Determinants and Prognostic Impact of Heart Failure

Complicating Acute Coronary Syndromes

Observations From the Global Registry of Acute Coronary
Events (GRACE)
Philippe Gabriel Steg, MD; Omar H. Dabbous, MD, MPH; Laurent J. Feldman, MD;
Alain Cohen-Solal, MD; Marie-Claude Aumont, MD; José López-Sendón, MD;
Andrzej Budaj, MD, PhD; Robert J. Goldberg, PhD; Werner Klein, MD;
Frederick A. Anderson, Jr, PhD; for the Global Registry of Acute Coronary Events
(GRACE) Investigators

Background—Few data are available on the impact of heart failure (HF) across all types of acute coronary syndromes
(ACS).
Methods and Results—The Global Registry of Acute Coronary Events (GRACE) is a prospective study of patients
hospitalized with ACS. Data from 16 166 patients were analyzed: 13 707 patients without prior HF or cardiogenic shock
at presentation were identified. Of these, 1778 (13%) had an admission diagnosis of HF (Killip class II or III). HF on
admission was associated with a marked increase in mortality rates during hospitalization (12.0% versus 2.9% [with
versus without HF], P⬍0.0001) and at 6 months after discharge (8.5% versus 2.8%, P⬍0.0001). Of note, HF increased
mortality rates in patients with unstable angina (defined as ACS with normal biochemical markers of necrosis; mortality
rates: 6.7% with versus 1.6% without HF at admission, P⬍0.0001). By logistic regression analysis, admission HF was
an independent predictor of hospital death (odds ratio, 2.2; P⬍0.0001). Admission HF was associated with longer
hospital stay and higher readmission rates. Patients with HF had lower rates of catheterization and percutaneous cardiac
intervention, and fewer received ␤-blockers and statins. Hospital development of HF (versus HF on presentation) was
associated with an even higher in-hospital mortality rate (17.8% versus 12.0%, P⬍0.0001). In patients with HF,
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in-hospital revascularization was associated with lower 6-month death rates (14.0% versus 23.7%, P⬍0.0001; adjusted
hazard ratio, 0.5; 95% CI, 0.37 to 0.68, P⬍0.0001).
Conclusions—In this observational registry, heart failure was associated with reduced hospital and 6-month survival across
all ACS subsets, including patients with normal markers of necrosis. More aggressive treatment of these patients may
be warranted to improve prognosis. (Circulation. 2004;109:494-499.)
Key Words: heart failure 䡲 prognosis 䡲 myocardial infarction 䡲 angina

C oronary artery disease, including the acute coronary

syndromes (ACS) of unstable angina, non–ST-segment
elevation myocardial infarction (NSTEMI) and ST-segment
elevation myocardial infarction (STEMI), is the most com-
mon cause of heart failure (HF).1 Conversely, heart failure is
a frequent complication of ACS2 and significantly worsens
the prognosis of patients with ischemic heart disease.3 Owing
to the strong association between ACS and HF, it is important
to understand the determinants of HF in patients hospitalized
with ACS, particularly those with unstable angina, and the
impact of HF on outcomes. Although the determinants and
impact of HF in patients with acute STEMI have been
studied,4,5 little information is available for other ACS sub-
sets, particularly unstable angina.
See p 440
The objective of the GRACE (Global Registry of Acute
Coronary Events) registry is to provide data on the treatment,
practice patterns, and outcomes of patients with ACS.2,6 The
aim of this report is to evaluate the determinants and impact
on outcomes of HF complicating ACS in a large unselected
population from the GRACE registry.

Received March 25, 2003; de novo received July 16, 2003; revision received October 23, 2003; accepted October 24, 2003.
From Centre Hospitalier Universitaire Bichat-Beaujon, Assistance Publique-Hôpitaux de Paris, France (P.G.S., L.J.F., A.C.-S., M.-C.A.); the
University of Massachusetts Medical School, Worcester, Mass (O.H.D., R.J.G., F.A.A.); Hospital Universitario Gregorio Marañon, Madrid, Spain
(J.L.-S.); Grochowski Hospital, Warsaw, Poland (A.B.); and Medizinische Universitätsklinik, Klinische Abteilung fur Kardiologie, Graz, Austria (W.K.).
Dr Steg has been a speaker and consultant for Aventis Pharma. GRACE is funded by an unrestricted educational grant from Aventis Pharma.
Correspondence to Philippe Gabriel Steg, MD, Cardiology, Hôpital Bichat, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. E-mail
gabriel.steg@bch.ap-hop-paris.fr
© 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000109691.16944.DA

494

Methods
Full details of the GRACE methodology have been published.2,6,7
Currently, 94 hospitals located in 14 countries are participating in
this observational study. Patients must be ⱖ18 years of age, be
admitted for ACS as a presumptive diagnosis, and have at least one
of the following: ECG changes consistent with ACS, serial increases
in serum biochemical markers of cardiac necrosis, and/or documen-
tation of coronary artery disease.7 The qualifying ACS must not have
been precipitated or accompanied by a significant comorbidity,
trauma, or surgery. At 6 months after hospital discharge, patients are
followed up by telephone, clinic visits, or calls to the primary care
physician. Where required, study investigators received approval
from their local hospital ethics or institutional review board.
Standardized definitions of all patient-related variables and clini-
cal diagnoses were used as well as hospital complications and
outcomes.7 All cases were assigned to one of the following catego-
ries: STEMI, NSTEMI, unstable angina, and other cardiac/noncar-
diac diagnoses. These definitions take into account clinical presen-
tation, ECG findings, and the results of serum biochemical markers
of necrosis. Specifically, unstable angina was defined as ACS with
normal biochemical markers of necrosis. Patients were categorized at
the time of hospital admission according to the classification of
Killip and Kimball8 for signs of HF. Because patients with Killip
class IV represent a small subset (⬇1% of the total cohort) with a
dismal prognosis, they were excluded from the data set. To distin-
guish HF complication on admission for ACS from chronic HF,
patients with prior HF were also excluded.
Statistical Analysis
Continuous variables in respective comparison groups are summa-
rized by medians (interquartile range) and were analyzed by means
of the Wilcoxon rank sum test. Categorical variables are reported as
frequencies and percentages and tested by ␹2 test. Ordinal categorical
variables were analyzed by a ␹2 trend test. Independent predictors of
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HF were identified by means of stepwise, multivariable, logistic
regression. The impact of HF on hospital and postdischarge to
6-month follow-up mortality rates was examined by means of
multiple logistic, Kaplan-Meier, and Cox regression analysis, respec-
tively. Predetermined clinically relevant variables “age, gender,
diastolic blood pressure, systolic blood pressure, initial creatinine,
medical history (angina, smoking, stroke, diabetes, hypertension,
coronary artery disease, myocardial infarction, peripheral vascular
disease, hyperlipidemia, atrial fibrillation, PCI, CABG, bleeding,
and renal dysfunction), cardiac arrest at admission, any significant Q
wave at admission, left bundle-branch block, ventricular pacing
rhythm, atrioventricular block, atrial fibrillation or flutter, prior use
of statins, diuretics, ACE inhibitors, and ␤-blockers, unstable angina,
STEMI, and NSTEMI” were entered into the multivariable backward
stepwise logistic and Cox regression analyses. Only significant
variables at a value of P⬍0.05 were retained in the final models.
Results
Between April 1999 and September 2001, 16 166 patients
with suspected ACS were enrolled. Of these, 13 707 had a
confirmed diagnosis of ACS without prior HF and Killip
class IV at the time of hospital presentation, and represent the
study sample. Among these, 1778 patients (13%) had HF
(Killip class II or III) at hospital admission.
Patient Population
Patients with HF were significantly older than patients
without HF and were less likely to be male or smokers (Table
1). A history of comorbidities was more common in patients
with HF compared with those without HF. The incidence of
HF was similar in patients with STEMI (15.6%) or NSTEMI
(15.7%) and was half as frequent in patients with unstable
angina (8.2%). Heart rate was higher in patients with versus
Steg et al Impact of Heart Failure on ACS 495
those without HF. Of the patients with HF, 46.2% had an
anterior myocardial infarction compared with 33.6% in those
without HF (P⬍0.0001). Q waves were present in a higher
proportion of patients with HF compared with those with
uncomplicated ACS (30.2% versus 24%, respectively;
P⬍0.0001) Left bundle-branch block was present in 7.7% of
patients with HF versus 3.1% of patients without
(P⬍0.0001). Atrial fibrillation/flutter was recorded in 9.9%
of patients with HF compared with 5.2% in those without
(P⬍0.0001).
Treatment Patterns
Patients with HF were less likely to undergo cardiac cathe-
terization procedures than patients without HF (Table 1).
ACE inhibitors, diuretics, digoxin, warfarin, antiarrhythmic
agents, and inotropic drugs were more frequently prescribed
during the acute hospitalization in patients who had HF
before admission. The use of ␤-blockers and statins was
significantly lower among patients with HF at the time of
hospital admission.
At discharge, patients with HF were more frequently pre-
scribed digoxin (12.0% versus 3.3%, P⬍0.0001), diuretics
(41.4% versus 14.4%, P⬍0.0001), and ACE inhibitors (63.7%
versus 49.5%, P⬍0.0001) than those without HF. The trend to
reduced prescribing of ␤-blockers and statins in patients with HF
continued at discharge (65.1% versus 73.4%, P⬍0.0001, and
(45.7% versus 52.1%, P⬍0.0001, respectively).
Hospital Outcomes
HF at admission was associated with a 4-fold increase in
crude hospital mortality rates (12.0% versus 2.9%; OR, 4.6;
95% CI, 3.85 to 5.40). This was true across all ACS subsets,
including unstable angina (16.5% versus 4.1% in STEMI;
10.3% versus 3% in NSTEMI; 6.7% versus 1.6% in unstable
angina; P⬍0.0001 for each comparison and for trend). The
mortality rates were 2.9%, 9.9%, and 20.4%, for patients in
Killip classes I, II, and III, respectively (P⬍0.0001). In
patients with myocardial infarction, the median duration of
hospitalization was ⬇2 days longer in patients with compared
with those without HF (9 versus 7 days, P⬍0.0001 for
STEMI; 8 versus 6 days, P⬍0.0001 for NSTEMI; 5 days for
both in unstable angina, P⫽0.3174).
When admission predictors of hospital death were analyzed
by multivariable logistic regression analysis, an admission diag-
nosis of HF was associated with a significantly increased risk of
dying (adjusted OR, 2.2; 95% CI, 1.75 to 2.67). Patients ⱖ75
years of age had the highest mortality rates across all ACS
subgroups. However, the interaction between age and HF was
statistically significant (P⫽0.0022). Patients ⬍55 years of age
had the highest relative increase in mortality rate related to HF,
and this was consistent across ACS subsets (Figure 1). When the
group of patients with a diagnosis of myocardial infarction was
broken down according to the presence or absence of Q waves
at discharge, it was apparent that HF on admission had a very
strong negative prognostic impact not only on patients with
Q-wave myocardial infarction (in-hospital mortality rate, 16.4%
versus 5.2%, P⬍0.0001) but also in those with non–Q-wave
myocardial infarction (in-hospital mortality rate, 12.4% versus
3.0%, P⬍0.0001).
 496 Circulation February 3, 2004

TABLE 1. Baseline Characteristics, Medical Setting, and Frequency of Hospital Procedures for
Patients With Acute Coronary Syndromes According to Presence of Heart Failure at Admission
Heart Failure No Heart Failure
(n⫽1778) (n⫽11 929) P
Age, y, median (IQR) 72.5 (63.7–79.5) 64.0 (54.1–72.9) ⬍0.0001
Male, % 60.1 69.6 ⬍0.0001
Medical history, %
Smoker 53.8 59.9 ⬍0.0001
TIA/stroke 11.6 6.5 ⬍0.0001
Diabetes mellitus 29.9 20.9 ⬍0.0001
Myocardial infarction 32.0 26.7 ⬍0.0001
PCI 9.7 14.0 ⬍0.0001
CABG 11.3 10.9 0.6300
Peripheral vascular disease 14.2 8.8 ⬍0.0001
Hypertension 59.5 55.7 0.0026
Hyperlipidemia 37.7 44.6 ⬍0.0001
Renal dysfunction 10.0 6.4 ⬍0.0001
Atrial fibrillation 9.9 5.2 ⬍0.0001
Presentation without chest pain 15.6 5.6 ⬍0.0001
Laboratory measurements
Initial creatinine, mg/dL, median (mean IQR) 1.1 (0.9–1.4) 1.0 (0.9–1.2) ⬍0.0001
Peak creatinine, mg/dL, median (mean IQR) 1.3 (1.0–1.7) 1.1 (0.9–1.3) ⬍0.0001
Initial cholesterol, mg/dL, median (mean IQR) 194.0 (163.3–224.5) 198.9 (169.0–230.0) 0.0586
Left ventricular ejection fraction ⱕ40%, % 48.7 20.2 ⬍0.0001
No. of patients with left ventricular ejection 71.3 69.0 0.0415
fraction measured, %
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Medical setting, %
Teaching hospital 67.6 64.6 0.1400
Access to (in-hospital) catheterization 76.0 76.5 0.6500
laboratory
Medical specialty (cardiologist vs 71.1 76.3 ⬍0.0001
noncardiologist)
Hospital procedures, %
Cardiac catheterization 46.5 54.2 ⬍0.0001
Percutaneous coronary intervention 26.0 31.8 ⬍0.0001
CABG 5.9 6.6 0.3087
IQR indicates interquartile range; TIA, transient ischemic attack.

Postdischarge Outcomes patients with an admission diagnosis of HF were more likely

Postdischarge data were available from 11 348 (83.0%) of the to be rehospitalized than those with uncomplicated ACS
patients eligible for follow-up at 6 months; 12.0% of these (STEMI, 25.0% versus 14.7%, P⬍0.0001; NSTEMI, 24.7%
patients had HF at hospital admission, and HF developed in a versus 15.8%, P⬍0.0001; unstable angina, 23.1% versus
further 5.6% during hospitalization. Across all ACS subsets, 17.7%, P⫽0.0200). Compared with similar patients without

Figure 1. Differential impact of HF upon admis-

sion on in-hospital mortality rates as a function
of age [OR of mortality rate relative to patients
without HF (95% confidence interval)].
 Steg et al Impact of Heart Failure on ACS 497

underwent in-hospital revascularization had a cumulative 6-month

mortality rate of 14.0 versus 23.7% in those who did not
(P⬍0.0001). After adjustment for baseline differences, mortality
rate remained lower for HF patients who had undergone revascu-
larization (adjusted HR, 0.5; 95% CI, 0.37 to 0.68, P⬍0.0001).

Admission Predictors of HF
Patient admission characteristics were studied to evaluate the
admission predictors of HF. Increased age, raised pulse rate,
STEMI, NSTEMI (compared with unstable angina), prior
diuretic use, diabetes, and left bundle-branch block were
among the factors found to be strong independent predictors
of HF (Table 2).

Figure 2. Mortality rates from hospital admission to 6-month Timing of Development of HF

follow-up (postdischarge) for patients with HF at admission ver-
sus no HF at admission. (HR for HF at admission, 3.8; 95% CI,
3.33 to 4.36.)
HF, those with STEMI (19.7% versus 2.8%; P⬍0.0001) or
NSTEMI (11.0% versus 3.6%; P⬍0.0001) complicated by
HF also had 3-fold higher postdischarge mortality rates.
Patients with HF at admission had an approximately 3-fold
increase in 6-month postdischarge mortality rate (8.5% ver-
sus 2.8%, respectively; P⬍0.0001) and were also more likely
to be rehospitalized (23.6% versus 15.7%, P⬍0.001) than
other patients with ACS. Postdischarge mortality rates did not
differ significantly between patients who presented with HF
and those in whom HF developed during hospitalization
(8.5% versus 7.7%, respectively, P⫽0.52). Postdischarge use
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Of the patients with HF, two thirds had it at presentation and
one third had it after admission. Patients with HF on admis-
sion tended to be older and were also more likely to have a
history of coronary artery disease, myocardial infarction,
atrial fibrillation, and CABG (Table 3). Patients with HF on
initial evaluation were less likely to undergo cardiac cathe-
terization or CABG, to require mechanical ventilation, or to
have a Swan-Ganz catheter inserted than those who had
development of HF during hospitalization. They were also
less likely to receive ACE inhibitors, ␤-blockers, diuretics,
and inotropic agents. Incidence and mortality rates according
to the presence and timing of CHF and to ACS subtype are
displayed in Figure 4. Patients who had development of HF
later on had a higher mortality rate than those with an

of revascularization was slightly lower in patients with HF admission diagnosis of HF (17.8% versus 12.0%, P⬍0.0001).
compared with those without HF (12.5% versus 14.8%,
P⫽0.02). TABLE 2. Factors Associated With Heart Failure at the Time of
Cumulative in-hospital and postdischarge mortality rate was Hospital Admission in Patients With Acute Coronary Syndromes
20.7% in patients with HF on admission compared with ␹2 OR CI
5.9% (P⬍0.0001) in those without HF on admission (P⬍0.001;
Age, 10-y increase 316.2 1.5 1.45–1.60
hazard ratio [HR], 3.8; 95% CI, 3.33 to 4.36) (Figure 2). Cumulative
Pulse, 10-beat increase 266.4 1.23 1.22–1.28
mortality rate was even higher in patients who had HF development
in the hospital compared with those with HF at admission (25.3% STEMI 99.2 2.1 1.84–2.47
versus 20.7%) (Figure 3). Among patients with HF, those who NSTEMI 43.2 1.6 1.41–1.91
Prior use of diuretics 31.0 1.5 1.31–1.75
History of diabetes 18.3 1.3 1.16–1.50
Left bundle-branch block 17.2 1.6 1.30–2.10
Initial creatinine (per 1-U increase) 15.3 1.1 1.10–1.19
History of myocardial infarction 12.3 1.3 1.03–1.50
Any significant Q wave at admission 12.2 1.3 1.10–1.43
Gender (female is reference) 10.2 0.8 0.72–0.93
History of peripheral vascular disease 10.0 1.3 1.10–1.55
Prior use of oral ␤-blockers 8.8 1.2 1.10–1.40
History of percutaneous coronary 8.7 0.75 0.62–0.91
intervention
History of smoking 7.5 1.2 1.10–1.34
Systolic blood pressure (per 10-mm Hg 6.0 0.9 0.96–0.99
decrease)
Atrioventricular block 5.5 2.30 1.18–4.60
Figure 3. Mortality rates from hospital admission to 6-month History of stroke 5.0 1.2 1.10–1.50
follow-up (postdischarge) for patients with HF at admission and
for patients who had development of HF during hospitalization. C statistic⫽0.75.
(HR for HF at admission, 1.3; 95% CI, 1.05 to 1.50.) Hosmer and Lemeshow goodness-of-fit test, P⫽0.3093.
 498 Circulation February 3, 2004

TABLE 3. Characteristics of Patients According to Timing of Development of

Heart Failure
Heart Failure at Heart Failure in
Characteristic Admission Hospital P
No. (%) 1778 (67.2) 869 (32.8)
Median age, y (IQR) 72.5 (63.7,79.5) 70 (61.0,78.0) ⬍0.0001
Male, % 1064 (60.1) 538 (62.4) 0.2430
Medical history, n (%)
CABG 200 (11.3) 70 (8.1) 0.0120
Diabetes mellitus 531 (29.9) 243 (28.1) 0.3300
Hypertension 1052 (59.5) 537 (62.0) 0.2300
MI 569 (32.0) 203 (23.4) ⬍0.0001
Smoker 956 (53.8) 470 (54.5) 0.8850
Procedures, n (%)
CABG 104 (5.9) 89 (10.3) ⬍0.0001
Cardiac catheterization 824 (46.5) 476 (54.8) ⬍0.0001
Percutaneous coronary intervention 459 (26.0) 287 (33.2) 0.0001
Hospital medical treatment, n (%)
ACE inhibitors 1192 (67.6) 630 (73.0) 0.0050
␤-Blockers 1239 (70.3) 664 (76.8) 0.0005
Diuretic 1203 (67.8) 683 (79.0) ⬍0.0001
Inotropes 327 (18.6) 272 (31.6) ⬍0.0001
Length of stay, d (median, IQR) 7 (4, 12) 10 (6, 15) ⬍0.0001
In-hospital death, n (%) 212 (12.0) 154 (17.8) ⬍0.0001

This was true overall but also for each ACS subset, except for ACS, regardless of the presence of HF, three recent trials
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patients with STEMI, in whom there was a nonsignificant
trend. Patients with later HF also had an increased duration of
hospitalization compared with patients with HF at admission
(10 versus 7 days, P⬍0.001).
Discussion
Heart failure on hospital admission was associated with an
approximately 3- to 4-fold increase in hospital and 6-month
death rates. HF was also associated with longer hospital stay and
higher readmission rates. As in previous studies, development of
HF during hospital stay (as opposed to HF at admission) was
associated with an even worse outcome.4,9 Although it is well
known that HF is a frequent and severe complication of acute
myocardial infarction,4,5,9 –11 this report provides evidence that
even in patients with unstable angina and normal biochemical
markers of necrosis, HF is a potent predictor of poor outcomes.
Using criteria as simple as Killip class, in a subset of almost
5000 patients with unstable angina, HF was associated with a
4-fold increase in mortality rates.
Importantly, there was a reduced frequency of PCI and
lower ␤-blocker usage among patients with HF on admission.
Similar findings were reported in a recent study of STEMI.4
In view of the poor prognosis of HF, aggressively identifying
patients who are suitable for revascularization would appear
to be justified to preserve left ventricular function, prevent
left ventricular remodeling, and improve survival. Indeed,
revascularization has been shown to be associated with
improved survival in patients with acute myocardial infarc-
tion and HF12,13 or shock.14 In non–ST-segment elevation
have provided consistent evidence of the benefit of early
revascularization.15–17 Given the high mortality rate of pa-
tients with HF and ACS, this group would be expected to
derive an even greater benefit from revascularization. Impor-
tantly, patients with HF who underwent revascularization had
lower cumulative 6-month mortality rates that those who did
not, even after adjustment for baseline differences. However,
the present study shows that cardiac catheterization and
revascularization are underused in patients with HF at admis-
sion. Among patients who had development of congestive HF
after admission, procedures were performed more frequently,
possibly because the development of HF despite therapy was
precisely considered ominous.
Limitations of the Study
In this multinational registry, the need to obtain, at certain
sites, informed consent from patients to gather follow-up data
may have prevented the inclusion of dying patients and
biased the sample toward a lower risk group. This may
explain the lower crude mortality rates observed among
patients with myocardial infarction compared with NRMI 1
and 2.4,5 However, the 3- to 4-fold increase in hospital
mortality rates related to HF is remarkably consistent across
all these studies.5,18 In GRACE, HF at admission was as-
sessed by clinical examination, which has limitations in the
acute setting, as symptoms may be nonspecific and physical
examination may lack sensitivity.19,20 Indeed, there may be
underrepresentation of patients with atypical symptoms in
GRACE, especially when the presenting symptoms are re-

Figure 4. Incidence and mortality rates of HF according to type
of ACS and timing of occurrence: A, incidence of HF (P⬍0.0001
for HF at admission versus no HF for each group); B, mortality
rate. *P⬍0.0001, †P⫽0.0013, ‡P⬍0.0001 for HF at admission
versus HF during hospitalization.
Downloaded from http://ahajournals.org by on May 23, 2019
lated to HF. However, such low sensitivity would be expected
to underestimate the prevalence of HF among patients with
ACS and therefore does not detract from our finding of the
ominous prognostic implications of HF. In addition, our data
suggest that simple clinical signs of HF, as assessed in the
Killip classification, are directly linked to higher in-hospital
and 6-month mortality rates. These findings extend prior
reports, which confirmed the persistent value of the Killip
classification in assessing prognosis after acute myocardial
infarction21–24 to all ACS subsets. Finally, analyses of post-
admission variables related to physician discretion (eg, med-
ications, interventions) may be strongly influenced by unmea-
sured confounders.
Conclusions
This analysis shows that HF is a common and ominous compli-
cation associated with all forms of ACS, including unstable
angina. It also suggests that patients with ACS and HF are
undertreated. A more aggressive treatment should be recom-
mended in this group of patients to improve outcomes.18
Acknowledgments
GRACE is supported by an unrestricted educational grant from Aventis
Pharma. The authors express their gratitude to all GRACE participants.
Further information is available at www.outcomes.org/grace.
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