Regional Patterns of Use of a Medical Management Strategy
for Patients With Non–ST-Segment Elevation Acute
Coronary Syndromes
Insights From the EARLY ACS Trial
Matthew T. Roe, MD, MHS; Jennifer A. White, MS; Padma Kaul, PhD;
Pierluigi Tricoci, MD, PhD, MHS; Yuliya Lokhnygina, PhD; Chadwick D. Miller, MD, MS;
Arnoud W. van’t Hof, MD; Gilles Montalescot, MD, PhD; Stefan K. James, MD, PhD;
Jorge Saucedo, MD; E. Magnus Ohman, MD; Charles V. Pollack, Jr, MD; Judith S. Hochman, MD;
Paul W. Armstrong, MD; Robert P. Giugliano, MD, SM; Robert A. Harrington, MD;
Frans Van de Werf, MD, PhD; Robert M. Califf, MD; L. Kristin Newby, MD, MHS
Downloaded from http://circoutcomes.ahajournals.org/ by guest on July 28, 2017
Background—Regional differences in the profile and prognosis of non–ST-segment elevation acute coronary syndrome
(NSTE ACS) patients treated with medical management after angiography remain uncertain.
Methods and Results—Using data from the Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute
Coronary Syndromes (EARLY ACS) trial, we examined regional variations in the use of an in-hospital medical management
strategy in NSTE ACS patients who had significant coronary artery disease (CAD) identified during angiography, factors
associated with the use of a medical management strategy, and 1-year mortality rates. Of 9406 patients, 8387 (89%)
underwent angiography and had significant CAD; thereafter, 1766 (21%) were treated solely with a medical management
strategy (range: 18% to 23% across 4 major geographic regions). Factors most strongly associated with a medical management
strategy were negative baseline troponin values, prior coronary artery bypass grafting, lower baseline hemoglobin values, and
greater number of diseased vessels; region was not a significant factor. One-year mortality was higher among patients treated
with a medical management strategy compared with those who underwent revascularization (7.8% versus 3.6%; adjusted
hazard ratio, 1.46; 95% CI, 1.21–1.76), with no significant interaction by region (interaction probability value⫽0.42).
Conclusions—Approximately 20% of NSTE ACS patients with significant CAD in an international trial were treated solely with
an in-hospital medical management strategy after early angiography, with no regional differences in factors associated with
medical management or the risk of 1-year mortality. These findings have important implications for the conduct of future
clinical trials, and highlight global similarities in the profile and prognosis of medically managed NSTE ACS patients.
Clinical Trial Registration—URL: www.clinicaltrials.gov. Unique identifier: NCT00089895.
(Circ Cardiovasc Qual Outcomes. 2012;5:205-213.)
Key Words: non–ST-segment elevation acute coronary syndrome 䡲 medical management 䡲 coronary artery disease
䡲 mortality
S
Acute Coronary Events (GRACE) registry demonstrated trends
for increasing use of both angiography and percutaneous coronary intervention (PCI) for NSTE ACS patients from 1999 to
2006 across 14 countries, with a concomitant decline in the use
of a medical management strategy without revascularization.3
Although an analysis from the Can Rapid Risk Stratification of
Unstable Angina Patients Suppress Adverse Outcomes With
ince 2002, clinical practice guidelines in the United States
and Europe have endorsed an early invasive management
strategy for patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS), consisting of early angiography
followed by either anatomy-driven revascularization or conservative medical management for patients without revascularization options.1,2 Data from the international Global Registry of
Received April 15, 2011; accepted February 9, 2012.
From the Duke Clinical Research Institute, Durham, NC (M.T.R., J.A.W., P.T., Y.L., E.M.O., R.A.H., R.M.C., L.K.N.); University of Alberta,
Edmonton, Alberta, Canada (P.K., P.W.A.); Department of Emergency Medicine, Wake Forest University School of Medicine, Winston-Salem, NC
(C.D.M.); Division of Cardiology, Hospital ‘De Weezenlanden,’ Zwolle, The Netherlands (A.W.V.); Institut de Cardiologie, Pitié–Salpêtrière Hospital,
Paris, France (G.M.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (S.K.J.); Division of Cardiology, University of Oklahoma
Medical Center, Oklahoma City, OK, (J.S.); Department of Emergency Medicine, Pennsylvania Hospital, Philadelphia, PA (C.V.P.); Department of
Medicine, NYU School of Medicine, New York, NY (J.S.H.); TIMI Study Group, Brigham and Women’s Hospital, Boston, MA (R.P.G.); Department
of Cardiovascular Diseases, Gasthuisberg University Hospitals Leuven, Leuven, Belgium (F.V.W.).
This manuscript was handled independently by Guest Editor Paul A. Heidenreich, MD. The Editors had no role in the evaluation of the article or the
decision about its acceptance.
Correspondence to Dr Matthew T. Roe, 2400 Pratt Street, Room 7035, Duke Clinical Research Institute, Durham, NC 27705. E-mail [email protected]
© 2012 American Heart Association, Inc.
Circ Cardiovasc Qual Outcomes is available at http://circoutcomes.ahajournals.org
205
DOI: 10.1161/CIRCOUTCOMES.111.962332
206
Circ Cardiovasc Qual Outcomes
March 2012
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Early Implementation of the ACC/AHA Guidelines (CRUSADE)
initiative demonstrated similar findings only in the United
States, regional differences were not reported in the GRACE
analysis; thus, regional variations in the use of a medical
management strategy after early angiography have not been well
characterized in contemporary practice.4 Given the increasing
use of early invasive management strategies for NSTE ACS
patients over the last decade, the profile and prognosis of patients
who are solely treated with a medical management strategy after
early angiography may have changed. It also remains unknown
whether the clinical factors associated with a medical management
strategy and the clinical outcomes of patients treated with this
strategy differ across geographic regions in contemporary practice.5
Therefore, we examined the Early Glycoprotein IIb/IIIa Inhibition in Non–ST-segment Elevation Acute Coronary Syndromes (EARLY ACS) trial database to (1) evaluate regional
variations in use of an in-hospital medical management strategy
among patients with significant coronary artery disease (CAD)
identified during early angiography, and (2) determine whether
there were regional differences in the clinical factors associated
with a medical management strategy and the 1-year mortality
risks associated with this treatment strategy.
WHAT IS KNOWN
●
●
●
A proportion of non–ST-segment elevation acute
coronary syndrome (NSTE ACS) patients who undergo early catheterization and are found to have
significant coronary artery disease are medically
managed without subsequent revascularization.
NSTE ACS patients treated with a medical management strategy are typically older, more commonly
have undergone prior revascularization procedures,
and have a greater burden of comorbidities.
NSTE ACS patients treated with a medical management strategy have an increased risk of adverse
outcomes, including mortality through at least 1 year
of follow up.
WHAT THE STUDY ADDS
●
●
●
The proportion of NSTE ACS patients with significant
coronary artery disease identified on early catheterization that are subsequently medically managed is similar
across geographic regions (approximately 20%).
Factors associated with the use of a medical management strategy and the increased risk of mortality
through 1 year with a medical management strategy
are similar across geographic regions.
The profile and prognosis of medically managed
NSTE ACS patients are similar across the globe and
have implications for the design and conduct of
future trials targeting NSTE ACS patients.
Methods
Study Population
Patients with NSTE ACS were enrolled in the EARLY ACS trial
from 2004 to 2008 in 29 countries worldwide. Inclusion criteria for
the EARLY ACS trial were ischemic symptoms at rest lasting at least
10 minutes within the previous 24 hours, randomization within 12
hours of initial hospital presentation, planned invasive strategy no
sooner than 12 hours after randomization, and at least 2 of the
following 3 enrichment criteria: age ⱖ60 years, positive cardiac
biomarkers, or ST-segment depression or transient ST-segment
elevation.6
Patients in this analysis underwent angiography and were found to
have significant CAD (at least 1 coronary lesion ⬎50% in at least 1
major epicardial coronary artery). From the original sample of 9406
patients randomized in the EARLY ACS trial, we excluded 1019
(11%) patients who either did not undergo angiography (n⫽240) or
who were found to have insignificant, nonobstructive CAD during
angiography (n⫽779), resulting in an analysis cohort of 8387
patients.
The use of guideline recommended medications during the initial
hospitalization was recommended for patients included in the trial,
but was not mandated by the study protocol. Most patients received
aspirin, clopidogrel, anticoagulants, and anti-ischemic medications
during the acute hospitalization, as detailed in the main study
manuscript.6
Designation of Geographic Regions
Among the 29 countries participating in the EARLY ACS trial, 4
geographic regions were prespecified and used to evaluate regional
differences in the main trial results.6 The 4 designated regions
included North America (United States and Canada), Western
Europe (Austria, Belgium, Denmark, Finland, France, Germany,
Italy, Netherlands, Sweden, Portugal, Spain, Switzerland, United
Kingdom), Eastern Europe (Czech Republic, Poland, Hungary,
Finland, Russia), and the Middle East, Africa, or Asia-Pacific (Israel,
Turkey, Hong Kong, India, Malaysia, Singapore, South Africa,
Australia, New Zealand).
Outcomes Comparisons
We evaluated clinical factors and angiographic findings associated
with the selection of an in-hospital medical management strategy, as
well as mortality rates through 1 year. All baseline clinical characteristics, time intervals from hospital arrival to randomization and
from randomization to angiography, and diagnostic angiographic
findings (extent of CAD and left ventricular ejection fraction
[LVEF]) were evaluated as potential factors associated with use of an
in-hospital medical management strategy, because these variables
would have been known to the treating physician before the decision
to treat with revascularization or a medical management strategy was
made. We chose to focus on 1-year mortality rates in the clinical
outcomes comparisons because the maximum duration of follow-up
for the EARLY ACS trial was 1 year and because (re)infarction
events were captured only during the first 30 days and primarily
occurred during the periprocedural timeframe for patients who
underwent PCI or coronary artery bypass grafting (CABG).6 Therefore, we felt that a comparison of death or (re)infarction rates
between medically managed and revascularized patients would be
too confounded for the purposes of this analysis.
Statistical Analyses
Baseline clinical characteristics and angiographic findings among
patients treated with an in-hospital medical management strategy
were compared with those of patients undergoing revascularization
separately by region, but statistical tests were not performed for these
comparisons, as the main purpose was to characterize the 2 patient
populations, which were expected to be different.
A predictive model was created to determine factors associated
with an in-hospital medical management strategy (versus revascularization) using logistic regression methodology. Baseline demographic and clinical factors, qualifying event details, and precatheterization findings were used as collected on the case report form.
The covariate list for this model included the following: age, weight,
sex, race, smoking status, diabetes, hypertension, family history of
CAD, prior medical or surgical history of vascular disease (CAD,
angina, myocardial infarction, peripheral vascular disease, stroke,
Roe et al
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transient ischemic attack, PCI, CABG), presenting blood pressure
(systolic and diastolic), presenting heart rate, Killip class at presentation, serum creatinine, hemoglobin, hematocrit, and white blood
cell count. Qualifying event variables included elevated cardiac
markers (creatine kinase-MB and troponin levels: positive or negative relative to the site’s upper limit of normal) and ischemic ECG
changes (ST-segment depression ⬎0.1 mV or transient ST-segment
elevation ⬎0.1 mV). Prerandomization medications (angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, aspirin,
␤-blockers, nitrates, morphine, proton-pump inhibitors, and statins)
also were included. Additionally, because noncatheterization patients were excluded from this analysis, the timing from randomization to catheterization, ejection fraction, and number of significantly
diseased vessels also were included.
The most appropriate functional form of each continuous variable
was selected into the model. Model development used stepwise
selection and bootstrap techniques to identify the predictive variables. Variables were selected for entry at a significance level of
P⫽0.10, and retained at P⫽0.05. To prevent loss of observations
during multivariable modeling, multiple imputation was performed
for all covariates. After all significant covariates were included,
region was added to the model. A directed approach to interactions
was used. Interactions with region were tested for the main effects
findings of prior CABG, number of diseased vessels, sex, and
elevated baseline troponin and region. Additionally, an interaction
with region was tested for number of diseased vessels and prior
CABG.
The use of evidence-based medications at hospital discharge was
compared among medically managed versus revascularized patients
within each geographic region to characterize regional differences in
treatment patterns among the 2 groups.
Mortality rates through 1 year were determined by the KaplanMeier method and were compared between patients undergoing
revascularization and those treated with medical management in the
overall sample, among those patients with 3-vessel or left-main
disease on angiography (because these patients would be considered
those to benefit the most from early revascularization), as well as
within each of the 4 regions analyzed. An adjustment model for
1-year mortality was developed using Cox proportional hazards
regression to determine the adjusted risk of mortality for patients
treated with an in-hospital medical management strategy versus
those who underwent revascularization. Predictive modeling steps as
described for the logistic analysis of factors associated with the use
of an in-hospital medical management strategy were employed
during the development of this model using the same variables, with
the exception of precatheterization and prerandomization medications in the covariate list. Additionally, risk factors from the GRACE
6-month mortality models also were included.7 An interaction term
with region was added to the model to determine whether the 1-year
mortality results differed by region.
Results
Medical Management of NSTE ACS
207
portion of patients medically managed within each
region⫽0.02).
Patient Characteristics and Angiographic Findings
Patients treated with an in-hospital medical management
strategy were older, more often female, more frequently had
diabetes mellitus, prior myocardial infarction, prior PCI, and
prior CABG, less often had an elevated baseline troponin
value or ischemic ECG changes, and had lower baseline
hemoglobin and estimated creatinine clearance compared
with patients who underwent revascularization (Table 1). The
median length of stay during the initial hospitalization was
shorter for medically managed patients compared with revascularized patients. While the frequency of these clinical
characteristics differed among regions, the differences between the medically managed versus revascularized patients
appeared to be similar within each region. Patients treated
with an in-hospital medical management strategy also more
frequently had 3-vessel CAD and left-main disease on angiography and an LVEF ⬍30%, with similar findings within
each region (Table 2).
Factors Associated With Selection of a Medical
Management Strategy
The factors most strongly associated with an in-hospital
medical management strategy included negative baseline
troponin, prior CABG, lower baseline hemoglobin values,
3-vessel or left-main CAD identified during angiography,
longer time from randomization to angiography, and lack of
ischemic ECG changes at presentation (Table 3). The model
c-statistic was 0.687, indicating only modest discrimination.
Region was not significantly associated with an in-hospital
medical management strategy, and interaction terms between
region and other variables were not significant. The interaction term between prior CABG and extent of coronary disease
was also not significant.
Discharge Medication Use
The use of evidence-based medications at discharge differed
among the 4 regions analyzed, but overall and within each
region (except for aspirin in Eastern Europe), patients who
were medically managed were consistently less likely to
receive both aspirin and clopidogrel at discharge, compared
with patients who underwent revascularization (Table 4).
Use of a Medical Management Strategy by Region
One-Year Mortality Rates
The approximate proportional enrollment of patients in this
analysis population across the geographic regions was 31% in
North America, 40% in Western Europe, 11% in Eastern
Europe, and 18% in Middle East/Africa/Asia-Pacific. Among
the 8387 patients with significant CAD identified during
angiography, 1766 (21%) were treated with an in-hospital
medical management strategy, 5402 (64%) underwent inhospital PCI, 1174 (14%) underwent in-hospital CABG, and
45 (0.5%) had both in-hospital PCI and CABG. An inhospital medical management strategy was used in 22.6% of
patients from North America, 20.2% from Western Europe,
18.4% from Eastern Europe, and 22.0% from Middle East/
Africa/Asia-Pacific (probability value for comparison of pro-
Unadjusted mortality rates through 1 year were consistently
higher among medically managed patients compared with
those who underwent revascularization (7.8% versus 3.6%,
P⬍0.0001; Figure 1). Similar findings were demonstrated
when the population was restricted to patients with 3-vessel
or left-main disease on angiography, although absolute mortality rates were higher in this restricted population, compared
with the overall population (12.1% versus 5.6%, P⬍0.0001;
Figure 2). This pattern was observed for each region: North
America (7.7% versus 4.3%, Figure 3A), Western Europe
(7.3% versus 3.4%, Figure 3B), Eastern Europe (9.4% versus
4.1%, Figure 3C), and Middle East/Africa/Asia-Pacific (8.3%
versus 2.9%, Figure 3D). In the overall population, the
0.6
11.6
0.8
Asian
21.6
35.2
37.8
16.5
30.7
23.3
13.1
6.5
Hypertension
Current smoking
Diabetes mellitus
Prior MI
Prior CHF
Prior PCI
Prior CABG
Prior PVD
Prior stroke
15.9
78 (67, 91)
142 (128, 160)
77 (67, 90)
Killip class II–IV, %
Heart rate, bpm*
SBP, mm Hg*
Weight, kg*
4 (3, 7)
5 (3, 8)
21.1 (16.6, 30.4)
5.5 (3.3, 8.7)
20.6 (5.6, 75.0)
14.2 (13.1, 15.2)
76 (58, 98)
80 (70, 90)
145 (130, 161)
76 (66, 88)
9.8
87.3
48.0
4.6
9.5
10.4
23.3
10.5
25.3
29.5
29.0
25.1
39.3
47.4
16.8
37.9
34.6
16.5
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
4 (3, 5)
⬍0.001
⬍0.001
6.9 (4.4, 10.2)
23.6 (18.0, 44.1)
⬍0.001
9.3 (2.1, 40.3)
⬍0.001
⬍0.001
71 (51, 92)
13.5 (12.0, 14.9)
⬍0.001
81 (70, 96)
80 (68, 96)
⬍0.001
144 (127, 163)
17.4
⬍0.001
0.046
81.8
⬍0.001
28.2
0.001
⬍0.001
7.9
82.5
⬍0.001
0.001
54.0
⬍0.001
4 (3, 7)
22.4 (17.4, 39.3)
6.5 (4.3, 9.1)
27.6 (7.3, 92.1)
14.2 (13.0, 15.3)
80 (58, 102)
84 (73, 96)
146 (130, 166)
79 (68, 92)
9.6
89.5
37.7
5.5
9.9
15.5
28.7
9.6
29.2
33.5
32.2
71.4
33.8
1.8
2.5
7.7
88.0
27.8
66 (59, 74)
Revasc
(n⫽1954)
5 (4, 8)
22.5 (18.4, 38.9)
6.0 (3.5, 9.3)
9.0 (2.0, 40.0)
13.9 (12.9, 15.0)
69 (53, 91)
78 (69, 89)
144 (130, 163)
77 (66, 90)
14.4
79.9
44.9
5.7
14.2
17.2
30.9
16.6
29.3
29.8
20.1
76.8
39.1
0.1
0
0.1
99.7
35.3
71 (64, 77)
MM
(n⫽682)
6 (4, 9)
21.0 (16.7, 28.3)
5.1 (3.1, 8.6)
19.5 (5.6, 70.0)
14.3(13.3, 15.2)
76 (58, 98)
80 (70, 90)
146 (130, 160)
75 (65, 86)
10.8
87.6
50.0
3.9
10.4
7.9
21.8
13.3
20.4
26.2
27.3
68.3
24.0
0.0
0.2
0.1
99.7
27.3
69 (61, 76)
Revasc
(n⫽2693)
Western Europe
6 (4, 13)
20.6 (16.6, 24.1)
4.3 (2.7, 7.8)
4.2 (0.8, 26.3)
13.6 (12.8, 14.5)
68 (53, 90)
76 (70, 85)
144 (130, 160)
75 (65, 88)
11.9
64.9
58.9
11.9
11.9
15.5
26.8
25.6
53.0
26.2
19.6
87.5
34.5
0
0
0
100.0
39.3
69 (62, 76)
MM
(n⫽168)
6 (4, 11)
18.9 (15.1, 23.5)
3.8 (2.2, 6.5)
27.3 (6.6, 108.1)
14.2 (13.2, 15.2)
77 (59, 99)
80 (70, 90)
140 (130, 160)
75 (65, 84)
6.7
85.0
58.0
5.5
10.8
6.7
15.7
11.9
29.7
26.9
26.6
78.2
20.6
0
0.4
0
99.6
35.7
67 (60, 74)
Revasc
(n⫽747)
Eastern Europe
4 (3, 5)
21.5 (16.5, 40.9)
5.2 (3.3, 9.0)
5.7 (1.4, 26.6)
13.3 (12.1, 14.6)
63 (48, 82)
69 (60, 80)
137 (123, 156)
80 (70, 91)
18.5
75.4
59.5
3.2
5.8
20.5
20.5
11.3
31.2
43.4
19.9
68.2
33.8
0.3
53.8
0.6
45.4
30.6
67 (59, 74)
MM
(n⫽346)
4 (3, 7)
21.3 (16.5, 35.3)
5.4 (3.3, 9.1)
13.8 (3.6, 49.0)
14.0 (12.8, 15.1)
72 (55, 94)
74 (65, 84)
140 (125, 160)
78 (66, 89)
10.1
84.7
53.9
4.2
6.0
10.0
22.3
5.0
26.9
32.2
28.9
60.8
26.7
0.2
31.6
0.5
67.6
23.4
64 (57, 73)
Revasc
(n⫽1227)
Middle East/Africa/Asia-Pacific
MM indicates medical management; revasc, revascularization; CAD, coronary artery disease; MI, myocardial infarction; CHF, congestive heart failure; PCI, percutaneous coronary intervention; CABG, coronary artery bypass
grafting; PVD, peripheral vascular disease; bpm, beats per min; SBP, systolic blood pressure; CrCl, creatinine clearance, ULN, upper limit of normal for site-reported troponin values.
*Continuous variables expressed as medians (25th, 75th percentiles).
†Determined with Cockroft-Gault formula.
Hospital length of stay, d*
6.0 (3.6, 9.5)
22.4 (17.8, 40.2)
Randomization to angiography, h*
.8.0 (1.8, 35.4)
13.7 (12.5, 14.9)
Hospital presentation to randomization, h*
Time variables
Maximum troponin ratio, xULN*
Other laboratory results
Hemoglobin, g/dL*
CrCl, mL/min*†
68 (51, 90)
78.2
Elevated initial troponin, %
Baseline laboratory results
43.7
Ischemic ST-changes, %
27.0
68.9
2.3
3.3
12.8
81.6
37.0
⬍0.001
69 (61, 77)
⬍0.001
MM
(n⫽570)
⬍0.001
P-Value
North America
Circ Cardiovasc Qual Outcomes
Presenting features
42.5
78.0
Prior CAD
Medical history, %
Other
6.7
4.3
2.4
83.2
90.3
27.7
67 (59, 74)
Revasc
(n⫽6621)
Black
35.3
69 (62, 76)
MM
(n⫽1766)
White
Race, %
Female sex, %
Age, y*
Demographics
Variable
Overall Population
Baseline Clinical Characteristics by Treatment Strategy Within Each Region
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Table 1.
208
March 2012
Roe et al
Table 2.
Medical Management of NSTE ACS
209
Angiographic Findings by Treatment Strategy Within Each Region
Overall Population
MM
(n⫽1766)
Revasc
(n⫽6621)
1-vessel
31.8
2-vessel
3-vessel
Western Europe
Eastern Europe
Middle East/Africa/
Asia-Pacific
MM
(n⫽570)
Revasc
(n⫽1954)
MM
(n⫽682)
Revasc
(n⫽2693)
MM
(n⫽168)
Revasc
(n⫽747)
MM
(n⫽346)
Revasc
(n⫽1227)
38.7
29.5
36.5
34.9
40.8
26.2
32.3
32.1
41.6
24.7
28.4
23.9
23.3
21.1
26.1
21.4
28.0
19.9
28.1
32.9
43.5
30.9
28.1
29.9
24.0
36.9
25.6
35.5
22.2
14.4
10.4
15.8
12.1
14.1
9.1
15.5
14.2
12.4
8.1
P-Value
⬍0.001
Extent of coronary disease, %*
Left main disease
North America
⬍0.001
EF, %†
ⱖ50%
64.1
69.1
58.2
62.5
71.0
74.6
66.7
75.0
59.0
63.9
30–49%
27.9
26.6
30.0
31.2
23.6
22.1
28.0
22.6
32.7
31.6
8.0
4.3
11.8
6.3
5.4
3.4
5.4
2.4
8.4
4.5
⬍30%
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MM indicates medical management; revasc, revascularization; EF, ejection fraction.
P-values compare the distribution of extent of coronary disease and ejection fraction categories.
*Determined based upon the No. of major epicardial coronary arteries with at least 1 lesion ⬎50% documented during angiography. Patients with a ⬎50% lesion
in the left main coronary artery listed as a separate category.
†Determined by left ventriculography or another method.
adjusted risk of 1-year mortality was almost 50% higher
among patients who were medically managed (adjusted HR,
1.46; 95% CI, 1.21–1.76), with no significant interaction with
region (interaction probability value⫽0.42).
Discussion
We have demonstrated that approximately 20% of NSTE
ACS patients with significant CAD identified during early
angiography in a contemporary, international clinical trial
Table 3. Baseline Clinical Characteristics and Angiographic Findings Significantly
Associated With Selection of a Medical Management Treatment Strategy After Angiography
Variable
X2
OR
95% CI
P-Value
Negative baseline troponin value
78.2
1.95
1.68 –2.26
⬍0.0001
Prior CABG
48.3
1.82
1.54–2.16
⬍0.0001
Baseline hemoglobin (per 5 mg/dL decrease)
33.3
1.82
1.49–2.23
Extent of coronary disease
⬍0.0001
⬍0.001
26.6 (3)*
2-vessel disease on angiography
0.98
0.84–1.14
3-vessel disease on angiography
1.35
1.17–1.55
Left main disease on angiography
1.34
1.11–1.61
⬍0.0001
Randomization to angiography (per 5 h increase)
23.9
1.25
1.14–1.36
Ischemic ST-segment ECG changes
23.7
0.75
0.67–0.84
⬍0.0001
Weight (per 5 kg decrease)
22.3
1.07
1.04–1.11
⬍0.0001
Baseline heart rate (per 10 bpm increase)
16.9
1.09
1.04–1.11
⬍0.0001
Killip class ⬎I on presentation
12.8
1.35
1.15–1.59
0.0003
Prior MI
11.3
1.26
1.10–1.45
0.0008
Hospital arrival to randomization (per 5 h increase)
11.3
1.12
1.05–1.20
0.0008
1.40
1.11–1.77
Ejection fraction
10.0 (2)†
⬍30%
30–50%
0.007
0.96
0.84–1.09
History of hypertension
7.2
1.20
1.05–1.37
0.008
History of CAD
6.9
1.22
1.05–1.41
0.009
Female sex
6.4
1.19
1.04–1.36
0.01
OR indicates odds ratio; CABG, coronary artery bypass grafting; MI, myocardial infarction; CAD, coronary artery disease.
Model c-statistic⫽0.687.
*Three degrees of freedom test; comparison is with 1-vessel coronary disease on angiography.
†Two degrees of freedom; comparison is with ejection fraction ⱖ50%. Note: Continuous variables are included in
the model as linear splines starting at knot points as follows: baseline hemoglobin ⬍15 mg/dL, time from
randomization to angiography ⬍20 hours, weight ⬍85 kg, heart rate ⬎80 beats/min, and time from hospital arrival
to randomization ⬍20 hours.
210
Table 4.
Circ Cardiovasc Qual Outcomes
March 2012
Discharge Medications by Treatment Strategy Within Each Region*
Overall Population
North America
Western Europe
Eastern Europe
Middle East/Africa/
Asia-Pacific
MM
(n⫽1766)
Revasc
(n⫽6621)
P-Value
MM
(n⫽558)
Revasc
(n⫽1909)
MM
(n⫽669)
Revasc
(n⫽2649)
MM
(n⫽162)
Revasc
(n⫽731)
MM
(n⫽338)
Revasc
(n⫽1209)
Aspirin
93.3
97.2
⬍0.001
94.6
96.5
91.5
97.6
96.9
96.6
92.9
97.7
Clopidogrel
58.3
83.3
⬍0.001
56.7
80.9
57.5
86.7
56.8
84.2
69.4
85.7
Beta-blockers
83.4
84.4
0.28
83.6
84.4
83.5
84.7
89.4
91.1
79.7
80.0
ACE inhibitors
67.6
64.5
0.02
65.4
58.6
66.0
65.6
83.9
83.0
66.6
60.3
ARBs
10.6
8.8
0.02
11.6
9.2
11.2
10.5
8.6
5.5
8.6
6.5
Statins
85.2
87.0
0.05
79.7
83.0
85.4
87.5
90.1
89.7
91.4
90.7
Medication, %
MM indicates medical management; revasc, revascularization; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
*Among patients who survived the initial hospitalization.
Downloaded from http://circoutcomes.ahajournals.org/ by guest on July 28, 2017
were treated solely with an in-hospital medical management
strategy, with only slight regional heterogeneity. Clinical
characteristics and angiographic findings predicted the use of
an in-hospital medical management strategy only modestly
well, with no significant differences among regions. Finally,
patients who were treated with an in-hospital medical management strategy had a higher risk of mortality through 1 year
compared with those who underwent in-hospital revascularization, with no interaction by region.
While significant variations in the use of early angiography
and revascularization across geographic regions have been
demonstrated in numerous international registries (and likely
relate to the availability of cardiac catheterization facilities),
factors associated with the use of a medical management
strategy after early angiography have not been widely studied
in contemporary practice from a regional perspective.8,9 A
previous analysis from the Superior Yield of the New
Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial (conducted from 2001–2003),
which also evaluated patients with significant CAD after
early angiography, demonstrated that non-United States
country location, as well as prior CABG and 3-vessel CAD,
were significant predictors of a medical management treatment strategy.5 In contrast to those findings, we have dem-
onstrated in a more contemporary trial that region was no
longer a significant predictor of a medical management
strategy, but that both prior CABG and multi-vessel CAD
(determined by a relatively imprecise dichotomous designation on the case report form of significant coronary disease in
each major epicardial vessel) remained as consistent predictors of a medical management strategy after early angiography. Despite the fact that the EARLY ACS trial was conducted after the publication of NSTE ACS guideline updates
in 2002 that strongly endorsed an early invasive management
strategy for high-risk patients, patients with severe CAD (ie,
those with prior CABG or multi-vessel disease identified
during early angiography) appeared less likely to undergo
revascularization for the index ACS event in this analysis.1,2
Similarly, the likelihood of finding multi-vessel CAD on
angiography for NSTE ACS patients has been shown to be
inversely related to the use of angiography in the CRUSADE
registry, which profiled the care of patients treated in routine
practice in the United States from 2001 to 2006.10 Despite
these findings, the decision-making process for selecting
NSTE ACS patients for both angiographic and revascularization procedures remains poorly characterized and understood.
Thus, further study is needed to delineate how patient clinical
and historical characteristics influence the initial decision to
Figure 1. Kaplan-Meier curves showing
1-year mortality for patients treated with a
medical management strategy versus
in-hospital revascularization in the overall
population. Probability value ⬍0.0001 for
comparison between medical management versus revascularization.
Roe et al
Figure 2. Kaplan-Meier curves showing the cumulative risk of
death through 1-year stratified by medical management versus
revascularization for patients with 3-vessel or left main disease
on angiography. Probability value ⬍0.0001 for comparison
between medical management versus revascularization.
Downloaded from http://circoutcomes.ahajournals.org/ by guest on July 28, 2017
perform coronary angiography for NSTE ACS patients and
how angiographic findings are then integrated with the other
patient information in terms of deciding whether or not to
perform subsequent revascularization procedures.
Revascularization for NSTE ACS patients is recommended
to mitigate the risk of death and recurrent ischemic events, so
the prognosis of patients treated with a medical management
strategy is typically much worse than those who are revascularized.1,2 Analyses from registries have shown that NSTE
ACS patients who do not undergo angiography or who
undergo angiography without subsequent revascularization
have a much higher risk of both short-term and long-term
mortality.4,11,12 Recent analyses from NSTE ACS trials have
confirmed these observations among patients who undergo
Medical Management of NSTE ACS
211
early angiography but who do not proceed to subsequent
revascularization procedures.5,13,14 Long-term mortality rates
for patients treated with a medical management strategy from
these analyses of clinical trial databases were 7.7% in the
SYNERGY trial (postdischarge through 1 year, only patients
with significant CAD), 4.3% in the Acute Catheterization and
Urgent Intervention Triage Strategy (ACUITY) trial (randomization through 1 year, all randomized patients), and 10%
in the Invasive Versus Conservative Treatment in Unstable
Coronary Syndromes (ICTUS) trial (postdischarge through 4
years, all randomized patients), all of which were higher than
the reported mortality rates for revascularized patients in the
respective trials.5,13,14 The present analysis complements
these observations by demonstrating a similar observation (a
1-year mortality rate of almost 8%) in medically managed
NSTE ACS patients with significant CAD identified during
early angiography in a more contemporary sample of invasively managed patients. Importantly, this analysis also delineates the novel finding that this risk of mortality is similar
across geographic regions.
Limitations
This analysis has several limitations. First, patients treated
with an in-hospital medical management strategy were highly
selected based on the fact that they were healthy enough to
be enrolled in a clinical trial and to be eligible for early
angiography, so these results may not apply to the broader,
more heterogeneous population of NSTE ACS patients
treated with a medical management strategy in routine clinical practice.11 However, the age enrichment criterion for the
Figure 3. Kaplan-Meier curves showing 1-year mortality for patients treated with a medical management strategy versus in-hospital revascularization stratified by region. A, North America. B, Western Europe. C, Eastern Europe. D, Middle East/Africa/Asia-Pacific. Probability values ⬍0.0001 for all comparisons between medical management and revascularization.
212
Circ Cardiovasc Qual Outcomes
March 2012
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EARLY ACS trial led to a relatively elderly population of
patients with a median age of 65 to 70 years across regions,
so the proportion of medically managed patients may have
been artificially enhanced by the selection of older patients
for the trial. Additionally, given the fact that a negative
baseline troponin value was the strongest predictor of medical
management in this analysis, there may have been a portion
of troponin-negative patients in this trial who were determined to be low to moderate risk by the treating physician
postrandomization (despite having ischemic ST-segment
changes per the inclusion criteria) and were thus selected for
medical management after angiography. Second, detailed
angiographic findings related to lesion complexity and risk,
as well as the technical suitability of coronary lesions for
revascularization, were not collected. Furthermore, the extent
of coronary disease in each major epicardial coronary vessel
was recorded dichotomously on the case report form only as
a stenosis ⬎50%, so we could not assess how more stringent
categorizations of significant coronary disease (ie, lesions
with stenoses ⬎70%, or previously developed indices or
scores of coronary disease severity) would influence this
analysis. For this analysis, we could only assess how a
relatively crude designation of extent of coronary disease
(2-vessel, 3-vessel, and left-main disease) influenced the
decision for medical management after angiography. Third,
factors that influenced the treating physicians’ decision making regarding the selection of a revascularization versus
medical management strategy for individual patients were not
collected; thus, the results of this analysis should not be
construed to imply that a greater use of revascularization
procedures for patients enrolled in the trial would have
improved outcomes. Fourth, postdischarge revascularization
procedures were not recorded through 1-year follow-up in the
EARLY ACS trial; thus, we could not determine what
proportion of patients who were initially medically managed
subsequently underwent late revascularization procedures.
Fifth, cause of death was not adjudicated, and so we could not
determine how cardiovascular versus noncardiovascular
deaths contributed to the increased mortality risk demonstrated in the medically managed patients. Finally, regional
enrollment in the EARLY ACS trial was disproportionate,
with approximately 70% of the patients enrolled in North
America and Western Europe; thus, our regional analyses
may have therefore been biased by the unequal proportions of
patients within each region.
Conclusions
We have demonstrated a similar profile and prognosis for
medically managed patients with significant CAD across
different regions of the world, a finding that highlights the
global similarities in the disposition and outcomes of invasively managed NSTE ACS patients who are not revascularized. These results have important implications for the
conduct of future global NSTE ACS trials in that the
proportion of medically managed patients will be expected to
be similar across regions but will have a strong influence on
expected mortality rates and resultant sample size and power
calculations. As such, specific enrichment strategies for
medically managed patients may need to be considered.
Finally, further study is needed to accurately determine the
factors influencing physicians in their decision-making regarding the selection of a medical management strategy for
NSTE ACS patients managed invasively.
Sources of Funding
The EARLY ACS trial was funded by Schering-Plough Corporation.
These analyses were funded by research grant support from Merck &
Co, Inc.
Disclosures
Dr Roe has received prior research support from Merck/ScheringPlough and compensation from Merck for clinical end point adjudication activities. Dr Tricoci has received advisory board and research
support from Merck. Dr Miller has received research support from
Schering-Plough/Merck. Dr van’t Hof has received lecture fees and
unrestricted grants from Schering Plough/Merck. Dr Montalescot has
received consulting/lecture fees from Schering-Plough/Merck. Dr
James has received research support and speaker fees from ScheringPlough. Dr Ohman is a principal investigator for Schering-Plough,
now Merck. Dr Pollack has received research support from ScheringPlough. Dr Hochman is on the advisory board for Schering-Plough/
Merck. Dr Armstrong has done consulting for Merck Frosst Canada
Ltd. and receives research support from Schering-Plough/Merck. Dr
Giugliano has received research support, advisory board, and honoraria for CME lectures from Schering-Plough/Merck. Dr Harrington
has received research support and consulting with Schering-Plough/
Merck. Dr Van de Werf has received research support, advisory
board, and speaker fee from Schering-Plough/Merck. Dr Califf has
received research funding and consulting with Schering-Plough, now
Merck (all consulting funds donated to not-for-profits). Dr Saucedo
has received research support, advisory board, and honoraria for
lectures from Schering-Plough/Merck. Dr Newby has received research support from Schering-Plough/Merck. Ms White and Drs
Lokhnygina and Kaul have no conflicts to disclose.
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Regional Patterns of Use of a Medical Management Strategy for Patients With Non−
ST-Segment Elevation Acute Coronary Syndromes: Insights From the EARLY ACS Trial
Matthew T. Roe, Jennifer A. White, Padma Kaul, Pierluigi Tricoci, Yuliya Lokhnygina,
Chadwick D. Miller, Arnoud W. van't Hof, Gilles Montalescot, Stefan K. James, Jorge Saucedo,
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Giugliano, Robert A. Harrington, Frans Van de Werf, Robert M. Califf and L. Kristin Newby
Circ Cardiovasc Qual Outcomes. 2012;5:205-213; originally published online February 28,
2012;
doi: 10.1161/CIRCOUTCOMES.111.962332
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