Download Evaluation Study of Congestive Heart Failure and

Trial Design
Evaluation Study of Congestive Heart Failure and
Pulmonary Artery Catheterization Effectiveness
(ESCAPE): Design and rationale
Monica R. Shah, MD,a Christopher M. O’Connor, MD,a George Sopko, MD,b Vic Hasselblad, PhD,a Robert M.
Califf, MD,a and Lynne W. Stevenson, MD,c for the ESCAPE Investigators* Durham, NC, Bethesda, Md, and
Boston, Mass
Background There is little information about how to adjust pharmacologic agents in the treatment of patients with
advanced congestive heart failure (CHF). Some studies have suggested that use of pulmonary artery catheterization to
guide reductions in filling pressures may improve outcomes for patients with heart failure who are hospitalized with evidence
of elevated filling pressures. However, there is no consensus regarding the true utility of this strategy. A randomized clinical
trial is needed to test the safety, efficacy, and treatment benefit of pulmonary artery catheterization in patients with
advanced CHF.
Study Design The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness
(ESCAPE) trial is a multicenter, randomized trial designed to test the long-term safety and efficacy of treatment guided by
hemodynamic monitoring and clinical assessment versus that guided by clinical assessment alone in patients hospitalized with
New York Heart Association class IV CHF. Five hundred patients will be randomly assigned to receive either medical therapy
guided by a combination of clinical assessment and hemodynamic monitoring (PAC arm) or medical therapy guided by clinical assessment alone (CLIN arm). The primary end point of ESCAPE will be the number of days that patients are hospitalized
or die during the 6-month period after randomization. Secondary end points will include changes in mitral regurgitation, peak
oxygen consumption, and natriuretic peptide levels. Other secondary end points will be pulmonary artery catheter–associated
complications, resource utilization, quality of life measures, and patient preferences regarding survival.
Implications The primary goal of ESCAPE will be to provide information about the utility of the pulmonary artery catheter in
patients with advanced heart failure, independent of various treatment approaches used by individual physicians. In addition, this
study will define current outcomes for this severely compromised population. (Am Heart J 2001;141:528-35.)
The pulmonary artery catheter (PAC) is used routinely
to diagnose, monitor, and treat different conditions,
including acute myocardial infarction (MI), congestive
heart failure (CHF), adult respiratory distress syndrome,
and sepsis. Many physicians accept that pulmonary
artery catheterization is necessary in specific situations,
such as in the evaluation for cardiac transplantation or
in the treatment of cardiogenic shock. For most clinical
situations, however, there is still uncertainty about the
indications for using this device.
From the aDuke Clinical Research Institute, Durham, NC, the bNational Heart, Lung,
and Blood Institute, National Institutes of Health, Bethesda, Md, and cBrigham and
Women’s Hospital, Boston, Mass.
Supported by the National Heart, Lung, and Blood Institute, National Institutes of
Health, Bethesda, Md.
Submitted April 19, 2000; accepted January 5, 2001.
Reprint requests: Monica R. Shah, MD, Duke Clinical Research Instiute, PO Box
17969, Durham, NC 27715.
E-mail: [email protected]
*A complete list of site investigators and committee members is provided in the
Appendix.
Copyright © 2001 by Mosby, Inc.
0002-8703/2001/$35.00 + 0 4/1/113995
doi:10.1067/mhj.2001.113995
A few randomized, controlled trials have suggested
some benefit with pulmonary artery catheterization, but
these studies were all marked by various limitations,
including small sample sizes and lack of clear definitions
for end points.1 Conversely, observational studies have
suggested that the PAC may actually increase morbidity
and mortality in critically ill patients.2-4 Critics argue,
however, that patients who require pulmonary artery
catheterization may be sicker than those who do not
and that methods to adjust for differences in baseline
characteristics cannot adequately adjust for such complex nonrandomized comparisons.4
Key concerns related to pulmonary artery catheterization include the potential for incorrect or inconsistent
use among both physicians and nurses and the risks of
medical care implemented as a response to hemodynamic data.5-7 PAC use may be a marker for an aggressive style of care that could be associated with a higher
mortality rate. For example, information about cardiac
output derived from the PAC may lead to excessive use
of inotropic drugs in patients who are otherwise clinically stable.8-10
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Volume 141, Number 4
In many situations, PAC use is surrounded by “clinical equipoise,” a condition for which there is no
consensus within the clinical practice community
regarding the true utility of an intervention.11 At a
workshop conducted by the National Heart, Lung,
and Blood Institute (NHLBI) and the US Food and
Drug Administration (FDA), advanced heart failure
was identified as an important disease state for which
to conduct a randomized clinical trial testing the
safety and efficacy of the PAC.12 The workshop ultimately led to a clinical trial entitled the Evaluation
Study of Congestive Heart Failure and Pulmonary
Artery Catheterization Effectiveness (ESCAPE). In this
article we describe the major challenges the investigators encountered in planning a trial of PAC in heart
failure and the resulting design and rationale for the
ESCAPE trial.
Background
Heart failure afflicts an estimated 4 to 5 million Americans, with approximately 400,000 new cases diagnosed
each year.13-15 Advances in medical therapy have had
an important impact on the symptoms and short-term
survival of patients with moderate to severe heart failure.7,16-18 There has been only limited success, however, with pharmacologic agents in the approximately
250,000 to 350,000 patients with New York Heart Association (NYHA) class III or IV symptoms.19 Even when
medical therapy has been optimized, the 2-year survival
rate for patients with persistent class IV symptoms may
be only 25%.20
Patients with NYHA class IV symptoms may benefit
from the principles of care originally developed from
experiences with cardiac transplant candidates. Hemodynamic monitoring to adjust therapy, often referred to
as “tailored therapy,” is a central component of this
care.21,22 The rationale for PAC-directed therapy is
based on two theories: (1) that knowledge of the pulmonary capillary wedge pressure (PCWP), systemic vascular resistance (SVR), and their responses to therapy
will lead to the most effective regimen that produces
acute symptomatic improvement without excessive
adverse effects and (2) that selection of medical regimens on the basis of these hemodynamic responses
will lead to long-term benefit.
In nonrandomized studies patients receiving tailored
therapy have had sustained improvements in hemodynamic parameters, reduction in severity of mitral regurgitation, improvement in exercise tolerance, and low
90-day hospital readmission rates.23-26 Without randomized trial data, however, uncertainty remains as to
whether these findings represent a true treatment benefit, a “healthy survivor” effect or biased patient selection. The ESCAPE trial was designed to evaluate definitively a treatment strategy for heart failure that
incorporates the use of PACs.
Shah et al 529
Methods
Study objectives
The primary objective of the ESCAPE trial is to evaluate the
safety and efficacy of pulmonary artery catheterization in
patients with decompensated heart failure. The primary
hypothesis is that in patients with NYHA class IV symptoms
therapy directed by invasive hemodynamic monitoring and
clinical assessment (PAC arm) will lead to fewer deaths and
hospital days during a 6-month period than will therapy
guided by clinical assessment alone (CLIN arm).
ESCAPE will also determine the effect of therapy tailored to
reduce filling pressures on mitral regurgitation, peak oxygen
consumption, natriuretic peptides, and quality of life; define
the relationship between these physiologic parameters and
overall outcome; and evaluate cost and resource utilization
associated with the PAC. Another objective includes determining the incidence and significance of PAC-related complications in academic institutions that have significant experience with hemodynamic monitoring. An additional objective
is to assess the usefulness of measured physiologic parameters
(eg, natriuretic peptide levels) to serve as biomarkers for
choosing effective therapies in patients with advanced heart
failure.
Study population
The ESCAPE study will include 500 patients with NYHA
class IV heart failure. Recruitment and enrollment will occur
over 27 months. Investigators will identify patients with
advanced heart failure who would be sufficiently ill so that
use of a PAC would be appropriate but sufficiently stable so
that management without the use of a PAC would also be considered reasonable. Because the ESCAPE protocol does not
involve any investigational agents or techniques, patients will
be eligible for dual randomization if they are on stable doses
of investigational drugs.
Randomization and blinding. After providing informed
consent, eligible patients will be randomized in a 1:1 ratio to
either the PAC arm or the CLIN arm. Because the ESCAPE trial
is not a blinded study, a number of substudies, assessed without knowledge of the randomization assignment, will be conducted. These substudies include an evaluation of changes in
mitral regurgitation on echocardiography and an evaluation of
changes in plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and norepinephrine values.
Eligibility criteria. The entry criteria for ESCAPE (Table I)
require patients to demonstrate at least one symptom of congestion, such as orthopnea, abdominal discomfort from
hepatic congestion, severe fatigue with minimal exertion, or
discomfort from edema or anasarca. In addition, patients must
exhibit one sign of fluid overload that may include >10 cm of
jugular venous distention, rales in more than one third of the
lung fields, peripheral edema, hepatomegaly, or ascites.
Enrollment criteria will also include a left ventricular ejection fraction of <30% and at least one prior hospitalization for
heart failure within the past year. Angiotensin-converting
enzyme (ACE) inhibitors and diuretics must have been initiated or attempted at least 3 months before randomization. In
addition, the systolic blood pressure should be ≤125 mm Hg
to avoid enrollment of patients who are likely to respond to
routine increases in vasodilators and diuretics.
American Heart Journal
April 2001
530 Shah et al
Table I. Inclusion and exclusion criteria
Inclusion criteria
Patients eligible for the trial must comply with all the following at randomization:
1. Age ≥16 y
2. Current admission under the care of the heart-failure service at the site
3. Current admission for NYHA class IV heart-failure symptoms
4. At least one prior admission for exacerbation of CHF within 12 months before randomization
5. Left ventricular ejection fraction <30% by contrast ventriculography, radionuclide ventriculography, or quantitative echocardiography within
1 year before randomization. The most recent measure of left-ventricular function should be used.
6. Documented history of heart failure for ≥3 mo
7. Attempted therapy with angiotensin-converting enzyme (ACE) inhibitors and diuretics for ≥3 mo before randomization
8. Systolic blood pressure ≤125 mm Hg
9. Elevated filling pressures, indicated by one symptom and one physical sign:
Symptoms: Dyspnea at rest, in the supine position, or immediately on routine activity within one room; abdominal discomfort, severe
anorexia, or nausea without apparent cause other than hepatosplanchnic congestion
Signs: Jugular venous pressure elevation >10 cm above the right atrium; square-wave Valsalva response; hepatomegaly, ascites, or
edema in the absence of other obvious causes; rales greater than one third lung fields
Exclusion criteria
1. Acute decompensation that, according to the attending heart-failure physician, will likely require PAC insertion during the next 24 h
2. Inability to undergo PAC placement within the next 12 h
3. Active listing for cardiac transplantation
4. Present or anticipated mechanical ventilation
5. Present or anticipated mechanical circulatory assist device insertion, including intra-aortic balloon pumps and left ventricular assist devices
6. Any administration of intravenous milrinone within the previous 48 h
7. Current administration of intravenous dopamine or dobutamine at >3 µg/kg/min or dopamine or dobutamine administration for >24 h
before randomization
8. Acute MI or cardiac surgery within the last 6 wk
9. Current admission for an acute coronary syndrome, including acute MI or unstable angina
10. Documented moderate to severe mitral or aortic stenosis
11. Anticipated revascularization procedure during the admission
12. Other planned surgical procedure during the admission
13. Documented primary pulmonary hypertension
14. Pulmonary infarction within the past month
15. Current pneumothorax
16. Current serum creatinine >3.5 mg/dL
17. Temperature >37.8°C
18. White blood cell count >13,000/mm3
19. Exacerbation of CHF because of a primary factor requiring specific therapy, such as severe anemia, clinical hypothyroidism, or active
systemic infection
20. Presence of any noncardiac disease, such as cancer, likely to shorten life expectancy to <1 y
21. Inability to return to the site’s CHF program at 14 ± 7 d, 30 ± 14 d, 60 ± 14 d, 90 ± 14 d, and 180 ± 14 d after randomization
22. Pregnancy or lactation or child-bearing potential in the absence of contraception by oral contraceptives, an intrauterine device, or surgical
sterilization. All women of child-bearing potential must have a negative pregnancy test before randomization.
Additional exclusion criteria (for which patients may be rescreened during same admission):
23. Estimated large volume reservoir (major ascites or anasarca) thought to require extensive diuresis (>48 h) before major adjustment of other
medications such as vasodilators
24. Temporary inability to place and monitor PAC, because of either patient factors such as excessive anticoagulation or to logistic factors such
as temporary lack of bedside monitoring equipment
The trial excludes patients with severe cardiac decompensation that requires urgent PAC insertion in the judgment of
the attending physicians. Patients with conditions that may
lead to a perceived need for PAC insertion will be excluded,
as well as those who have received milrinone within 48
hours before randomization or dopamine or dobutamine at
≥3 µg/kg/min or within 24 hours before randomization.
Patients with a serum creatinine of >3.5 mg/dL will also be
excluded. To avoid enrolling patients with rapidly reversible
components of illness, patients with recent MI, mechanical
ventilation, or temperature >37.8°C will be excluded. Finally,
patients in whom a PAC cannot be inserted for technical reasons and those who are unable to return for follow-up visits
will be excluded.
Treatment strategies
In the PAC arm therapeutic recommendations will be based
on a combination of hemodynamic data and clinical findings.
This trial will address whether the increased precision of
hemodynamic assessment leads to a better outcome than
treatment decisions in the CLIN arm, which will be guided
primarily by physical signs and symptoms.
In the PAC arm, the goal is to reduce left ventricular filling
pressures to reach a PCWP ≤15 mm Hg and a right atrial pressure ≤8 mm Hg. To achieve these goals, investigators are
encouraged to reduce SVR to normal levels without producing
symptomatic hypotension. Blood pressure or SVR limits have
not been specified because patients become symptomatic at
different levels. In the CLIN arm medications will be adjusted
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until both the symptoms and signs of congestion have resolved.
In both arms, medications will be further adjusted as necessary until the following specific goals have been achieved:
absence of physical signs indicating elevated intracardiac filling pressures, evidence of adequate peripheral perfusion, and
serum creatinine ≤3.0 mg/dL. Therapy may be adjusted for
evidence of postural hypotension. Both groups will receive
medications recommended in published guidelines for the
advanced heart failure population.27-30 Patients may receive
any of the standard therapies for heart failure, regardless of
their treatment group.
Discharge criteria include ≥24 hours on oral medications
without a major change in diuretic or vasodilator doses, ≥24
hours without positive inotropic agents, and stable fluid balance as demonstrated by achievement of a specific dry weight
on oral diuretics. In addition, before discharge patients will
receive instructions about follow-up appointments, diet, exercise, preventive care, and flexible diuretic regimens. After discharge, patients will return to the heart failure clinic for routine evaluation at 7 to 14 days, 1 month, 2 months, 3 months,
and 6 months.
Crossovers. Patients randomized to the CLIN arm may cross
over to the PAC arm at any time if hemodynamic monitoring
becomes necessary. Criteria for possible crossover from the
CLIN arm to the PAC arm include progressive hemodynamic
decompensation leading to the need for high-dose inotropic
or mechanical support; inability to wean from intravenous
inotropic agents; and progressive, oliguric renal insufficiency.
Other indications for crossover include refractory symptomatic hypotension, worsening pulmonary edema, and diagnostic uncertainty of the primary process causing decompensation. In the case of crossover, the site clinician will contact
a study-designated cardiologist who will document the reason
for change in the assigned treatment strategy.
End points
The primary end point of the ESCAPE trial will be the number of days that patients are hospitalized or die during the 6month period after randomization (Table II). The primary end
point is a continuous measure that includes the most clinically relevant events in the advanced heart failure population.
The investigators estimate that patients enrolled in the trial
will have an average of two hospital admissions and an estimated mortality rate of 35% during the 6-month follow-up
period.
The secondary end points will include time to rehospitalization or death during the 6-month follow-up period and time to
death alone. Physiologic parameters, such as changes in mitral
regurgitation, natriuretic peptide levels, peak oxygen consumption, and 6-minute walk distance will also be used as secondary end points. Other secondary end points will be
resource and cost utilization, quality of life as measured by the
Minnesota Living with Heart Failure Score and Time Trade-off
Assessment, and PAC-associated complications. The secondary
end point will also include two clinical performance measurements: the frequency of concordance between estimates of
hemodynamics made by physicians with actual hemodynamic
measurements and the correlation between estimates of death
and rehospitalization made by all clinicians with actual death
and rehospitalization rates.
Shah et al 531
Table II. Study end points
Primary end points
Days hospitalized or death during 6 mo after randomization
Secondary end points
Components of primary end points
Time to rehospitalization or death during 6 mo
Time to death throughout trial
Additional secondary end points
Cost and resource utilization
Patient-preference adjusted survival
Changes in mitral regurgitation
Changes in natriuretic peptides (ANP, BNP)
Changes in peak oxygen consumption
Changes in 6-min walk distance
Improvement in Minnesota Living with Heart Failure score
Patient time-trade off assessment
PAC-related complications
(PAC arm only) Frequency of concordance of measured hemonamics within range estimated by physician investigator
Predictive value of rehospitalization estimates made by physician
investigator at time of randomization, discharge, and 1 mo
Predictive value of rehospitalization estimates made by nurse
investigator at time of randomization, discharge, and 1 mo
Statistical analysis
All analyses, except those of PAC-related complications, will
use the intention-to-treat principle. An overall α of .05 will be
used for the primary hypothesis. We will use the Cox proportional hazards model to assess whether there is a statistical difference between the two treatment arms.31,32 The statistical significance of interim treatment differences will be assessed by
use of the group-sequential methods of Lan and DeMets.33 This
approach will incorporate a spending function with an upper
boundary that approximates the O’Brien-Fleming boundary.34
Cardiac transplants. A small percentage of ESCAPE patients
may undergo cardiac transplantation during the study. Rather
than censoring these data, two separate computations will be
done in the statistical analysis for this group. In the first
method, patients who undergo transplantation will be
regarded as having reached the end point of death on the day
of the transplantation. The number of hospital days they have
accumulated to the point of transplantation will be used, along
with the date of transplantation as the components of the primary end point. In the second method, the primary end point
will be calculated as the number of days of hospitalization during the 6-month follow-up period and the actual date of death,
if it occurs. The overall analyses of the primary end point will
then be compared by use of these different computations for
patients who undergo transplantation. Because of number of
transplant patients is expected to be very small, there will
likely be no significant difference in the results of the overall
primary and secondary end points with either method.
Organizational structure
The organization of ESCAPE includes (1) a steering
committee, (2) an executive committee, (3) an operations committee, (4) a clinical coordinators council,
and (5) the Data Safety and Monitoring Board (DSMB)
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April 2001
532 Shah et al
Figure 1
Trial organization. DCRI, Duke Clinical Research Institute.
(Figure 1). The steering committee is responsible for
the overall scientific direction of the trial and consists
of the site investigators, the executive committee, and
the core laboratories. The site investigators represent a
consortium of 39 academic physicians from 26 US and
Canadian sites. The executive committee consists of a
central group of steering committee members who will
assess trial progress and address scientific, policy, and
operational issues that do not require full steering committee review. The coordinators council, which consists of study coordinators from all the clinical sites, will
review trial-related nursing issues.
An independent DSMB, appointed by the NHLBI, is
responsible for ongoing review of patient safety. In
addition, the DSMB will review and interpret emerging
study data at preplanned interim analyses and provide
recommendations to the executive committee about
any necessary modifications of the protocol or termination of the study.
Hemodynamic data collection
Another goal of ESCAPE is to standardize hemodynamic data collection across the participating sites. The
ESCAPE investigators have implemented a PAC education program (PACEP) created by the Pulmonary Artery
Catheterization and Clinical Outcomes Committee, a
working group composed of representatives from the
NHLBI, the FDA, and critical care subspecialties. By
using the PACEP module, the ESCAPE investigators will
be able to describe an experience implementing uniform guidelines for the collection and interpretation of
hemodynamic data. Ultimately, the goal is to create
national standards for PAC use.
Discussion
Despite the scientific value of PACs, observational studies have indicated that these devices may actually
increase morbidity and mortality. The ESCAPE trial will
provide critical information on the use of PACs in the
heart failure population by testing the hypothesis that
treatment guided by PAC monitoring will lead to better
outcomes than those achieved through clinical assessment alone. However, like other recent trials of therapies
in this uniquely compromised population, ESCAPE will
only test the hypothesis about PACs in patients for whom
there is clinical equipoise.35 Extrapolation of the data to
all patients with advanced heart failure will require
knowledge of the denominator of patients in whom clinicians feel the PAC is essential for management.
A positive result for ESCAPE may reflect several
important benefits. If achieving and maintaining nearnormal filling pressures is indeed beneficial, then the
PAC-based strategy may lead to better outcomes
because investigators are able to identify high filling
pressures more accurately with the device than with
clinical assessment alone.36 The PAC also allows physicians to evaluate the hemodynamic response to drugs
during titration of therapy—information that may help
refine combinations of drugs and maintain lower filling
pressure over longer periods. With knowledge of the
PCWP, SVR, and other parameters, investigators may be
able to titrate ACE inhibitors to higher doses than
would have otherwise been achieved. It may also be
possible to avoid excessive vasodilation in sensitive
individuals that could contribute to neurohormonal
activation and renal dysfunction.
There are also many potential reasons why the
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Volume 141, Number 4
ESCAPE trial may be negative. There may be a higher
incidence of major PAC complications such as infection, pneumothorax, and pulmonary hemorrhage than
previously reported. Factors influencing hemodynamics
during the long term may be more important than the
hemodynamic status at discharge. Clinicians may react
to measured hemodynamics by increasing the use of
agents that may have a deleterious impact on outcomes. Finally, physicians with extensive experience in
heart failure management may use information from the
history and physical examination so effectively that pulmonary artery catheterization is unnecessary.
The ultimate goal of the ESCAPE trial is to provide information that can be generalized to all patients with
advanced heart failure, regardless of the specific therapeutic approaches used by individual physicians. The
ESCAPE trial does not specify concomitant medications
for either arm of the study because of the paucity of clinical trial data regarding the safety and efficacy of specific
therapies for advanced heart failure. In addition, the array
of strategies for the management of NYHA class IV heart
failure varies according to institution and physician experience. For these reasons, standard protocols for the use
of inotropic agents, diuretics, and vasodilators such as
nitroprusside and nitroglycerin were not specified.
Use of inotropic therapy is believed by some investigators to represent a qualitatively different approach to
the treatment of advanced heart failure. If so, randomization of patients treated with these agents would
introduce a distinctly different group into ESCAPE and
alter the potential interpretation of the trial results. The
following rationale was offered for the decision to limit
restrictions on the use and duration of inotropic agents.
Most of the ESCAPE investigators believed that
inotropic therapy was just one of many potential therapeutic options for patients with advanced heart failure
and that low-dose inotropic therapy did not compromise the basic premise of the trial. Also, by allowing
investigators to select inotropic agents as they would in
clinical practice, the results of the trial would better
reflect routine patient care and the effects of pulmonary artery catheterization in a broad population of
patients with advanced heart failure.
Crossovers
Crossover patients present a unique challenge because
all results will be analyzed by use of the intention-to-treat
principle. A certain number of crossovers from the CLIN
group to the PAC group are expected when treatment
responses are not adequate. Such resistance to therapy
will help to confirm that the trial has recruited true
NYHA class IV heart failure patients. Although there are
many valid reasons for crossover, a high crossover rate
would dilute the apparent impact of the PAC.
The entry criteria clearly discourage enrollment of
patients with a high likelihood of crossover to PAC (eg,
Shah et al 533
those with high inotropic support, acute coronary syndromes, marked renal insufficiency, and assisted ventilation). The protocol offers clinicians latitude in selecting therapies for heart failure; therefore physicians may
explore various treatment approaches before pursuing
crossover to the PAC. Finally, the ESCAPE trial requires
investigators to contact the clinical coordinating center
to discuss alternative therapeutic plans before
crossover. This approach should minimize the number
of crossovers and provide a better understanding of
why changes in treatment strategies occur.
Recruitment of women and minorities
One step to ensure wide applicability of study results
in ESCAPE is the anticipated recruitment of at least 30%
women and 30% racial and ethnic minorities.37 Inclusion of these groups will enhance the scientific validity
of ESCAPE and provide insight into the unique features
of advanced heart failure in these subgroups.38 This
information may be a launching point for further
prospective studies.
Conclusion
An impressive storehouse of clinical trial data exists
in the areas of acute coronary syndromes and chronic
heart failure, yet there is still a paucity of information
available with regard to management of severely ill
patients. A clinical strategy, rather than a single agent,
will be tested in the ESCAPE trial. A focus on clinically
relevant outcomes may translate to improved patient
care. Ultimately, by addressing a critical question about
PACs and challenging assumptions about current practice, the ESCAPE study may become a paradigm for
future trials in the field of advanced heart failure.
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Appendix
Executive Committee:
Study chair: Lynne W. Stevenson, MD, Brigham and
Women’s Hospital; primary investigators: Robert M. Califf,
MD, Christopher M. O’Connor, MD, and Monica R. Shah, MD,
Duke Clinical Research Institute.
Sponsor contacts:
George Sopko, MD, and Carol Webb, RN, National Heart,
Lung, and Blood Institute.
Lead statistician:
Vic Hasselblad, PhD, Duke Clinical Research Institute.
Site Principal Investigators:
William T. Abraham, MD, University of Kentucky (cochair,
Publications Committee); Kirkwood Adams, Jr, MD, University
of North Carolina (cochair, Publications Committee); Frederick R. Cobb, MD, Duke University Medical Center/Department of Veterans’ Affairs Medical Center, Durham, NC; Robert
Cody, MD, University of Michigan; Maria R. Costanzo, MD,
Rush-Presbyterian-St Luke’s Medical Center; G. William Dec,
MD, Massachusetts General Hospital; Teresa DeMarco, MD,
University of California at San Francisco; Thomas DiSalvo, MD,
Massachusetts General Hospital; Mark Drazner, MD, University of Texas Southwestern Medical Center; Uri Elkayam, MD,
LAAC-USC Medical Center; Gregg Fonarow, MD, Ahmanson-
American Heart Journal
Volume 141, Number 4
UCLA Cardiomyopathy Center/Division of Cardiology; Gary
Francis, MD, Cleveland Clinic Foundation; Robert P. Frantz,
MD, Mayo Clinic; Mihai Gheorghiade, MD, Northwestern Medical School; Michelle Hamilton, MD, Ahmanson-UCLA Cardiomyopathy Center/Division of Cardiology; Joshua Hare, MD,
Johns Hopkins Hospital; James Hill, MD, University of Florida;
Maryl Johnson, MD, Northwestern Medical School; Walter
Kao, MD, Rush-Presbyterian-St Luke’s Medical Center; Edward
K. Kasper, MD, Johns Hopkins Hospital; Todd Koelling, University of Michigan; Carl V. Leier, MD, Ohio State University
Medical Center (cochair, Publications Committee); Leslie
Miller, MD, University of Minnesota/Cardiovascular Division;
Daniel F. Pauly, University of Florida; Ileana Pina, MD, University Hospitals of Cleveland; Barry K. Rayburn, MD, University
of Alabama at Birmingham; Stuart D. Russell, MD, Duke Uni-
Shah et al 535
versity Medical Center; Heather Ross, MD, University of
Toronto; Melvin J. Tonkon, MD, Anaheim Heart and Research
Institute; Guillermo Torre, MD, Baylor College of Medicine;
Lynne Wagoner, MD, University of Cincinnati; J. Wayne Warnica, Foothills Provincial General Hospital; John Wilson, MD,
Vanderbilt Heart Failure Program; Clyde W. Yancy, MD, University of Texas Southwestern Medical Center; James B.
Young, MD, Cleveland Clinic Foundation.
Peptide core laboratory:
John Burnett, MD, Mayo Clinic.
Echocardiographic core laboratory:
Sharon Reimold, MD, University of Texas Southwestern
Medical Center.