c o m o r b id it y w ith p o t e n t ia l in f lu e n c e o n

W e d e f i n e d a n e a r ly in v a s iv e s t r a t e g y a s r e c e i p t o f

tre a tm e n t a n d

o u tc o m e s w a s id e n t if ie d t o

fu rth e r e n

d ia g n o s t ic c o r o n a r y a n g io g r a p h y w ith in 7 2 h o u rs o f t h e

h a n c e p r e d ic t iv e c a p a b ilit ie s . O f n o te , th e IC D - 1 0 s y s

i n d e x h o s p i t a l i z a t i o n . T h is d e f i n i t i o n w a s in a c c o r d a n c e

te m

w ith t h e E u r o p e a n S o c ie ty o f C a r d io lo g y g u id e lin e s f o r

( 1 9 ) . T y p e 2 M l is a s p e c i a l c a s e in w h i c h a n i m b a l a n c e

does

n o t r e fle c t th e

u n iv e r s a l c l a s s i f i c a t i o n

of Ml

N S T E - A C S s a n d t h e t i m e f r a m e s e t b y t h e D a n is h f a s t -

b e tw e e n s u p p ly a n d d e m a n d o f m y o c a r d ia l o x y g e n r e

tr a c k p r o t o c o ls (1 5 , 1 6 ). A

s u lt s in m y o c a r d i a l d a m a g e . T h e p r e v a l e n c e o f t y p e 2

c o n s e r v a tiv e

in v a s iv e s t r a t

e g y w a s d e f in e d a s r e c e ip t o f a n a n g io g r a p h ic a s s e s s

M l in

m e n t a t le a s t 7 2 h o u r s a f t e r t h e i n d e x h o s p i t a l i z a t i o n o r

2 6 % , a n d it is a s s o c i a t e d w i t h l o w u s e o f c a r d ia c c a t h e

n o c a r d i a c c a t h e t e r i z a t i o n . W e f u r t h e r c h a r a c t e r iz e d t h e

t e r i z a t i o n a n d h ig h m o r t a l i t y c o m p a r e d w i t h M l d u e t o

in v a s iv e

tre a tm e n t

subsequent
b o th ),

by

r e v a s c u l a r i z a t io n

le n g t h

h o s p it a l s ,

s tra te g y

o f th e

and

th e ra p y

h o s p it a l

subsequent

u s in g

u n s e le c t e d

p a tie n ts w ith

M l m a y b e a s h ig h

as

in f o r m a tio n

on

c o r o n a r y a r t e r y d is e a s e ( 2 0 , 2 1 ) . P a t ie n t s w i t h t y p e 2 M l

(P C I, C A B G ,

or

c o m m o n l y r e c e iv e s e c o n d a r y d i a g n o s e s o f c a r d ia c a r

s ta y , t r a n s f e r s

b e tw e e n

r h y t h m ia ,

h e a rt

d u a l- a n t ip la t e le t

th e r a p y .

b le e d in g ,

r e n a l in s u ffic ie n c y , c h r o n ic

f a i lu r e ,

s e v e re

in f e c tio n ,

a n e m ia

o b s t r u c t iv e

or
p u l

W e c a l c u l a t e d t h e l e n g t h o f t h e h o s p i t a l s ta y b y a p p l y

m o n a ry

i n g a n a l g o r i t h m t h a t c o m b i n e d u n i q u e h o s p it a l c o d e s ,

r e s p ir a to r y in s u ffic ie n c y (2 2 ). W e t h e r e f o r e in c lu d e d in

d a t e s o f h o s p i t a l i z a t i o n , a n d d a t e s o f d is c h a r g e i n t o

fo r m a t io n o n th e s e in d ic a to r s t o a d d r e s s t h e p o t e n t ia lly

d a te s

s t r o n g c o n f o u n d i n g e f f e c t o f t y p e 2 M l. In t h e a b s e n c e

to ta l

in d e x

h o s p it a liz a tio n ,

p r o v id e d

o v e r la p p e d . T h e s a m e a lg o r it h m
as

th e

w a s u s e d to

in te r h o s p ita l tra n s fe rs . W e d e fin e d

o f d u a l- a n t ip la t e le t t h e r a p y

th a t

id e n t if y

p o s td is c h a r g e

r e d e m p t io n

of a

use
p re

o f c o re
e re d

d is e a s e

(C O P D ),

c e r e b r o v a s c u la r

c lin ic a l v a r ia b le s , d r u g

a p r o x y f o r id e n t if ie d

e x p o s u re

c a r d ia c

u s e o f a n tih y p e r t e n s iv e m e d ic a t io n

d is e a s e ,

or

w a s c o n s id

r is k f a c t o r s . T h u s ,
in d ic a t e d a h is to r y

s c r ip t io n f o r a s p ir in a n d a n a d e n o s in e d ip h o s p h a t e r e

of

c e p t o r in h ib it o r ( c lo p id o g r e l, t ic a g r e lo r , o r p r a s u g r e l)

d r u g s i n d i c a t e d t h e p r e s e n c e o f d i a b e t e s m e l l it u s , a n d

w i t h i n 6 0 d a y s o f h o s p i t a l i z a t i o n o r p o s s e s s io n o f a s u f

use

f ic ie n t q u a n tity o f m e d ic a tio n

h y p e r c h o le s te r o le m ia .

b e f o r e h o s p it a liz a tio n t o

c o v e r th e e n tir e f o llo w - u p .

h y p e r te n s io n ,

d e fin e d

a d v e r s e c a r d i a c o u t c o m e s a s c a r d ia c

C a r d ia c

d e a th

w as

d e fin e d

a s a p r im a r y

c a r d i a c c a u s e o f d e a t h ( I C D - 1 0 c o d e I 0 0 - 2 5 , I2 7 , o r 130S I ) as a s s e s s e d b y th e tr e a tin g
p it a liz a tio n s

w ith

p r im a r y

i n s u lin

d ru g s

or

g lu c o s e - lo w e r in g

s u g g e s te d

h is to r y

H o s p ita l- le v e l d a ta w e r e g e n e r a t e d fr o m

d e a th o r r e h o s p ita liz a t io n f o r M l w it h in 6 0 d a y s o f h o s
p it a liz a tio n .

lip id - lo w e r in g

of

of

H osp ital C h aracteristics

M ain O utcom e M easu res

W e

of

use

p h y s ic ia n . O n ly r e h o s

d ia g n o s is

of

Ml

(IC D -1 0

th e

d a ta

a t h a n d , in c lu d in g th e a n n u a l n u m b e r o f A C S h o s p it a l
iz a t io n s a n d a v a i l a b i l i t y o f P C I a n d C A B G f a c i li t i e s . T h e
h o s p it a l v o lu m e

o f p a tie n ts w ith

A C S s c o r r e la te s w e ll

w i t h o t h e r h o s p it a l c h a r a c t e r is t ic s , s u c h a s t h e n u m b e r
o f b e d s a n d th e p r e s e n c e o f c o r o n a r y c a re u n its (2 3 ).

S tatistical A n alysis

c o d e 121 x ) a n d a l e n g t h o f s ta y o f a t le a s t 2 d a y s w e r e

C o n t in u o u s a n d d is c r e t e d a ta a re p r e s e n te d as m e

c o u n t e d a s o u t c o m e s t o e x c lu d e p o t e n t ia l e le c tiv e h o s

d ia n s a n d

p it a l i z a t i o n s . A l l - c a u s e d e a t h w a s i n c l u d e d a s a s e c o n d

a s c o u n t s a n d p e r c e n t a g e s . B a la n c e b e t w e e n t r e a t m e n t

a ry o u tc o m e m e a s u re .

r a n g e s , a n d c a te g o r ic a l d a ta a re p r e s e n te d

g r o u p s w a s a s s e s s e d u s in g a b s o l u t e s t a n d a r d i z e d

d if

f e r e n c e s ( 2 4 ) . T h is m e a s u r e i n d e x e s t h e a b s o l u t e d i f f e r

D em o g ra p h ic C h aracteristics, C om orbidity,
a n d M ed ication s
W e a s s e s s e d s o c io e c o n o m ic s ta tu s b y a n n u a l n e t

e n c e in m e a n s o r p r o p o r t i o n s t o a p o o l e d

e s tim a te o f

th e

p o in ts

SD. A

v a lu e

le s s t h a n

10

p e rc e n ta g e

in d i

c a te s b a la n c e b e tw e e n g r o u p s .

f a m i l y i n c o m e , c a l c u l a t e d s e p a r a t e ly f o r p a t i e n t s a g e d

W e u s e d p r o p e n s ity s c o re m a tc h in g to e n s u re b a l

6 5 y e a rs o r y o u n g e r a n d th o s e o ld e r th a n 6 5 y e a rs t o

ance

a c c o u n t f o r c h a n g e s a fte r r e tir e m e n t, h ig h e s t a c h ie v e d

g r o u p s (2 5 ). T h e p r o p e n s ity s c o re w a s e s tim a te d b y f i t

e d u c a t i o n a l le v e l, a n d

t in g a n o n p a r s im o n io u s lo g is t ic r e g r e s s io n m o d e l w ith

c o h a b ita tio n

s ta t u s . A n n u a l n e t

in

b a s e li n e

f a m i l y i n c o m e w a s d i v i d e d i n t o t e r t i l e s o f lo w , m e d i u m ,

r e c e ip t o f a n

and

d e p e n d e n t v a r ia b le

h ig h

in c o m e .

le v e l w a s d i v i d e d

The
in to

h ig h e s t a c h ie v e d
3 g ro u p s :

e d u c a tio n a l

9 o r fe w e r y e a rs

of

a c te r is tic s

as

c h a r a c t e r is t ic s

a c ro s s

tre a tm e n t

e a r ly in v a s iv e t r e a t m e n t s t r a t e g y a s t h e
and

o b s e rv e d

p re tre a tm e n t c h a r

in d e p e n d e n t v a r ia b le s

( A p p e n d ix ) .

We

s c h o o l, h i g h s c h o o l o r v o c a t i o n a l t r a i n i n g , o r u n i v e r s i t y

m a t c h e d p a t i e n t s r e c e i v i n g a n e a r ly i n v a s iv e s t r a t e g y t o

d e g r e e . T h e s h o r t e s t d is t a n c e n e e d e d t o t r a v e l b y r o a d

th o s e

to

1:1

re a c h

a h o s p it a l w ith

PCI a n d

CABG

fa c ilitie s

w as

c a l c u l a t e d f o r e a c h p a t i e n t b y u s in g t h e r a n g e ( in k i l o

r e c e iv in g

a c o n s e r v a tiv e

r a tio a n d a p p lie d

a llo w

in v a s iv e a p p r o a c h

in a

a g r e e d y m a tc h in g a lg o r it h m

to

a m a x im a l d if f e r e n c e o f 0 .2 tim e s th e S D o f th e

m e te r s ) f r o m t h e p a t ie n t 's h o m e a d d r e s s as o f 1 J a n u

p r o p e n s i t y s c o r e . P a t ie n t s w i t h o u t a n a d e q u a t e

a ry

w e r e e x c l u d e d . T h is p r o c e d u r e w a s s t r a t i f i e d b y h o s p i

o f th e

year

o f a d m is s i o n .

D a ta

on

d e m o g r a p h ic

m a tc h

c h a r a c t e r is t ic s w e r e m is s i n g in 4 1 4 4 ( 7 % ) p a t i e n t s ; w e

ta l to

a d d re s s e d

in t r e a t m e n t , I C D - 1 0 c o d i n g , a n d a v a i l a b i l i t y o f c a r d ia c

th is

by

p e r f o r m in g

m u ltip le

im p u t a tio n

a n a ly s is ( A p p e n d i x , a v a i l a b le a t w w w . a n n a l s . o r g ).
w w w .a n n a ls .o r g

a c c o u n t f o r p o t e n t ia l a c r o s s - h o s p ita l d if fe r e n c e s

c a t h e t e r i z a t i o n f a c i li t i e s .

Annals of Internal Medicine Vol. 163 No. 10 17 November 2015 739

O riginal R esearch

Effectiveness of Early Invasive Treatment Strategies in ACS

A b s o lu t e t im e - t o - e v e n t m e a s u r e s w e r e c a lc u la te d
u s in g t h e

K a p la n - M e ie r e s t im a t o r f o r c a r d ia c a n d a ll

m e n t g r o u p in 3 9 h o s p it a ls ; t h e 7 e x c lu d e d h o s p it a ls
c o u ld n o t p r o v id e a n y m a t c h e d p a ir s ( A p p e n d ix F ig u r e

c a u s e d e a t h a n d t h e c u m u la t iv e in c id e n c e f u n c t io n f o r

1). S t a n d a r d iz e d d if f e r e n c e s d id

r e h o s p it a liz a t io n s , a c c o u n t in g f o r d e a t h as a c o m p e t in g

c e n ta g e

p o in t s

fo r

any

n o t exceed

o b s e rv e d

7 .7 p e r

p r e t r e a t m e n t v a r i

ris k . T h e c u m u la t iv e in c id e n c e c u r v e f o r c a r d ia c d e a th

a b le s , le n d in g s u p p o r t t o t h e a s s u m p t io n t h a t t h e v a r i

w a s g e n e ra te d

a b le s w e r e w e ll- b a la n c e d

in a c c o r d a n c e w it h t h e m e t h o d o f S i

b e tw e e n tr e a tm e n t g ro u p s

m o n a n d M a k u c h (2 6 ), a n d t h e c u r v e f o r r e h o s p it a liz a

( T a b le

t io n s w a s c r e a t e d b y a p p ly in g a n o n p a r a m e t r ic e x t e n

(5 6 .3 % ) p a t ie n t s h a d c a r d ia c c a t h e t e r iz a t io n

s io n o f t h e N e ls o n - A a le n e s t im a t o r . W e e s t im a t e d th e

d a y s 3 a n d 3 0 , 1 2 9 (1 .3 % ) h a d it b e t w e e n d a y s 31 a n d

1).

In t h e

c o n s e r v a tiv e

in v a s iv e

g ro u p ,

5549

b e tw e e n

r e la t iv e h a z a rd o f c a r d ia c a n d a ll- c a u s e d e a th b y u s in g

6 0 , a n d t h e r e m a in in g 4 1 7 9 (4 2 .4 % ) r e c e iv e d n o in v a

p r o p o r t io n a l h a z a rd s C o x r e g r e s s io n

m o d e ls t h a t in

s iv e e x a m in a t io n w it h in 6 0 d a y s . P a tie n t c h a r a c te r is t ic s

c lu d e d r e c e ip t o f a n e a r ly in v a s iv e s t r a t e g y as a t im e -

d if f e r e d a c ro s s t h e s e 3 g r o u p s , w it h t h e la s t 2 c o m p r is

d e p e n d e n t c o v a r ia te . T h is m o d e l im p lie d t h a t p a tie n ts

in g h ig h e r - r is k p a t ie n t s ( A p p e n d ix T a b le 3 , a v a ila b le a t

d id

w w w . a n n a ls . o r g ).

n o t c o n t r ib u t e

t im e

a t ris k t o

th e

e a r ly in v a s iv e

g r o u p u n til t h e d a y o f c a r d ia c c a th e t e r iz a t io n , t h u s lim
it in g

p o t e n t ia l

im m o r t a l t im e

T a b le 2 lis ts t r e a t m e n t c h a r a c te r is t ic s b y t r e a t m e n t

b ia s (2 7 ). B e c a u s e t h e

g r o u p in t h e p r o p e n s it y s c o r e - m a t c h e d c o h o r t . P a tie n ts

a s s u m p t io n o f c o n s t a n t h a z a rd d id n o t h o ld f o r r e h o s

r e c e iv in g a n e a r ly in v a s iv e s t r a t e g y w e r e m o r e lik e ly t o

p it a liz a tio n s , t im e - in d e p e n d e n t c o n d it io n a l lo g is t ic r e

h a v e s u b s e q u e n t PCI ( 6 9 .2 % vs. 3 6 .1 % ), h a d

g r e s s io n w a s p e r f o r m e d a n d o d d s r a tio s w it h 9 5 % C Is

h o s p it a l s ta y s ( m e d ia n , 4 vs. 5 d a y s ), a n d w e r e m o r e

s h o rte r

a re r e p o r t e d . W e t e s t e d t h e s e n s itiv ity o f o u r r e g r e s s io n

lik e ly

e s tim a te s t o

c h a r g e ( 7 3 .2 % vs. 5 8 .7 % ) th a n t h o s e in t h e c o n s e r v a tiv e

p o t e n t ia l v io la t io n s o f t h e a s s u m p t io n o f

to

in it ia t e

d u a l- a n t ip la t e le t

th e ra p y

a fte r

d is

ig n o r a b le t r e a t m e n t a s s ig n m e n t b y u s in g t h e m e t h o d s

in v a s iv e

d e s c r ib e d b y L in a n d c o lle a g u e s (2 8 ).

g r o u p w e r e e x a m in e d w it h c o r o n a r y a n g io g r a p h y a t an

In a n e x p lo r a t o r y a n a ly s is , w e t e s t e d f o r d if f e r e n c e s
in t h e

e s t im a t e d

tre a tm e n t

s u b g r o u p s . A a le n

a d d it iv e

e f f e c t w it h in
h a z a rd s

g ro u p .

M o re

p a t ie n t s

in

th e

e a r ly

in v a s iv e

in v a s iv e h e a r t c e n t e r ( 8 3 .9 % vs. 6 7 .7 % ).

p r e d e f in e d

In t h e p r o p e n s it y s c o r e - m a t c h e d c o h o r t , u s e o f a n

r e g r e s s io n s w e r e

e a r ly in v a s iv e t r e a t m e n t s t r a t e g y w a s a s s o c ia t e d w it h a

p e r f o r m e d t h a t in c lu d e d in t e r a c t io n t e r m s f o r t h e t r e a t

lo w e r ris k f o r a d v e r s e c a r d ia c e v e n ts t h a n a c o n s e r v a

m e n t in d ic a t o r a n d s u b g r o u p v a r ia b le s ( A p p e n d ix ) . A ll

t iv e a p p r o a c h ( T a b le 3 a n d F ig u r e 1). S p e c ific a lly , a t 3 0

s ig n if ic a n c e te s ts a n d C Is w e r e b a s e d o n r o b u s t SEs t o

d a y s , p a t ie n t s in t h e e a r ly in v a s iv e g r o u p h a d lo w e r c u

a c c o u n t f o r t h e m a t c h e d d e s ig n a n d r e f le c t e d v a r ia n c e

m u la t iv e in c id e n c e o f c a r d ia c d e a t h (5 .4 % vs. 6 .7 % ; d i f

w it h in

im p u t a t io n s . A ll h y p o th e s is te s ts

fe r e n c e , 1 .3 p e r c e n t a g e p o in t s ; a d ju s t e d h a z a rd r a tio

h a d a 2 - s id e d s ig n if ic a n c e le v e l o f 0 .0 5 . A n a ly s e s w e r e

[H R ], 0 .7 8 [9 5 % C l, 0 .6 9 t o 0 .8 8 ]; P < 0 .0 0 1 ) a n d r e h o s

and

b e tw e e n

p e r f o r m e d u s in g S ta ta , v e r s io n 1 3 .0 ( S ta ta C o r p ) .

p it a liz a t io n f o r M l ( 2 .8 % vs. 4 .1 % ; d if f e r e n c e , 1 .3 p e r
c e n t a g e p o in t s ; a d ju s t e d o d d s r a tio [O R ], 0 .6 8 [C l, 0 .5 8

R ole o f th e F u nd in g S ource
T h is s tu d y w a s s u p p o r t e d

to
b y th e

D e p a rtm e n t o f

C a r d io lo g y a t U n iv e r s ity H o s p ita l G e n t o f t e a n d g r a n ts
f r o m A b b o t t V a s c u la r R e s e a rc h a n d t h e M a s te r M a s o n
L a u r itz P e te r C h r is te n s e n a n d w if e K ir s te n S ig r id C h r is
t e n s e n F o u n d a t io n . T h e f u n d e r s h a d n o in v o lv e m e n t in
t h e d e s ig n o r c o n d u c t o f th e s tu d y ; c o lle c t io n , m a n a g e
m e n t, a n a ly s is , o r in t e r p r e t a t io n o f t h e d a ta ; o r p r e p a
r a tio n , r e v ie w , o r a p p r o v a l o f t h e m a n u s c r ip t.

0 .7 9 ];

P<

0 .0 0 1 ) t h a n

th o s e

in

th e

c o n s e r v a tiv e

g r o u p . T h e s e d if f e r e n c e s w e r e m a in t a in e d a t 6 0 d a y s
( c a r d ia c d e a t h : 5 .9 % vs. 7 .6 % ; d if f e r e n c e , 1 .7 p e r c e n t
age

p o in t s ; a d ju s t e d

HR, 0 .7 5 [C l, 0 .6 6 t o

0 .8 4 ]; P <

0 .0 0 1 ; r e h o s p it a liz a t io n f o r M l: 3 .4 % vs. 5 .0 % ; d if f e r
e n c e , 1 .6 p e r c e n t a g e p o in t s ; a d ju s t e d O R , 0 .6 7 [C l,
0 .5 8 t o 0 .7 7 ]; P < 0 .0 0 1 ) . S im ila r ly , p a t ie n t s h a v in g a n
e a r ly in v a s iv e s t r a t e g y a ls o h a d a lo w e r ris k f o r a ll- c a u s e
d e a th th a n t h o s e in t h e c o n s e r v a tiv e g r o u p a t 3 0 d a y s
(6 .5 % vs. 9 .1 % ; d if f e r e n c e , 2 .6 p e r c e n t a g e p o in t s ; a d
ju s t e d

e s u lt s

days

T h e o v e r a ll s t u d y c o h o r t in c lu d e d 5 4 6 9 4 p a tie n ts

HR, 0 .6 8 [C l, 0 .6 1
(7 .3 %

vs.

1 0 .6 % ;

t o 0 .7 6 ]; P <
d if f e r e n c e ,

0 .0 0 1 ) a n d 6 0

3 .3

p e rc e n ta g e

p o in t s ; a d ju s t e d HR, 0 .6 5 [C l, 0 .5 9 t o 0 .7 2 ]; P < 0 .0 0 1 )

a t 4 6 h o s p it a ls w ith a f ir s t A C S b e t w e e n 1 J a n u a r y 2 0 0 5

( T a b le

a n d 31 D e c e m b e r 2 0 1 1 ( T a b le 1 a n d A p p e n d ix F ig u r e

.a n n a ls .o r g ) .

1, a v a ila b le a t w w w . a n n a ls . o r g ). F o r t y - f o u r p e r c e n t h a d

s c o r e - m a t c h e d c o h o r t s u g g e s t e d t h a t t h e a s s o c ia t io n

an

e a r ly

f o llo w - u p

in v a s iv e
am ong

tre a tm e n t

s u r v iv in g

s tr a t e g y ,

and

m ean

p a t ie n t s w a s 6 0 d a y s . A l

b e tw e e n

and

an

A p p e n d ix
S u b g ro u p

F ig u r e
a n a ly s e s

2 , a v a ila b le
in

th e

in v a s iv e t r e a t m e n t s t r a t e g y

d e a th d if f e r e d

at w w w

p r o p e n s it y
and

c a r d ia c

b y s e x (P f o r in t e r a c t io n = 0 .0 2 1 ) , a g e

m o s t h a lf o f t h e h o s p it a ls h a d a n a n n u a l v o lu m e o f a t

(P < 0 .0 0 1 ) , d ia g n o s is (P < 0 .0 0 1 ) , a n d in d e x h o s p it a l

le a s t 4 0 0

(P = 0 .0 5 8 ) ( F ig u r e 2 ). D e s c r ip t iv e t a b le s s h o w e d t h a t

p a t ie n t s w ith A C S s , a n d

C A B G f a c ilit ie s ( A p p e n d ix T a b le

10%

h a d PC I a n d

1, a v a ila b le a t w w w

p a t ie n t c h a r a c te r is t ic s w e r e p o o r ly b a la n c e d w it h in t h e

.a n n a ls .o r g ) . A n in itia l c o m p a r is o n o f b a s e lin e c h a r a c

s tra ta

te r is t ic s b e t w e e n p a t ie n t s in t h e e a r ly a n d c o n s e r v a tiv e

u n r e lia b le .

in v a s iv e g r o u p s s h o w e d
and

h o s p it a l- r e la t e d

m a jo r im b a la n c e s in p a t ie n t -

fa c to rs

( A p p e n d ix

T a b le

2,

o f y e a r o f a d m is s io n ,

r e n d e r in g

th e s e

r e s u lts

W e c o n d u c t e d s e v e r a l s e n s itiv ity a n a ly s e s t o a s s e s s
t h e r o b u s tn e s s o f o u r r e s u lts . W e p e r f o r m e d a lt e r n a t e

s c o re -

p r o p e n s it y s c o r e m a t c h in g w it h s t r a t if ic a t io n f o r s u b

m a t c h e d c o h o r t in c lu d e d 9 8 5 2 p a t ie n t s in e a c h tr e a t -

g r o u p v a r ia b le s , t h u s e n s u r in g im p r o v e d b a la n c e in p a -

a v a ila b le

a t w w w . a n n a ls . o r g ). T h e

p r o p e n s it y

740 Annals of Internal Medicine Vol. 163 No. 10 17 November 2015

w w w .a n n a ls .o r g

O riginal R esearch

Effectiveness of Early Invasive Treatment Strategies in ACS

T a b le 1. Baseline Characteristics in the O verall Study C ohort and A m o n g Propensity Score-M atched Patients*
Characteristic
Demographic characteristics
Median age (range), y
Male
Net household income
Low
Medium
High
M issingf
Educational level
<9 y o f school
High school or vocational training
University degree
M issingf
No cohabitant partner
M issingf
Median distance to nearest invasive
heart center (range), km
M issingf
Risk factors
C oncomitant heart disease
Cardiac arrhythmia
Heart failure
Pulmonary edema
Cardiogenic shock
Valvular heart disease
Concom itant com orbidity
Cerebrovascular disease
Cancer
COPD
Diabetes with com plications
Acute renal failure
Chronic renal failure
PAOD
Pneumonia
Sepsis
Anemia
Respiratory insufficiency
Prior revascularization
Prior in-hospital bleeding
M edication before admission
Antihypertensive medication
Aspirin
Statin/other lipid-low ering drug
A ntidiabetic medication
Loop diuretic
Vitamin K antagonist
COPD medication
Index hospitalization
Hospital facilities
H igh-volum ef
PCI and CABG facilities
ACS diagnosis
Unstable angina pectoris
NSTEMI
STEMI
AMI w ithout specification
Year o f admission
2005
2006
2007
2008
2009
2010
2011

Overall Study Cohort

(n = 54 6 9 4)

Early Invasive Strategy

(n = 9 8 52)

Conservative Invasive
Strategy (n = 9 8 5 2 )

68 (30-90)
34 793(63.6)

67 (30-90)
6388(64.8)

66 (30-90)
6428(65.3)

2.1
1.0

18 172 (33.2)
17 950(32.8)
18 316(33.5)
256(0.5)

3007 (30.5)
3182(32.3)
3620(36.7)
43(0.5)

2957(30.0)
3199(32.5)
3656(37.1)
40(0.4)

1.1
0.4
0.8
1.5

20 440(37.4)
22 634(41.4)
7782(14.2)
3838(7.0)
22 731 (41.6)
170(0.3)
43(0-198)

3718(37.7)
4202 (42.6)
1493(15.2)
439(4.5)
3931 (39.9)
31 (0.3)
42 (0-197)

3503(35.6)
4201 (42.6)
1478(15.0)
670(6.8)
3889(39.5)
29(0.3)
42 (0-197)

4.4
0.0
0.6
10.2
0.8
0.4
1.2

159(0.3)

32 (0.3)

29(0.3)

0.4

6357(11.6)
5204(9.5)
356(0.7)
357(0.7)
1849(3.4)

1001 (10.2)
819(8.3)
51 (0.5)
82(0.8)
255 (2.6)

976(9.9)
840(8.5)
57(0.6)
79(0.8)
275 (2.8)

1.0
0.7
1.4
0.3
1.2

2547 (4.7)
1495 (2.7)
3182(5.8)
2431 (4.4)
559(1.0)
938(1.7)
1365(2.5)
3676(6.7)
505 (0.9)
1537(2.8)
679(1.2)
1456(2.7)
1198(2.2)

356 (3.6)
204 (2.1)
461 (4.7)
344(3.5)
70(0.7)
120(1.2)
209(2.1)
444 (4.5)
48(0.5)
140(1.4)
85 (0.9)
308(3.1)
149(1.5)

373(3.8)
216(2.2)
440 (4.5)
362 (3.7)
87(0.9)
149(1.5)
226(2.3)
427 (4.3)
90(0.9)
146(1.5)
86(0.9)
318(3.2)
166(1.7)

1.1
0.7
1.0
1.1
2.2
2.6
1.4
1.0
4.8
0.8
0.1
0.6
1.6

27 747 (50.7)
17 525 (32.0)
15 115(27.6)
6760(12.4)
8546(15.6)
2786(5.1)
8055 (14.7)

5124 (52.0)
3262 (33.1)
3070 (31.2)
1164(11.8)
1231 (12.5)
441 (4.5)
1395(14.2)

5041 (51.2)
3161 (32.1)
3028(30.7)
1171 (11.9)
1140(12.1)
439(4.5)
1359(13.8)

1.6
2.1
1.1
0.3
1.2
0.1
1.2

37 800(69.1)
19 137 (35.0)

6819(69.2)
3095 (31.4)

6819(69.2)
3096(31.4)

0.0
0.0

8696(15.9)
17 976(32.9)
14 273 (26.1)
13 749 (25.1)

1987 (20.2)
3390(34.4)
1693(17.2)
2782 (28.2)

1885 (19.1)
3166(31.1)
1988(20.2)
2813(28.6)

2.8
4.9
7.7
0.9

8526(15.6)
8101 (14.8)
8064(14.7)
7751 (14.2)
7519(13.8)
7456(13.6)
7277(13.3)

1451 (14.7)
1349(13.7)
1283(13.0)
1383(14.1)
1454(14.8)
1413(14.3)
1519(15.4)

1411 (14.3)
1358(13.8)
1261 (12.8)
1402(14.2)
1461 (14.8)
1417 (14.4)
1542(15.7)

1.1
0.3
0.6
0.3
0.2
0.3
0.8

ASD

ACS = acute c o ronary syndrom e; A M I = acute m yocardial infa rction; ASD = a b solute standardized d iffe ren ce; CABG = coronary artery bypass g ra ft
surgery; COPD = ch ro n ic o b stru ctive p u lm ona ry disease; NSTEMI = non-S T-segm ent elevation m yocardial infa rction; PAOD = p e riphe ral arterial
occlusive disease; PCI = pe rcuta neo us coronary inte rventio n; STEMI = S T-segm ent eleva tion m yocardial infarction.
Values are num bers (p ercen tage s) unless oth erw ise indica ted,
t Values w ere im p u te d and w ere w ell-b alance d.
t > 40 0 cases o f ACS yearly.
D efine d using codes fro m th e International C lassification o f Diseases, 10th Revision: unstable angina pe ctoris (I200), NSTEMI (1210A, 1211 A, and
1214), STEMI (I210B, 1211 B, and 1213), and AMI w ith o u t spe cifica tion (1219).

w w w .a n n a ls .o rg

Annals of Internal Medicine Vol. 163 No. 10 17 November 2015

741

O riginal R esearch

Effectiveness of Early Invasive Treatment Strategies in ACS

Table 2. T reatm ents in the Propensity Score-M atched C o ho rt*

V a ria b le

Early Invasive S trategy

(n = 9 8 5 2 )

C onservative Invasive
S trate g y (n = 9 8 5 2 )

5427(55.1)
4(0-60)

2542 (25.8)
5(0-60)

62.6
28.3

9852(100.0)
1(0-2)

5678(57.6)
5 (3-60)

121.3
128.2

1144(11.6)
5599(56.8)
1711 (17.4)
1398(14.2)

1122(19.8)
2741 (48.3)
928(16.3)
887(15.6)

22.7
17.1
2.9
3.9

1585 (16.1)
8267 (83.9)

1834 (32.3)
3844(67.7)

38.5
38.5

7656(77.7)
6813 (69.2)
1033(10.9)
1 (0-60)

4450 (42.2)
3557(36.1)
965 (9.8)
7(0-60)

77.7
70.3
2.3
96.3

377(4.9)
7279(95.1)

368(8.3)
4082 (91.7)

13.7
13.7

7207 (73.2)
8684(88.1)
7693(78.1)

5786(58.7)
8057(81.8)
6243(63.4)

31.0
17.7
32.7

ASD

H os p ita lizatio n

Transfer between hospitals

Median hospital stay (range),

Invasive tre a tm e n t

Coronary angiography
Procedures
Median tim e to procedure (range),
Extent o f C A D t
Nonobstructive disease
1- o r 2-vessel disease
3-vessel disease
Missing
H ospitalf
Smaller hospital u n itt
Invasive heart center
Revascularization
Procedures
PCI
CABG
Median tim e to procedure (range),
H ospitalf
Smaller hospital u n itf
Invasive heart center

A n tith ro m b o tic reg im e n

Dual-antiplatelet therapy
Aspirin
ADP receptor inhibitor

ADR = adenosine d ip h o s p h a te ; ASD = ab solute standardized diffe ren ce; CABG = co ronary artery bypass g ra ft surgery; CAD = corona
disease; PCI = pe rcutaneous coronary inte rventio n.
* Values are num bers (percentages) unless oth erw ise indica ted,
t Values are num bers (p ercen tage s o f procedures).
W ith cardiac catheterization facilities only.
Perform prim ary PCI and CABG in a d d itio n to cardiac catheterization.

tie n t characteristics w ithin subgroups rather than hospi

tal strata (Appendix and Appendix Tables 4 and 5,
available at w w w.annals.org). Results were similar, al
th ou gh risk differences were attenuated. We also inves
tig ate d the effect o f a sim ulated unm easured confo un de r on the relative hazard fo r cardiac death at 60
days (Appendix). W e found that a m oderate to strong
unm easured confounder (one associated with a 50%

decrease in the p ro b a b ility o f having an early invasive

strategy and a 6-fold increase in the relative hazard fo r
cardiac death) was required to render our estimates
insignificant. O nly a very strong unm easured confo u n d e r w ould result in m isinterpretation o f a p ote n
tially harmful treatm ent effect as beneficial. Finally, ex
clusion o f patients with STEMI from our propensity
score-m atched cohort did not noticeably affect the es-

Table 3. C um ulative Incide nee o f O utcom es in the Propensity Score-M atched and U nm atched C ohorts*
V a ria b le

Early In vasive S trategy

(n = 9 8 5 2 )

C onservative Invasive
S trate g y (n = 9 8 5 2 )

P ropensity S core -M a tc h e d
C o h o rt (n = 1 9 7 0 4 )

U n m atched C ohort
(n = 5 4 6 9 4 )

3-d outcom es

Cardiac death
Rehospitalization fo r Ml
All-cause death

181 (2.9)
33 (0.3)
207 (3.3)

423 (3.2)
6(0.1)
519(4.0)

604(3.0)
39(0.2)
726(3.7)

1659 (3.0)
65 (0.1)
2086(3.8)

433 (5.4)
278(2.8)
527 (6.5)

761 (6.7)
402 (4.1)
1017 (9.1)

1194 (6.0)
680 (3.4)
1544(7.8)

3504 (6.4)
1891 (3.5)
4740 (8.7)

475 (5.9)
333 (3.4)
601 (7.3)

838(7.6)
491 (5.0)
1159(10.6)

1313(6.7)
824 (4.2)
1760(8.9)

3916(7.1)
2343 (4.3)
5535 (10.1)

3 0 -d outcom es

Cardiac death
Rehospitalization for Ml
All-cause death
6 0 -d outcom es

Cardiac death
Rehospitalization for Ml
All-cause death

Ml = m yocardial infarction.
* Values are num bers o f events (cum ulative incide nce p e r 100 patients at risk).
742

Annals of Internal Medicine

Vol. 163 No. 10

17 November 2015

www.annals.org

O riginal R esearch

Effectiveness of Early Invasive Treatment Strategies in ACS

F igure 1. C um ulative incidence curves fo r cardiac death and rehospitalization fo r Ml w ith in 60 d o f index hospitalization.

Rehospitalization for Ml

Cardiac Death

E
U

HR, 0.75 (95% Cl, 0.66-0.84)

P < 0.001

1~
10

---------- 1------------------1---------------- I

20

30

40

~r~
50

~r~
60

Days Since Hospitalization

At risk, n
CIS 19 704
EIS 0

9050
9462

8907
9383

8834
9325

8775
9294

Days Since Hospitalization

8729
9269

8692
9250

At risk, n
CIS 19 704
EIS 0

CIS

8906
9334

8601
9162

8443
9054

8344
8999

8274
8959

8224
8932

EIS

The HR and OR reflect outcomes at 60 d. CIS = conservative invasive strategy; EIS = early invasive strategy; HR = hazard ratio; Ml = myocardial
infarction; OR = odds ratio.

F igure 2. Associations betw een early versus conservative invasive strategies and cardiac death, by selected p a tie n t
characteristics.

Cardiac Deaths/Patients
(Cumulative Incidence per
100 Patients at Risk), n
Subgroup
Sex
Male
Female
Age
<75 y
Z75y
ACS diagnosis
Unstable angina
Myocardial infarction
Index hospital
PCI and CABG facilities
High-volume hospital
Other
Year of admission
2005-2007
2008-2009
2010-2011

EIS

CIS

Risk Difference
(95% Cl)

269/6388 (5.1)
206/3464 (7.3)

465/6428 (6.4)
373/3424 (9.8)

-1.3 (-2.2 to -0.5)

-2 .5 (-3.9 to -1.1)

190/7049 (3.4)
285/2803 (11.9)

300/6909 (3.7)
538/2943 (17.3)

-0 .3 (-0.9 to 0.4)
-5 .4 (-7.3 to -3.5)

23/1987 (1.5)
452/7865 (6.9)

19/1885 (0.9)
819/7967 (9.3)

0.6 (-0.2 to 1.3)

-2 .4 (-3.2 to -1.5)

168/3095 (6.2)
144/3724 (5.0)
163/3033 (6.8)

334/3096 (9.9)
251/3723 (6.1)
253/3033 (7.2)

-3 .7 (-5.1 to -2.3)
-1.1 (-2.2 to 0.0)
-0 .4 (-1.8 to 1.0)

263/4083 (7.4)
137/2837 (6.2)
75/2932 (3.2)

395/4030 (8.9)
232/2863 (7.1)
211/2959 (6.4)

-1 .5 (-2.8 to -0.3)
-0 .9 (-2.3 to 0.5)
-3.2 (-4.3 to -2.1)

P Value for
Interaction

Hazard Ratio
(95%CI)

0.021
0.77 (0.64-0.93)
0.71 (0.57-0.88)

I - * I 1

<0.001
0.91 (0.73-1.13)
0.65 (0.53-0.79)

1 H

h*H ;
<0.001

1.51 (0.77-2.98)
0.72 (0.61-0.86)

---------I
'

i *
h *H

0.058
1 1
IH

0.61 (0.44-0.84)
0.76 (0.54-1.09)
0.91 (0.76-1.10)

i- h !
*di
W
j

0.81 (0.69-0.96)
0.83 (0.58-1.20)
0.47 (0.39-0.56)

0.93
i

0.125
Favor EIS

Favor CIS

Reported P values for additive interaction were adjusted for multiple comparisons by using the Holm-Bonferroni method. ACS = acute coronary
syndrome; CABG = coronary artery bypass grafting; CIS = conservative invasive strategy; EIS = early invasive strategy; PCI = percutaneous coronary
intervention.
www.annals.org

Annals of Internal Medicine Vol. 163 No. 10 17 November 2015 743

O riginal R esearch
timates, suggesting th a t our results are applicable to
patients with NSTE-ACSs.

is c u s s io n

This study used national adm inistrative health data

reflecting actual clinical practice to evaluate the p ro g
nostic effect o f early invasive strategies in patients with
ACSs. We found evidence that, com pared with a con
servative invasive approach, an early invasive approach
was associated with a decreased risk fo r adverse car
diac events, including cardiac death, in patients hospi
talized with a first ACS.
Com parative effectiveness research is an im portant
adjunct to clinical trials. Treatments that may seem ben
eficial under the ideal conditions o f a random ized, con
tro lle d trial may not perform as well in a real-w orld set
ting. In the case o f routine use o f early invasive
strategies in NSTE-ACSs, findings have been a m b ig u
ous, given significant heterogeneity o f settings, trea t
ments, and end p o in t definitions (5). However, the
available trials have ta u g h t us 3 im portant lessons. First,
patients with high-risk features, such as elevated b io
markers and ST-segment deviations, benefit the most
in term s o f death and Ml (29). Second, the larger trials
showed consistent reductions in the softer end points
o f rehospitalization and recurrent ischemia (29, 30).
Third, meta-analyses have reported early hazards of
death and periprocedural Ml in patients having early
invasive m anagem ent (29, 31), findings that are sup
ported by observational studies (32). Thus, the 2 most
recent versions o f the NSTE-ACS guidelines from the
Am erican Heart Association and Am erican C ollege of
C ardiology (33) and the European Society o f C ardio l
ogy (15) advocate a risk-stratified approach and recom
m end th a t only patients at interm ediate to high risk
have early diagnostic coronary angiography w ithin 24
to 72 hours. O ur data suggest that the benefits o f an
early treatm ent strategy, at least in term s o f cardiac
death and rehospitalization fo r Ml, are achievable in
clinical practice, thus co rroborating current guidelines
and fast-track protocols.
A lthough only exploratory, our subgroup analysis
p rovided interesting results. First, an early invasive
strategy in patients with Ml (and thus those with posi
tive cardiac biom arkers) was associated with a lower
risk fo r cardiac death. Second, elderly patients (aged
>75 years) seemed to benefit the m ost from an early
invasive approach, which may partially explain the ap
parent benefit in fem ale patients, w ho were an average
o f 5 years o ld e r than male patients. Finally, an early
invasive strategy seemed m ost effective in patients ad
m itted directly to an invasive heart center. These fin d
ings and sim ilar results from recent trials su pp ort the
risk-stratified approach to patients with ACSs recom
m ended in current guidelines (34). O n go ing studies
are assessing the potential o f prehospital risk stratifica
tion using tro p o n in m easurements in the em ergency
m edical services setting (35). Such an approach may
help identify high-risk patients w itho ut obvious electro
cardiographic abnorm alities and ensure swift transfer
744 Annals of Internal Medicine Vol. 163 No. 10 17 November 201S

Effectiveness of Early Invasive Treatment Strategies in ACS

to hospitals with PCI and CABG facilities, potentially im
proving patient outcom es (36).
Several lim itations must be considered when our
results are interpreted. First, the observational design
and use o f national adm inistrative health data pre
cluded inform ation on im p orta nt clinical variables, such
as e le ctrocardiographic findings, cardiac tro p o n in mea
surements, Global Registry o f Acute Coronary Events
scores, type o f Ml, and left ventricular ejection fraction.
Consequently, the effect o f unm easured confounders
cannot be ruled out. Second, the diagnoses o f STEMI
and non-ST-segm ent elevation Ml (NSTEMI) have not
been properly validated in the Danish National Patient
Register, and 25% o f patients were diagnosed with un
specified AMI in the study cohort. As a result, all pa
tients with AMI were poo le d in the analyses to avoid
potential misclassification. Third, the propensity scorem atched cohort excluded alm ost tw o thirds o f patients
from both treatm ent groups. A lthough this may raise
doubts a bo ut the patient population to which the esti
mated treatm ent effect applies, the distribution of
patient- and hospital-related characteristics in the p ro
pensity score-m atched co ho rt rem ained sim ilar to that
in the overall ACS cohort. Fourth, inform ation on ad
junctive pharm acotherapy adm inistered in the hospital
and periprocedural com plications was not available,
which precluded a m ore com prehensive description o f
treatm ent interventions. Finally, the results o f our sub
g ro up analyses should be interpreted with caution.
In conclusion, the use o f an early invasive treatm ent
strategy am ong patients hospitalized with a first ACS
was associated with a decreased risk fo r short-term ad
verse cardiac events com pared with a conservative in
vasive approach. O ur findings confirm those o f several
random ized clinical trials. Thus, health care providers
are encouraged to adhere to the tim e frames stated in
international guidelines and fast-track protocols.
From University Hospital Bispebjerg, University o f C openha
gen, and University o f Southern Denmark, C openhagen; Uni
versity Hospital G entofte, H ellerup; University Hospital Holbaak, Holbaek; and O dense University Hospital, Odense,
Denmark.

Note: Dr. Hansen had full access to all o f the data in th e study
and takes responsibility fo r the in te g rity o f the data and the
accuracy o f th e data analysis.

Acknowledgment: The authors thank the physicians p ro vid in g

data to the Danish Heart Registry fo r th e ir hard w ork and con
tinuous efforts.

Financial Support: By the D e pa rtm e nt o f C a rd io lo g y at Univer

sity Hospital G entofte and grants from A b b o tt Vascular Re
search and the M aster Mason Lauritz Peter Christensen and
w ife Kirsten Sigrid Christensen Foundation.

Disclosures: A uthors have disclosed no conflicts o f interest.

Forms can be view ed at w w w .acpo nline .org/au thors/icm je
/C onflictO flnterestF orm s.do ?m sN u m = M 15-0303.
www.annals.org

Effectiveness of Early Invasive Treatment Strategies in ACS

Reproducible Research Statement:

S t u d y p r o t o c o l a n d d a ta

s e t : N o t a v a ila b le . S t a t is t ic a l c o d e : A v a ila b le fro m Dr. Hansen

(e -m a il, k im .w a d t.h a n s e n @ re g io n h .d k ).

Requests for Single Reprints: Kim W a d t H ansen, M D , D e p a rt

m e n t o f C a rd io lo g y , B is p e b je rg U n ive rsity H o s p ita l, B u ild in g
67, B is p e b je rg B akke 23, 2 4 0 0 C o p e n h a g e n , D e n m a rk.

C u rre n t a u th o r a d d re s s e s a n d a u th o r c o n trib u tio n s are a v a il

a b le a t w w w .a n n a ls .o rg .

R eferences
1. Pereira M, Azevedo A, Lunet N, Carreira H, O 'Flaherty M,
Capewell S, et al. Explaining the decline in coronary heart disease
m ortality in Portugal between 1995 and 2008. Circ Cardiovasc
Qual Outcom es. 2013;6:634-42. [PMID: 24192571] d o i:10 .1161
/CIRCOUTCOMES.113.000264
2. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V,
et al. G lobal and regional m ortality from 235 causes o f death fo r 20
age groups in 1990 and 2010: a systematic analysis fo r the Global
Burden o f Disease Study 2010. Lancet. 2012;380:2095-128. [PMID:
23245604] doi: 10.1016/S0140-6736(12)61728-0
3. Mehta SR, Cannon CP, Fox KA, W allentin L, Boden WE, Spacek R,
et al. Routine vs selective invasive strategies in patients with acute
coronary syndromes: a collaborative meta-analysis o f randomized
trials. JAMA. 2005;293:2908-17. [PMID: 15956636]
4. Bainey KR, Gafni A, Rao-Melacini P, Tong W, Steg PG, Faxon DP,
et al; TIMACS Investigators. The cost im plications o f an early versus
delayed invasive strategy in acute coronary syndromes: the TIMACS
study. J M ed Econ. 2014;17:415-22. [PMID: 24702256] do i:1 0.3111
/1 3696998.2014.911184
5. Q ayyum R, Khalid MR, A do m aityte J, Papadakos SP, Messineo
FC. Systematic review: com paring routine and selective invasive
strategies fo r the acute coronary syndrome. Ann Intern Med.
2008;148:186-96. [PMID: 18252682] doi: 10.7326/0003-4819-148-3
-200802050-00005
6. Chung SC, G edeborg R, Nicholas O, James S, Jeppsson A, W olfe
C, e t al. Acute m yocardial infarction: a com parison o f short-term
survival in national outcom e registries in Sweden and the UK.
Lancet. 2014;383:1305-12. [PMID: 24461715] doi: 10.1016/S0140
-6736(13)62070-X
7. Hannan EL. Randomized clinical trials and observational studies:
guidelines fo r assessing respective strengths and limitations. JACC
Cardiovasc Interv. 2008; 1:211 -7. [PMID: 19463302] do i:1 0.1016/j.jcin
.2008.01.008
8. Lucas FL, Siewers AE, Malenka DJ, W ennberg DE. Diagnostictherapeutic cascade revisited: coronary angiography, coronary ar
tery bypass graft surgery, and percutaneous coronary intervention in
the m odern era. Circulation. 2008;118:2797-802. [PMID: 19064681]
d o i:1 0.1161/CIRCULATIONAHA.108.789446
9. Andersen TF, Madsen M, Jorgensen J, M ellem kjoer L, Olsen JH.
The Danish National Hospital Register. A valuable source o f data fo r
m odern health sciences. Dan Med Bull. 1999;46:263-8. [PMID:
10421985]
10. A b ild stro m SZ, Kruse M, Rasmussen S, Madsen JK, Nielsen PH,
Madsen M; Danish Heart Registry. [The Danish Heart Registry-a clin
ical database], Ugeskr Laeger. 2008;170:532-6. [PMID: 18291083]
11. Gaist D, Sorensen HT, Hallas J. The Danish prescription regis
tries. Dan Med Bull. 1997;44:445-8. [PMID: 9377907]
12. Juel K, Helweg-Larsen K. The Danish registers o f causes o f death.
Dan M ed Bull. 1999;46:354-7. [PMID: 10514943]
13. Madsen M, Davidsen M, Rasmussen S, A bild stro m SZ, O sier M.
The validity o f the diagnosis o f acute m yocardial infarction in routine
statistics: a com parison o f m ortality and hospital discharge data with
the Danish M O NICA registry. J Clin Epidem iol. 2003;56:124-30.
[PMID: 12654406]
w w w .a n n a ls .o r g

O riginal R esearch
14. Joensen AM, Jensen MK, O vervad K, Dethlefsen C, Schm idt E,
Rasmussen L, et al. Predictive values o f acute coronary syndrom e
discharge diagnoses differed in the Danish National Patient Registry.
J Clin Epidem iol. 2009;62:188-94. [PMID: 18722087] doi: 10.1016/j
.jclinepi.2008.03.005
15. Hamm CW, Bassand JP, Agew all S, Bax J, Boersma E, Bueno H,
et al; ESC Com m ittee fo r Practice G uidelines. ESC guidelines fo r the
m anagem ent o f acute coronary syndrom es in patients presenting
w ithout persistent ST-segment elevation: The Task Force fo r the
M anagem ent o f Acute Coronary Syndromes (ACS) in Patients Pre
senting W ith o u t Persistent ST-Segment Elevation o f the European
Society o f C ardiology (ESC). Eur Heart J. 2011 ;32:2999-3054. [PMID:
21873419] doi: 10.1093/eurheartj/ehr236
16. Steg PG, James SK, A tar D, Badano LP, Blom strom -Lundqvist C,
Borger MA, et al; Task Force on the M anagem ent o f ST-Segment
Elevation Acute M yocardial Infarction o f the European Society of
C ardiology (ESC). ESC guidelines fo r the m anagem ent o f acute m yo
cardial infarction in patients presenting with ST-segment elevation.
Eur Heart J. 2012;33:2569-619. [PMID: 22922416] doi:10.1093
/eurheartj/ehs215
17. Tu JV, Austin PC, W alld R, Roos L, Agras J, M cDonald KM. De
velop m ent and validation o f the O ntario acute m yocardial infarction
m ortality prediction rules. J Am Coll Cardiol. 2001;37:992-7. [PMID:
11263626]
18. So L, Evans D, Quan H. ICD-10 coding algorithm s fo r defining
com orbidities o f acute m yocardial infarction. BMC Health Serv Res.
2006;6:161. [PMID: 17173686]
19. Thygesen K, A lp e rt JS, Jaffe AS, Simoons ML, Chaitman BR,
W hite HD, et al; W riting G roup on the Joint ESC/ACCF/AHA/W HF
Task Force fo r the Universal D efinition o f M yocardial Infarction.
Third universal definition o f m yocardial infarction. Eur Heart J. 2012;
33:2551-67. [PMID: 22922414] doi:10.1093/eurheartj/ehs184
20. Saaby L, Poulsen TS, Diederichsen AC, Hosbond S, Larsen TB,
Schm idt H, et al. M ortality rate in type 2 m yocardial infarction: obser
vations from an unselected hospital cohort. Am J Med. 2014; 127:
295-302. [PMID: 24457000] doi:10.1016/j.am jm ed.2013.12.020
21. Saaby L, Poulsen TS, Hosbond S, Larsen TB, Pyndt Diederichsen
AC, Hallas J, et al. Classification o f m yocardial infarction: frequency
and features o f type 2 m yocardial infarction. Am J M ed. 2013;126:
789-97. [PMID: 23856021] do i:1 0.1016/j.am jm ed.2013.02.029
22. Baron T, Hambraeus K, Sundstrom J, Erlinge D, Jernberg T, Lin
dahl B; TOTAL-AMI study group. Type 2 m yocardial infarction in
clinical practice. Heart. 2015;101:101-6. [PMID: 25331532] doi:10
.1136/heartjnl-2014-306093
23. McClellan M, McNeil BJ, Newhouse JP. Does m ore intensive
treatm ent o f acute m yocardial infarction in th e elderly reduce m or
tality? Analysis using instrumental variables. JAMA. 1994;272:85966. [PMID: 8078163]
24. Austin PC. Using the standardized difference to com pare the
prevalence o f a binary variable between tw o groups in observational
research. Com m un Stat Simul Com put. 2009;38:1228-34.
25. Rosenbaum PR. O bservational Studies. 2nd ed. New York:
Springer-Verlag; 2002.
26. Simon R, Makuch RW. A non-param etric graphical representa
tio n o f the relationship between survival and the occurrence o f an
event: application to responder versus non-responder bias. Stat
Med. 1984;3:35-44. [PMID: 6729287]
27. Suissa S. Immortal tim e bias in pharm aco-epidem iology. Am J
Epidem iol. 2008;167:492-9. [PMID: 18056625]
28. Lin DY, Psaty BM, Kronmal RA. Assessing the sensitivity o f regres
sion results to unmeasured confounders in observational studies. Bi
ometrics. 1998;54:948-63. [PMID: 9750244]
29. Mehta SR, G ranger CB, Boden WE, Steg PG, Bassand JP, Faxon
DP, et al; TIMACS Investigators. Early versus delayed invasive inter
vention in acute coronary syndromes. N Engl J Med. 2009;360:216575. [PMID: 19458363] d o i:1 0.1056/NEJM oa0807986
30. Cannon CP, W eintraub WS, D em opoulos LA, Vicari R, Frey MJ,
Lakkis N, et al; TACTICS (Treat Angina with A ggrastat and Deter
mine Cost o f Therapy w ith an Invasive or Conservative S trategy)Throm bolysis in M yocardial Infarction 18 Investigators. Com parison

Annals of Internal Medicine Vol. 163 No. 10 17 November 2015 745

O riginal R esearch
of early invasive and conservative strategies in patients with unstable
coronary syndromes treated with the glycoprotein llb/llla inhibitor
tirofiban. N Engl J Med. 2001;344:1879-87. [PMID: 11419424]
31. Hoenig MR, Aroney CN, Scott IA. Early invasive versus conserva
tive strategies for unstable angina and non-ST elevation myocardial
infarction in the stent era. Cochrane Database Syst Rev. 2010:
CD004815. [PMID: 20238333] doi:10.1002/14651858.CD004815
.pub3
32. Sorajja P, Gersh BJ, Cox DA, McLaughlin MG, Zimetbaum P,
Costantini C, et al. Impact of delay to angioplasty in patients with
acute coronary syndromes undergoing invasive management: anal
ysis from the ACUITY (Acute Catheterization and Urgent Intervention
Triage strategY) trial. J Am Coll Cardiol. 2010;55:1416-24. [PMID:
20359590] doi:10.1016/j.jacc.2009.11.063
33. Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats
TG, Holmes DR Jr, et al; American College of Cardiology. 2014
AHA/ACC Guideline for the Management of Patients with Non-ST-

Effectiveness of Early Invasive Treatment Strategies in ACS

Elevation Acute Coronary Syndromes: a report of the American Col
lege of Cardiology/American Heart Association Task Force on Prac
tice Guidelines. J Am Coll Cardiol. 2014;64:e139-228. [PMID:
25260718] doi:10.1016/j.jacc.2014.09.017
34. Savonitto S, Cavallini C, Petronio AS, Murena E, Antonicelli R,
Sacco A, etal; Italian Elderly ACS Trial Investigators. Early aggressive
versus initially conservative treatment in elderly patients with non-STsegment elevation acute coronary syndrome: a randomized
controlled trial. JACC Cardiovasc Interv. 2012;5:906-16. [PMID:
22995877] doi: 10.1016/j.jcin.2012.06.008
35. de Beider MA. Interventional management of acute coronary
syndromes: applying the lessons of ST-elevation services to non-STelevation myocardial infarction. Heart. 2012;98:1407-11. [PMID:
22791653] doi:10.1136/heartjnl-2012-302459
36. Acute Versus Subacute Angioplasty in Patients With NON-STElevation Myocardial Infarction (NONSTEMI) [clinical trial]. Accessed
at https://clinicaltrials.gov/ct2/show/NCT01638806 on 1 June 2015.

A d L ibitum
erran t gull
the sun is once again behind me and I

your wings so sure I had seen you in that

have come a long way to see you as I

instant years ago so far off the path

thought I had once before and again the

unasked for in my life arriving for no

day is ending with you hidden from my

reason lost blown by arctic winds come to

sight

wake my senses

standing by the sea wall arms elbows

and now less sure I am back and so I

tucked in tightly scanning the

dreamt w ere you nemesis last on my

brightening waves the light ready to

obsessive list and though I know more

depart lifts from the ground around me

than before how your feathers may be worn

and cuts slowly through the

I am no longer satisfied by a backlit

trees behind before it catches the taller

silhouette in a distant view but would see

waves the further breaches warm breaks in

you descending upon me a vision in an

the gray as your dancing brethren wheel

opened

like golden kites hoping to hide you from

my sweeping gaze

sky significant or wanting that would own

you outright remorse failing within my empty
weathered grasp

I took comfort once in believing that I

had actually seen you the telltale dark
along your back your buoyant flight just
waiting to be convinced by the pureness
of light shining through

D.A. Frater, MD
Dallas, Texas
C urrent A u th o r Address: D.A. Frater, MD; e-mail, dfrater@ ebarrow m edical.m d.

2015 American College of Physicians

746 Annals of Internal Medicine Vol. 163 No. 10 17 November 2015

www.annals.org

Copyright American College of Physicians 2015.