High-risk is defined as age older than 80 years, chronic renal insufficiency,
prior congestive heart failure (CHF), prior stroke, signs of CHF at presentation,
or presenting systolic blood pressure less than 90 mm Hg. There are missing
data for troponin positive and negative as some patients qualified for entry
based on creatine kinase-MB or electrocardiographic criteria and did not have
a troponin measurement.
P values for comparisons within each risk group
were <.001. PURSUIT indicates the Platelet glycoprotein IIb/IIIa in Unstable
angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy trial.
Bhatt DL, Roe MT, Peterson ED, Li Y, Chen AY, Harrington RA, Greenbaum AB, Berger PB, Cannon CP, Cohen DJ, Gibson CM, Saucedo JF, Kleiman NS, Hochman JS, Boden WE, Brindis RG, Peacock WF, Smith, SC, Pollack, CV, Gibler WB, Ohman EM, CRUSADE Investigators FT. Utilization of Early Invasive Management Strategies for High-Risk Patients With Non–ST-Segment Elevation Acute Coronary SyndromesResults From the CRUSADE Quality Improvement Initiative. JAMA. 2004;292(17):2096–2104. doi:10.1001/jama.292.17.2096
Context The American College of Cardiology/American Heart Association (ACC/AHA)
guidelines for the management of non–ST-segment elevation acute coronary
syndromes (NSTE ACS) recommend early invasive management for high-risk patients,
given the benefits with this approach demonstrated in randomized clinical
Objectives To determine the use and predictors of early invasive management strategies
(cardiac catheterization <48 hours following presentation) in high-risk
patients with NSTE ACS and to examine the association of early invasive management
Design, Setting, and Patients The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients
Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines)
Quality Improvement Initiative evaluated care patterns and outcomes for 17 926
high-risk NSTE ACS patients (positive cardiac markers and/or ischemic electrocardiographic
changes) based on ACC/AHA guidelines recommendations at 248 US hospitals with
catheterization and revascularization facilities between March 2000 and September
Main Outcome Measures Use of early invasive management within 48 hours of presentation, predictors
of early invasive management, and in-hospital mortality.
Results Of the 17 926 patients analyzed, 8037 (44.8%) underwent early cardiac
catheterization less than 48 hours following presentation. Predictors of early
invasive management included cardiology care, younger age, lack of prior or
current congestive heart failure, lack of renal insufficiency, ischemic electrocardiographic
changes, positive cardiac markers, white race, and male sex. Patients treated
with early invasive management were more likely to be treated with medications
and interventions recommended by the ACC/AHA guidelines and had a lower risk
of in-hospital mortality after adjusting for differences in clinical characteristics
and after comparing propensity-matched pairs (2.5% vs 3.7%, P<.001).
Conclusions An early invasive management strategy is not utilized in the majority
of high-risk patients with NSTE ACS. This strategy appears to be reserved
for patients without significant comorbidities and those cared for by cardiologists
and is associated with a lower risk of in-hospital mortality.
In the past decade, several advances have occurred in the management
of non–ST-segment elevation acute coronary syndromes (NSTE ACS). Pharmacotherapies,
such as intravenous platelet glycoprotein (Gp) IIb/IIIa inhibitors, low-molecular-weight
heparin, and clopidogrel, have demonstrated incremental benefits for patients
with NSTE ACS.1- 4 Complementary
to advances in antithrombotic and antiplatelet therapies, catheterization-based
strategies for revascularization have also improved.5 Randomized
clinical trial data collectively support the use of an early invasive approach
with prompt cardiac catheterization compared with an initial conservative
approach that reserves cardiac catheterization for patients who develop recurrent
ischemia despite medical therapy.6,7 The
Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive
or Conservative Strategy (TACTICS)-Thrombolysis in Myocardial Infarction (TIMI)-18
trial found that catheterization within the first 48 hours after presentation
was superior to an initial strategy of medical management, particularly in
high-risk patients with elevated troponin levels or ST-segment depression.6 Similarly, The Fast Revascularization during Instability
in Coronary artery disease (FRISC II) trial demonstrated a significant reduction
in long-term mortality with early invasive management for NSTE ACS.8
Professional practice guidelines have rapidly incorporated advances
in the treatment of NSTE ACS.9,10 However,
there is a time lag between clinical trial advances, revision of guidelines,
dissemination of recommendations to practicing physicians, and integration
into clinical practice.11 Therefore, we sought
to characterize the contemporary utilization of early invasive management
strategies and determine the relationship between early invasive management
and mortality in a group of high-risk NSTE patients included in the CRUSADE
(Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse
Outcomes With Early Implementation of the ACC/AHA [American College of Cardiology/American
Heart Association] Guidelines) Quality Improvement Initiative.
Patients included in the ongoing CRUSADE Quality Improvement Initiative
have ischemic symptoms at rest within 24 hours prior to presentation and high-risk
features including ST-segment depression, transient ST-segment elevation,
or positive cardiac markers (elevated troponin I or T and/or creatine kinase-MB
> upper limit of normal for participating institutions).12
Data were collected only during the hospitalization in an anonymous
fashion without informed consent after the institutional review board of each
institution approved participation in this quality improvement initiative.
Data collected included baseline clinical characteristics, use of acute medications
(within 24 hours of hospital arrival), use and timing of invasive cardiac
procedures, laboratory results, in-hospital clinical outcomes, and discharge
therapies and interventions. Decisions regarding the use of invasive procedures
were made by the treating physicians. Contraindications to specific therapies
given Class IA or IB recommendations by the ACC/AHA guidelines were recorded.9,13 Data collectors at each participating
site classified patients according to race and/or ethnicity based on chart
abstraction using standard definitions that were provided. These data were
collected as part of baseline demographic information to see if there were
differences in care based on race/ethnicity.
To account for the expected delays in timing of diagnostic cardiac catheterization,
percutaneous coronary intervention (PCI), and coronary artery bypass grafting
(CABG) for patients presenting to institutions without full revascularization
capabilities, patients presenting to hospitals without angioplasty or surgical
facilities were excluded from the analysis. Furthermore, we excluded patients
who were transferred in from other institutions or transferred out from the
initial presenting institution since complete presenting characteristics,
acute treatments, clinical outcomes, and use and timing of invasive procedures
were not available for these patients. Thus, the final analysis cohort comprised
patients who presented directly to hospitals with catheterization laboratories
and angioplasty or cardiac surgical capabilities.
Baseline characteristics and hospital features were compared among patients
who did or did not receive early invasive management (cardiac catheterization
within 48 hours of hospital presentation per the ACC/AHA guidelines recommendations).
Medians with 25th and 75th percentiles were reported for continuous variables
and frequencies for categorical variables. χ2 Tests were used
for categorical variables, and Wilcoxon rank-sum tests were used to compare
To determine the factors that predict the likelihood of early invasive
management, a multiple logistic regression model was developed using the stepwise
approach. The predictive ability of this model was summarized using a C-index.
Since CRUSADE is an observational study, patients were not randomized
by treatment. In comparing patients who underwent early catheterization to
those who did not undergo early catheterization with respect to in-hospital
outcomes (eg, postadmission infarction, cardiogenic shock, congestive heart
failure [CHF], red blood cell transfusion, death, and the composite outcome
of postadmission infarction or death), we adjusted for baseline patient clinical
risk factors including age, sex, body mass index, race, family history of
coronary artery disease, hypertension, diabetes, smoking status, hypercholesterolemia,
prior MI, prior PCI, prior CABG, prior CHF, prior stroke, renal insufficiency,
ST-segment depression, transient ST-segment elevation, positive cardiac markers,
signs of CHF, heart rate, systolic blood pressure, and insurance status as
well as for provider and hospital characteristics (physician specialty, total
number of hospital beds, region of the country, PCI or CABG capabilities,
and type of hospital [academic or nonacademic]) and hours of presentation.
For these analyses, generalized estimating equation (GEE) models were used
to adjust for correlations among clustered responses (eg, within-hospital
correlations) since patients within a single hospital are more likely to be
similar.14 Furthermore, since patients who
died within 48 hours would not have the chance to receive early catheterization,
we performed sensitivity analyses to investigate the relationship between
early catheterization and in-hospital mortality after excluding early deaths
within 24 to 48 hours. We also performed subgroup analyses to explore further
the association between early catheterization and in-hospital mortality across
The Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression
Using Integrilin (eptifibatide) Therapy (PURSUIT) 30-day mortality risk model
for NSTE ACS was modified for this analysis to predict the risk of in-hospital
mortality in the original PURSUIT population from presenting clinical characteristics.15 The original PURSUIT population was divided into
equal tertiles based on the adjusted risk of in-hospital mortality. The tertiles
of patients were then categorized as low-risk, moderate-risk, and high-risk.
The modified PURSUIT model was then applied to the CRUSADE population, which
was divided into risk groups based on the predicted in-hospital mortality
rate calculated for each patient from presenting clinical characteristics.
The association between early catheterization and unadjusted in-hospital mortality
was examined within each risk group to characterize further the impact of
early catheterization among patients with similar baseline risk features.
As an additional way of accounting for nonrandom treatment assignment,
we adjusted for factors favoring selection of one treatment over another using
propensity scores.16 Using multivariable GEE,
a propensity score model was created to estimate the likelihood of early catheterization.
Greedy matching techniques were used to match each patient with another patient
of similar propensity score of receiving early catheterization.17 The
Pearson χ2 test was used to compare mortality rates for these
matched pairs between patients who did and did not undergo early catheterization.
A P value of <.05 was established as the
level of statistical significance for all tests. All analyses were performed
using SAS software (version 8.2, SAS Institute, Cary, NC).
The population for this analysis consisted of 30 295 patients with
high-risk NSTE ACS who were treated at 248 US hospitals between March 1, 2000,
and September 30, 2002. After we excluded 8816 patients who were either transferred
in from other hospitals or transferred out from the presenting institution,
a total of 21 479 patients were left. Among these patients, 185 did not
have information on hospital surgical capabilities, 1140 were admitted to
hospitals without catheterization capabilities, and 2228 were admitted to
hospitals without PCI or CABG capabilities. After excluding these patients,
17 926 were included in the final analysis population who presented to
248 US hospitals with diagnostic cardiac catheterization facilities and capabilities
for PCI or CABG or both.
Among the 17 926 patients included in this analysis, 11 153
(62.2%) underwent cardiac catheterization at some point during their hospitalization,
8037 (44.8%) underwent early invasive management (cardiac catheterization
within 48 hours of presentation), and 3116 (17.4%) underwent cardiac catheterization
more than 48 hours following presentation. Of the 8037 patients who underwent
early invasive management, 75% were revascularized: 4733 (58.9%) underwent
PCI and 1296 (16.1%) underwent CABG. There was a large variation in the use
of early invasive management at the 248 hospitals included in this analysis
as the median use of early catheterization was 47.8%, but the interquartile
range was 33.3% to 57.6%. Temporal analyses demonstrated a slight upward trend
in the use of early invasive management from the third quarter of 2001 until
the third quarter of 2002 (46.8%, 41.2%, 43.4%, 44.4%, and 48.6%, respectively).
Patients who underwent early catheterization were younger, more often
male and white, more likely to be admitted to a cardiology service, and less
likely to have CHF or renal insufficiency (Table
1). The strongest independent predictors of early invasive management
included cardiology care, younger age, lack of renal insufficiency, lack of
prior CHF, slower presenting heart rate, and lack of signs of CHF on presentation
(Table 2). The C-index for the predictive
model was 0.761.
Patients who underwent early invasive management were more likely to
receive ACC/AHA guidelines–recommended acute and discharge medications
and interventions compared with patients who did not undergo early invasive
management (Table 3, Table 4).
The unadjusted incidence of in-hospital mortality was 2.0% for patients
who underwent early invasive management within 48 hours compared with 6.2%
for patients who did not undergo early invasive management. The unadjusted
frequencies of other adverse outcomes were lower in patients who underwent
early invasive management (Table 5).
The adjusted risks of death and death or MI were lower in patients who underwent
early invasive management, whereas the adjusted risks of cardiogenic shock
and red blood cell transfusion were higher. Median length of stay was also
lower in patients undergoing early invasive management (3 days: 25th, 75th
percentiles: 2, 6 days) compared with patients not treated with this approach
(5 days: 25th, 75th percentiles: 3, 8 days) (P<.001).
Sensitivity analyses (eg, excluding deaths within 24 or 48 hours) demonstrate
similar findings with respect to the association between an early invasive
strategy and lower mortality as seen in the overall analysis (Figure 1). Analyses of patient subgroups revealed similar reductions
in mortality with early invasive management except for the subgroups of patients
aged 75 years or older and those who were troponin-negative (Figure 1).
Patients were also stratified into low, medium, and high clinical risk
based on the modified PURSUIT risk score. In all 3 risk categories, patients
undergoing early invasive management had a significantly lower risk of unadjusted
in-hospital mortality, although the highest-risk patients appeared to derive
the greatest absolute benefit from early invasive management (Figure 2).
Propensity matching of patients by early invasive management status
produced groups (5486 patients in each group) that were similarly matched
for clinical, demographic, and hospital characteristics (all P values >.05 except smoking) (Table 6). In this propensity-matched pairs sample, the frequency of in-hospital
mortality was lower in patients who underwent early invasive management (2.5%
vs 3.7%, P <.001).
We have demonstrated that utilization of an early invasive management
strategy was associated with a significantly lower risk of in-hospital mortality
in high-risk patients with NSTE ACS presenting to US hospitals with both catheterization
and revascularization capabilities, although less than half of patients were
managed with this approach. Patients undergoing early invasive management
were younger and more commonly cared for by cardiologists, whereas older patients
with comorbidities were less likely to undergo early invasive management.
The relationship between early invasive management and improved guidelines
adherence for acute and discharge medication use indicates that appropriate
overall guidelines-based care is more commonly delivered to patients treated
with an early invasive strategy.
The updated ACC/AHA guidelines recommend an early invasive strategy
for NSTE ACS patients presenting with high-risk features including ischemic
electrocardiographic changes, elevated troponin levels, new CHF symptoms,
left ventricular dysfunction, prior PCI within 6 months, prior CABG, and hemodynamic
instability.9 Whereas ischemic electrocardiographic
changes, positive cardiac markers, and prior PCI were significant predictors
of early invasive management in this analysis, patients with prior CABG, prior
or current CHF, and faster presenting heart rate were significantly less likely
to undergo early invasive management. These findings may be explained by the
strong association of cardiology care with early invasive management, as cardiologists
have been shown to provide appropriate evidence-based care more commonly than
general practitioners, but also suggest that features that may be perceived
to increase the risks associated with invasive procedures (renal insufficiency,
advanced age, CHF) also strongly influence decisions regarding use of invasive
cardiac procedures.18,19 Factors
influencing physician decision making are difficult to ascertain, but it appears
that younger, healthier patients selectively undergo early invasive management
in the United States, while older patients with more comorbidities are treated
conservatively, even though these patients have a higher risk of mortality
and may derive greater absolute benefit from aggressive management.
Disparities in the utilization of invasive cardiac procedures demonstrated
in this analysis appear to be related to longstanding treatment biases. A
previous registry of NSTE ACS patients from the last decade showed that elderly
patients, women, and minorities were significantly less likely to be referred
for cardiac catheterization during the initial hospitalization.20 Other
studies have also demonstrated similar referral biases and underutilization
of cardiac catheterization in the elderly, women, and minorities.21,22 Even though recent studies have shown
significant reductions in adverse clinical outcomes with early invasive management
and revascularization in patients with NSTE ACS who are at highest risk for
adverse outcomes, the elderly, and those with renal insufficiency, we have
shown high-risk features, advanced age, and renal insufficiency are negative
predictors of early invasive management.23- 27 Thus,
preexisting treatment biases present significant obstacles that must be overcome
to improve the outcomes of undertreated subgroups of patients with NSTE ACS
who are unlikely to be managed aggressively in current practice.
Notwithstanding biases in the use of invasive procedures, the greater
use of acute evidence-based medical therapies in patients receiving early
invasive management suggests that overall guidelines adherence tends to mirror
trends in procedural utilization. Antiplatelet therapies, including clopidogrel
and intravenous Gp IIb/IIIa inhibitors, have been shown to reduce the composite
of death or MI in patients with NSTE ACS, and these therapies were used much
more commonly in patients undergoing early invasive management.1,4,28,29 Furthermore,
patients undergoing early invasive management also more commonly received
other acute and discharge therapies designated as Class IA or IB recommendations
by the ACC/AHA guidelines.9,13 While
the differential impact of multiple medical therapies and revascularization
on clinical outcomes in an observational analysis is difficult to elucidate
and highly confounded by the periprocedural use of medications (heparin, clopidogrel,
Gp IIb/IIIa inhibitors) in patients undergoing PCI, these results suggest
that evidence-based medical therapies are underutilized in higher-risk patients
in the same fashion as early invasive management strategies.
Several contemporary randomized clinical trials have shown clinical
benefits with a strategy of early invasive management and revascularization,
but early invasive management was associated with a significant survival benefit
only in the FRISC II trial.6,8 Older
trials such as Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital
(VANQWISH) did not find a benefit with an early invasive strategy, but technological
advances such as intracoronary stents and better adjuvant pharmacotherapies
may explain the difference between VANQWISH and trials such as TACTICS-TIMI
18 or FRISC II and perhaps the current finding from CRUSADE.23,24,30 Whereas
the mortality benefit with early invasive management in FRISC II was not apparent
until after 3 months,8 the survival advantage
demonstrated in CRUSADE occurred during the initial hospitalization, but the
higher rate of in-hospital mortality in CRUSADE compared with clinical trials
may have led to a greater degree of absolute benefit. However, the relationship
of lower mortality with early invasive management in CRUSADE may have been
somewhat overestimated given the significant selection biases demonstrated
in the use of early invasive management. Finally, there is also a greater
separation of strategies in this analysis from CRUSADE compared with randomized
trials (in which patients assigned to a conservative approach would still
undergo catheterization and revascularization for recurrent or inducible ischemia).
This early CRUSADE experience clearly documents a gap between the evidence-based
ACC/AHA guidelines recommendations and actual clinical practice. Indeed, lack
of compliance with guidelines appears to be prevalent across a variety of
medical conditions.31 In the case of application
of an early invasive strategy, perhaps part of the reluctance of physicians
to apply the guidelines is due to concerns that the guidelines may not be
valid in certain subsets of high-risk patients encountered in daily clinical
practice32 but not enrolled or underrepresented
in clinical trials, such as women or elderly patients or those with heart
or renal failure. However, observational analyses such as this one may provide
some degree of reassurance of the applicability of randomized trial data to
patients treated in routine practice.25 Another
possible reason for the disconnect between guidelines recommendations and
actual practice may have to do with inadequacies in the way that care for
ACS is delivered and it may be best approached as health care systems’
deficiencies rather than as an individual practitioner’s shortcoming.33 For example, regionalization of care for NSTE ACS
at “heart attack” centers, in a manner analogous to trauma centers,
has been proposed as a means to improve care, which would certainly lead to
an appropriate increase in use of an early invasive strategy, especially if
community hospitals were specifically directed to transfer rapidly high-risk
NSTE ACS patients for early catheterization, but significant political obstacles
must be overcome before this type of system could be implemented.34
As a dynamic quality improvement initiative, CRUSADE will attempt to
modify practice via continuous feedback to participating institutions regarding
benchmarked adherence to the ACC/AHA guidelines, implementation of quality
improvement interventions such as standardized admission orders, and other
educational efforts. Within this context, the slight upward trends in the
use of early invasive management during the study period are encouraging.
The CRUSADE initiative will complement other ongoing efforts to improve cardiovascular
care through adherence to established guidelines, such as the AHA’s
Get with the Guidelines program and the ACC’s Guidelines Applied in
There are certain limitations in this retrospective, observational analysis.
First, the revisions to the ACC/AHA guidelines that gave a Class IA recommendation
for early invasive management were first released in March 2002 and were not
published until October 2002 (spanning the end of the study period), so this
study may not have been long enough to evaluate the full effect of the updated
guidelines on practice patterns.9 However,
the original 2000 ACC/AHA guidelines for NSTE ACS gave a Class IB recommendation
for early invasive management, so presumably this approach should have been
considered in the same fashion as other generally accepted Class IB acute
care recommendations from the 2000 guidelines, such as β-blockers and
heparin.13 Second, these data may represent
a “best-case” scenario, as sites participate in CRUSADE on a voluntary
basis and may have had an interest in quality improvement and therefore may
have been more likely to adhere to practice guidelines than other US hospitals.
Third, cardiology care was the strongest predictor of early invasive management,
but this variable only described the primary admitting service and did not
account for the impact of cardiology consultation on treatment decisions.
Fourth, the decision to perform cardiac catheterization was not randomized
but was at the discretion of the treating physician. Unmeasured confounding
variables may have accounted for some of the differences in mortality, although
propensity matching and sensitivity analyses were performed to attempt to
address this limitation. Fifth, there may have been appropriate contraindications
to cardiac catheterization that were not collected, unlike the situation with
medications where contraindications were documented and were used to determine
medication usage rates in “ideal” patients. Sixth, the impact
of revascularization procedures following catheterization on clinical outcomes
was not assessed in this analysis, so the impact of an early invasive management
strategy was not fully characterized. Seventh, because long-term outcomes
are not followed in CRUSADE, the long-term outcomes of early invasive management
were not determined. Finally, we analyzed treatment only at hospitals with
revascularization capabilities, but the underutilization of early invasive
management may be even greater for patients who initially present to community
hospitals without catheterization or revascularization facilities and exclusion
of these patients from the analysis represents a selection bias.
An early invasive management strategy is associated with lower in-hospital
mortality in NSTE ACS patients treated in routine clinical practice. This
strategy, already validated in randomized clinical trials, is utilized in
a minority of high-risk NSTE ACS patients and appears to be preferentially
reserved for younger patients without comorbidities who were cared for by
cardiologists. Therefore, quality improvement efforts should focus on educational
interventions that target noncardiologists involved in the care of NSTE ACS
patients and on improving the appropriate use of invasive cardiac procedures
and other guidelines recommendations for all high-risk patients.
Corresponding Author: Deepak L. Bhatt, MD,
Cleveland Clinic Foundation, Department of Cardiovascular Medicine/Desk F25,
9500 Euclid Ave, Cleveland, OH 44195 (email@example.com).
Author Contributions: Dr Bhatt had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Bhatt, Roe, Li, Harrington,
Berger, Cannon, Pollack, Gibler.
Acquisition of data:Bhatt, Roe, Peterson, Cannon,
Cohen, Kleiman, Peacock, Pollack, Gibler.
Analysis and interpretation of data: Bhatt,
Roe, Peterson, Li, Chen, Harrington, Greenbaum, Berger, Cannon, Cohen, Gibson,
Saucedo, Hochman, Boden, Brindis, Peacock, Smith, Pollack, Gibler, Ohman.
Drafting of the manuscript: Bhatt, Roe, Li,
Critical revision of the manuscript for important
intellectual content: Bhatt, Roe, Peterson, Chen, Harrington, Greenbaum,
Berger, Cannon, Cohen, Gibson, Saucedo, Kleiman, Hochman, Boden, Brindis,
Peacock, Smith, Pollack, Gibler, Ohman.
Statistical analysis:Bhatt, Li, Chen, Cannon.
Obtained funding: Peterson, Harrington, Pollack,
Administrative, technical, or material support:
Roe, Harrington, Hochman, Boden, Peacock.
Study supervision: Roe, Peterson, Gibson, Ohman.
Executive Committee Oversight:Brindis.
Funding/Support: CRUSADE is funded by Millennium
Pharmaceuticals Inc and Schering Corporation. Bristol-Myers Squibb/Sanofi
Pharmaceuticals Partnership provides an unrestricted grant in support of the
program. Duke Clinical Research Institute owns the CRUSADE database and independently
manages data collection, data analysis, and data interpretation without sponsor
Role of the Sponsors:All manuscripts in CRUSADE
are prepared by independent authors who are not governed by the funding sponsors
and are reviewed by an academic publications committee before submission.
The funding sponsor has a representative (Theresa Palabrica, MD, Millennium
Pharmaceuticals Inc) on the committee who provides input into manuscript design
and content, but does not have authority to change any aspect of the manuscript.