(Circulation. 1995;92:174-181.)
© 1995 American Heart Association, Inc.
Articles |
Target Heart Failure Populations for Newer Therapies
From the Divisions of Cardiology and Cardiothoracic Surgery, Brigham and Women's Hospital, Boston, Mass, and the University of California, Los Angeles.
Correspondence to Lynne Warner Stevenson, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background The scarcity of donor hearts has created a large population of heart failure patients who are unlikely to undergo transplantation. Newer surgical therapies that might sustain such patients at home previously have been applied in critical situations in which early outcome is jeopardized by multiorgan failure. The optimal population for studies of extended support would be ambulatory patients with low operative risk but high risk of later unfavorable outcome.
Methods and Results Baseline clinical,
echocardiographic, and hemodynamic data
were collected prospectively between 1988 and 1993 in 500 patients who
were discharged on tailored medical therapy after evaluation for
transplantation. Specific criteria were examined to identify high risk
of death or need for urgent transplantation during the next 2 years. In
265 patients with ejection fraction 
25% and initial New York Heart
Association class IV symptoms, survival at 2 years was 55% (without
urgent transplantation, 45%). Lower cardiac index or higher filling
pressures at the time of referral did not confer higher risk, which was
predicted by persistence of higher pressures after therapy. Serum
sodium below 133 was associated with 34% 2-year survival without
urgent transplantation, and ventricular dimension >80 mm
with a rate of 25%. Patients with initial peak oxygen consumption >10
mL/kg per minute had a 2-year event-free rate of 72% compared with
48% for those with <10 mL/kg per minute and 32% for those unable to
exercise at referral. Demonstration of a 30% decrease in mortality
with a controlled trial of new therapy in patients with ejection
fraction 25% would require 600 patients with class III symptoms or
almost 300 patients with class IV symptoms unless another criterion
were added.
Conclusions Ambulatory populations with high predicted event rates can be identified at initial evaluation, when hemodynamic criteria may be less useful than ventricular dimension, serum sodium, and ability to exercise. The use of outcome data from previous eras may lead to overestimation of benefits from newer therapies and underestimation of the sample size required in a prospective trials.
Key Words: cardiomyopathy • transplantation • heart failure
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The promise of transplantation has encouraged the identification and referral of patients with heart failure previously considered to be terminal. The shortage of donor hearts and the complications of immunosuppression and rejection limit the benefits of transplantation to a select minority of patients with advanced heart failure.1 Newer surgical therapies such as insertion of mechanical support devices have been reserved until patients are hospitalized with severe decompensation from which multiorgan dysfunction often hinders recovery.2 3 Approaches using skeletal muscle have focused on the ambulatory population without severe decompensation.4 The optimal population for extended support would be ambulatory patients who have low operative risk and yet have high risk of unfavorable outcome over the next 2 years.
Efficient design of prospective trials requires estimation of the current "natural history" for groups of heart failure patients, which is influenced by many factors. The expertise and intensity of follow-up care for posttransplant patients have in some centers been extended to the medical therapy of potential transplant candidates as well. The availability of transplantation also changes survival rates. Because cardiac transplantation is the best current therapy for eligible patients with truly refractory decompensation, in whom death would otherwise be imminent, such patients cannot be merely "censored" from survival analyses of other therapies. It is also misleading, however, to infer retrospectively that transplantation was necessary merely because it was performed, particularly in the absence of uniform adherence to selection criteria such as those approved by the Bethesda Conference.5
Many risk factors for mortality with mild to moderate heart failure have been identified.6 7 Only those that are relevant and easily applied in advanced heart failure could be used to define patient populations for multicenter studies of newer therapies that carry significant early risk. The purposes of this study were (1) to determine from data acquired prospectively the current frequency of the combined end point of mortality and urgent transplantation for patients followed in a specialized heart failure/transplant center and (2) to identify broad parameters of risk that are relatively independent of therapeutic vigor and could be applied uniformly at multiple centers. These parameters ideally should define a high-risk study group of adequate size for controlled trials of current investigational therapies.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Baseline information including clinical, echocardiographic, and hemodynamic profiles was collected and recorded prospectively on all patients discharged after hospitalization and complete evaluation for cardiac transplantation at the Ahmanson–University of California, Los Angeles, Cardiomyopathy Center. To analyze outcomes in the current era of therapy, analysis was restricted to patients evaluated between January 1988 and March 1993. Patients considered to have New York Heart Association class I or II symptoms at referral were excluded from this analysis, except for 43 patients added to one analysis of left ventricular dimension and ejection fraction
25%. Because the large majority of
patients in this relatively young population had systolic
failure, only patients with ejection fractions 25% were
included. Echocardiography was performed within 1 week of initial hospitalization. Left ventricular ejection fraction was measured with the use of a modified Simpson's rule. Left ventricular end-diastolic dimension was measured just beyond the level of the mitral leaflets. Right heart catheterization was performed as part of the transplant evaluation. The hemodynamics obtained at this time were considered "initial."
Exercise gas analysis was performed with the use of the Medical Graphics 2000 metabolic cart and a 15-W ramp bicycle protocol in patients who were ambulatory at the time of initial evaluation without symptomatic congestion at rest or severe angina. Only exercise testing during initial evaluation is included in this data analysis.
Medical Management
Therapy was adjusted during hemodynamic
monitoring for patients with initial pulmonary capillary wedge
pressure >20 mm Hg or cardiac index <2.2
L · min-1 · m-2. Vasodilators
and
diuretic agents were tailored to approach
hemodynamic goals of pulmonary capillary wedge
pressure 15 mm Hg and systemic vascular resistance 1200
dyne · s · cm-5 (in the
average-sized individual) while maintaining systolic blood
pressure 
80 mm Hg, as previously described for this
population.8 9 From 1988 to mid-1990, vasodilator
therapy
included either captopril or hydralazine in combination with
oral nitrate therapy; after the results of the Hy-C Trial in October
1990,10 all patients initially received
angiotensin-converting enzyme inhibitors
and isosorbide dinitrate if tolerated. Hydralazine was added if
necessary to achieve adequate vasodilation without unacceptable side
effects. In these patients, the hemodynamic
parameters recorded on the adjusted oral regimen also
were recorded and analyzed for predictive value.
The flexible diuretic regimen of loop diuretics was based on daily weights, with intermittent supplementation with metolazone if necessary. Freedom from signs or symptoms of congestion was maintained in the majority of patients. Amiodarone was the preferred antiarrhythmic agent if therapy was considered to be indicated for atrial or ventricular arrhythmias. Patients subsequently were followed in the Cardiomyopathy Center in collaboration with their referring cardiologists.
Candidacy for Transplantation
Indications for cardiac
transplantation followed the general
guidelines now accepted.5 Absolute and relative
contraindications were considered according to standard
practice.5 11 Patients in whom relative
contraindications
such as noncompliance led to initial rejection with subsequent chance
for reevaluation were rejected at initial evaluation for this
analysis. Patients were hospitalized in an intensive care unit
for further therapy with intravenous inotropic agents or
mechanical assistance when adequate systemic perfusion and noncardiac
organ function could not be maintained otherwise or when intractable
ventricular arrhythmias or clinical
ischemia could not be controlled otherwise. Persistence of
these conditions in the intensive care unit was considered an
indication for urgent transplantation in eligible candidates. The
waiting period for urgent transplantation varied from 1 to 90 days
during this period.
End Points
Outcomes were determined as of April 1994, at
which time all
surviving patients had a minimum of 1 year of follow-up. Only 2.5%
of patients were lost to follow-up. Sudden death was defined as
death occurring out of the hospital instantaneously, within 15 minutes
of a change in symptoms, or unexpectedly during sleep. Hospitalizations
were recorded as end points when they included transplantation.
Statistical Analysis
All statistical analyses were performed
with the
BDMP statistical package.12 The majority of
analyses were performed in patients with both ejection fraction
25% and initial symptoms considered to be New York Heart Association
class IV. Actuarial survival rates and actuarial survival rates without
urgent transplantation were determined by the Kaplan-Meier product
limit estimate. Comparison between two groups was performed with the
Mantel-Cox statistic. Because of the small numbers of patients with
greater than 2-year follow-up, the survival analyses were
truncated at 730 days. Comparison of multiple groups defined by values
of serum sodium or left ventricular dimension was performed
with the Mantel-Cox and Breslow statistics for trend.
The Cox
multivariate analysis was performed
with the use of variables of initial and final filling pressures
and cardiac indexes, presence of coronary artery disease,
echocardiographic ejection fraction, left
ventricular diastolic dimension, and serum
sodium. Exercise performance was examined but was available in
only 107 patients. The median values for hemodynamic
parameters before and after hemodynamically
guided therapy in New York Heart Association class IV patients were
used to probe for groups with greater risk than that conferred by the
ejection fraction 25% and class IV clinical class. The
parameters of left ventricular dimension and
serum sodium were studied in the most detail. Therapy with
angiotensin-converting enzyme inhibitors
and amiodarone also were included as variables, although
the selection of therapies was influenced by other clinical
parameters.
Sample-size calculations were performed according to the
method of
Freedman.13 Trial design was based on the assumption that
a new therapy might decrease mortality by 30% with an 
error of 5%
and a 1-ß of 80%. The two-tailed t test was used.
All means are expressed as ±SD.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Patients With New York Heart Association Class IV Symptoms and Ejection Fraction <25%
The survival rate for the 404 patients (1988 to 1993) discharged after referral for transplantation with New York Heart Association class III or IV symptoms and left ventricular ejection fraction
25% was 74% at 1 year and 61% at 2
years. Survival without urgent
transplantation was 67% at 1 year and 53% at 2 years, respectively
(Fig 1
). Including only patients with ejection fraction 20%
reduced
the population size to 250, in whom survival without transplantation
was reduced only to 63% and 49% at 1 and 2 years, respectively.
Although threshold ejection fractions of 30% and 25% were little
different, the value of 25% was chosen as a more typical descriptor of
patients evaluated with advanced heart failure.
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For the 265 patients
with ejection fraction 25% and New York Heart
Association class IV symptoms, the actuarial survival rate was 68% at
1 year and 55% at 2 years (Fig 2).
Including the likelihood of urgent transplantation (29 patients) over
the 2 years, the overall freedom from death or urgent transplantation
was 59% and 45% at 1 and 2 years, respectively. Sudden death
accounted for 37% of mortality. These numbers are compared with
published results for class IV heart failure in previous eras (Fig
214 15 ).
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The majority of
patients were men, and coronary disease was
implicated in 
50% of the patients (Table 1). Therapy at the
time of discharge
included angiotensin-converting enzyme
inhibitors in 61% of patients and amiodarone in
47% of patients. After 1990, absence of therapy with
angiotensin-converting enzyme inhibitors indicated
intolerance to these agents, which is more likely in the setting of
severe decompensation.10 The changes between initial
hemodynamics and hemodynamics on the
discharge regimen reflect the impact of therapy tailored to reduce
ventricular filling pressures and systemic vascular
resistance.
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As a result of initial evaluation, 143 of the 265 (54%)
patients with
ejection fraction 25% and initial New York Heart Association class
IV symptoms were found acceptable for transplantation, although actual
listing was frequently deferred or inactivated as patients
improved. Outpatient transplantation, which was a censored event, was
performed in 42 patients during the first year after initial evaluation
and in another 4 patients during the second year. For the 122 patients
found to have major contraindications during initial evaluation,
actuarial survival rates were 51% at 1 year and 37% at 2 years,
compared with 65% at 1 year and 56% at 2 years without urgent
transplantation in potentially acceptable candidates
(P=.004).
Multivariate Analysis of Clinical
Profiles
Although this study was not designed to be another
multivariate analysis of all possible
prognostic factors, multivariate proportional hazards
analysis was performed to confirm the importance of
variables selected for further analysis. Including ejection
fraction, coronary artery disease, serum sodium, left
ventricular dimension, and initial and treated cardiac
indexes, pulmonary capillary wedge pressures, and right atrial
pressures, analysis yielded pulmonary capillary wedge
pressure on therapy, right atrial pressure on therapy, left
ventricular diastolic dimension, and serum
sodium as predictive of outcome (Table 2).
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Left
ventricular ejection fraction was of borderline
significance in some analyses (the exact composition of the
subjects varied as a result of occasional missing data such as
unmeasurable left ventricular dimensions) but was not an
independent predictor in any analysis. Although
coronary artery disease has been a predictor in broader
populations, in this population, defined by initial New York Heart
Association class IV symptoms and ejection fraction 25%, survival
without urgent transplantation at 1 year was 57% with and 61% without
coronary artery disease and at 2 years was 42% versus 48%
with and without coronary artery disease, respectively
(P=.21). Sudden death–free survival also was similar:
86% at 1 year with coronary artery disease compared with 87%
without. The presence of a history either of syncope or cardiac arrest,
both shown to predict poor outcome in a wider population of heart
failure, was not associated with higher mortality in
univariate or multivariate proportional
hazards analysis; the sudden death survival rate in patients
with a positive history was 82% at 1 year compared with 88% without
such a history (P=.3). Further analysis of sudden
death was not done because of the limited number of sudden death end
points.
Limitations of Hemodynamic Criteria
Hemodynamic criteria were
examined closely, as
they traditionally have been used to define severity of disease and
indications for support devices and other advanced therapies. Because
there were large changes between hemodynamics at
referral and hemodynamics on the tailored oral regimen
before discharge (Table 3), both sets
were considered. The groups were first divided at the median values for
initial cardiac index, pulmonary capillary wedge pressure, and
right atrial pressure. Comparing the 2-year actuarial curves for groups
above and below the initial medians showed values worse than the mean
to confer no increase in the chance of adverse outcome (Fig 3).
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After undergoing therapy directed to minimize filling pressures,
patients with pulmonary capillary wedge pressure above the
median treated value of 16 mm Hg had a 38% 2-year survival rate
without urgent transplant compared with 50% for lower
pulmonary capillary wedge pressure (P=.007). A
similar difference was conferred by the lower right atrial pressure.
Use of either of these criteria for population selection increased the
frequency of end points but not by a large amount (Fig 4). The
survival rate without urgent
transplantation was 45% at 2 years for patients whose cardiac index on
revised therapy was above the median 2.5
L · min-1 · m-2 and the same
for
those whose treated cardiac index on revised therapy was below the
median.
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Serum Sodium and Left Ventricular
Dimension
Survival for New York Heart Association class IV patients
with
ejection fraction 25% was determined for patients using different
threshold values for serum sodium. Because the purpose was to define
the largest possible group with high risk, the survival data shown in
Table 4 indicate the worsening actuarial survival rates
obtained by eliminating successively more patients on the basis of
higher serum sodium concentration at the time of hospital discharge.
The strictest criterion for sodium, <130 mEq/L, identified patients
with a 2-year survival rate without urgent transplantation of only
33%. This criterion, however, restricted the population to only 46
patients, while using a threshold serum sodium of 134 mEq/L included
116 patients with only slightly higher chance of favorable 2-year
outcome (37%).
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Similar analysis of the left ventricular
end-diastolic dimension from
echocardiography could be done for 240 of the
patients with initial New York Heart Association class IV symptoms and
ejection fraction 25% (Table 5).
Including only those with dimension 80 mm identified a group of 78
patients with likelihood of 2-year survival without urgent
transplantation of 25%.
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Because the optimal criteria for broad
application are those requiring
no subjective clinical assessment, the analysis was repeated
excluding all classification of New York Heart Association class, which
was included in the above analyses. The two
echocardiographic criteria of left
ventricular ejection fraction 25% and left
ventricular diastolic dimension 80 mm Hg
selected 128 patients for whom survival without urgent transplantation
was 56% at 1 year and 34% at 2 years (Fig 5). In this group 31
of the 65 deaths
occurred suddenly at home and 17 patients underwent urgent
transplantation.
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Exercise Testing in Class IV Patients
For the 107 patients
who performed exercise testing at the time of
presentation with New York Heart Association class IV
symptoms and ejection fraction 25%, peak oxygen consumption was not
predictive of outcome by multivariate analysis.
This most likely reflects the small number of tests and the selection
bias against exercise in patients with resting symptoms. If the mere
performance of an exercise test were included in
multivariate analysis, it was an independent
predictor of good outcome in this compromised population. Among the
exercising patients, the 26 with peak
|$$O2 10 mL/kg per minute had a
2-year rate of survival without urgent transplantation of 48% compared
with 72% (P=.03) for all patients with higher initial peak
|$$O2, with rates of 76%,
78%, and 75% for peak |$$O2 10
to 12, 12 to 14, and 14 to 16 mL/kg per minute. Patients not exercising
had a 32% rate of survival at 2 years without urgent transplantation
(Fig 6).
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Influence of Specific Therapies
The period of this study
encompassed evolving therapies, which
were given according to best clinical judgment at the time, or in some
cases, specific randomized protocols.10 Therapy with
angiotensin-converting enzyme inhibitors,
which is more likely to be tolerated in patients with less severe
hemodynamic compromise,10 was an
independent predictor of survival. Therapy with amiodarone,
given for symptomatic ventricular
arrhythmias, atrial fibrillation, or frequent high-grade
ventricular ectopy, also was found to confer survival
benefit despite the possible adverse prognostic impact of the
indications for therapy with this agent (Table 2
).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Prognosis and Trials in New York Heart Association Class IV Heart Failure
This analysis of patients discharged after referral for heart transplantation between 1988 and 1993 confirms the improving survival rate for patients presenting with New York Heart Association class IV heart failure.14 15 Therapeutic advances over the past 10 years include the broader use of angiotensin-converting enzyme inhibitors,10 16 17 avoidance of type I antiarrhythmic agents18 19 in favor of amiodarone, and aggressive reduction of elevated filling pressures.8 9 20 The expected survival rate on medical therapy at 2 years for class IV heart failure and ejection fraction
25%, however, remains <50% when urgent transplantation is included
as a true end point for failure of medical therapy. The survival rate
with heart transplantation is much higher, currently 70% to 80% at 2
years.21 This grim outlook without transplantation confronts the 40% to 70% of patients who have advanced heart failure but are found to be ineligible at major centers. In addition, the scarcity of donor hearts has created long lists for outpatient candidates, who face considerable risks during the wait of over 18 months for transplantation.1 This wait is predicted to increase even further during the next 4 years, after which there may be little chance of transplantation for any outpatient candidate if current trends continue.
From these ineligible and waiting groups of ambulatory patients, it should be possible to select target groups for alternative interventions such as mechanical devices, skeletal muscle assistance, or experimental drug therapy. The true impact of these interventions will be better assessed when applied in patients who have not deteriorated to multiorgan failure that compromises early outcomes. Because controlled trials in these challenging patients require extensive adjunctive care and heavy commitment of resources, both the relative risks and costs could be minimized by identifying an ambulatory population sufficiently large to ensure enrollment but at sufficiently high risk with current therapy to ensure adequate end points for comparison. The present comprehensive analysis of initial clinical-hemodynamic profiles and subsequent outcomes in patients referred to a heart failure–transplant center is the largest currently available from which to design a trial in ambulatory patients with advanced heart failure.
Hemodynamic Parameters
Initial hemodynamic criteria have been
used in
some previous trials of mechanical support2 3 as
appropriate for patients in intensive care. Among the patients who
could be rendered ambulatory in this study, however, initial
hemodynamic parameters, defined as the
median group values, would restrict the size of the population without
increasing the event rate. The vigor of recent therapy is the main
determinant of initial filling pressures and cardiac index in patients
presenting with severe symptoms. After therapy adjusted to minimize
filling pressures and reduce systemic vascular resistance, persistence
of elevated filling pressures did confer significantly worse prognoses.
The importance of minimal filling pressures has been shown previously
for the population of patients referred for transplantation with
ejection fractions 20%22 and more recently for the 660
patients discharged on vasodilator therapy after referral to
transplantation.23 Like the current analysis, that
study showed cardiac index to be of no value in prognosis. It should be
emphasized that cardiac index may be predictive in other populations in
which few patients present with New York Heart Association class IV
symptoms.7
Other Potential Criteria for Trial Design
The lability and
lack of specificity of
hemodynamic parameters make them difficult
criteria to use in multicenter trials of patients considered to be New
York Heart Association class IV. The alternative prognostic factors
selected for further analysis were those identified from
previous eras in this center and
others.24 25 26 Lower serum
sodium, as a reflection of neurohormonal activation and the net effect
of stimuli for fluid retention, was helpful in describing this
population. Excluding patients with serum sodium values >136 would
reduce the population by not quite half, with an expected increase in
event rate. Strict exclusion to serum sodium values <130 would create
only a very small population without a large increase in event rate.
Such specific selection may be appropriate only for therapies
specifically targeted to this neurohormonal activation, as described
previously for hyponatremia and
angiotensin-converting enzyme
inhibition.24
Peak oxygen consumption has become an integral part of evaluation for transplantation, particularly as more standard indications are sought.5 26 In this population of patients presenting with New York Heart Association class IV symptoms of heart failure, however, the majority of patients were not considered sufficiently stable to undergo testing during initial evaluation. In those who did, only the threshold value of 10 mL/kg per minute identified a higher risk group. Standard use of exercise testing immediately before hospital discharge might be a consistent way for multiple centers to identify patients with comparable functional limitation. Testing at any one time, however, would be strongly influenced by the period of prior bed rest and deconditioning.
Massive left ventricular dilation was associated with higher risk of sudden death and progression to heart failure death or urgent transplantation, as has been shown in analysis of an earlier population at this center.25 Left ventricular dilation leads to greater wall stress, myocardial oxygen demands, heterogeneity of repolarization, and activation of intracardiac reflexes. This deleterious effect appeared to be independent of direct hemodynamic correlates.25
Left ventricular dimension was
previously found to be
relatively stable over weeks on therapy, unlike many
parameters of heart failure.25 This stability,
combined with the possible objectivity of measurement, makes left
ventricular dimension a desirable criterion for selection
of high-risk patients from multiple centers. Eliminating even the
subjective New York Heart Association classification and using only the
echocardiographic parameters of left
ventricular ejection fraction 25% and left
ventricular diastolic dimension 80 mm
identified 128 ambulatory patients, of whom only 34% would be
predicted to survive 2 years without urgent transplantation.
The
outcome data from this population may facilitate design of
controlled trials to test these newer therapies against optimal medical
therapy.13 To test a newer therapy reducing mortality by
30% in a controlled trial of class III patients on optimal medical
therapy could require a sample size of 660 patients and accepting an
error of 5% and a ß error of 20%, with a two-tailed test
(Table 6). To test a therapy with similar
potential for New York Heart Association class IV patients with
ejection fraction 25% and left ventricular
diastolic dimension >78 mm would require 170 patients.
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Limitations
Left ventricular ejection fraction was measured
from echocardiography, which may differ from other
techniques but is the method most commonly used for screening of this
population. The importance of peak oxygen consumption in this
compromised population cannot be assessed easily because of the number
of patients too compromised to undergo testing. This analysis
is necessarily retrospective. All baseline data and outcome data were
collected prospectively, however, in a database that included all
patients undergoing evaluation. The specific factors found to influence
outcome have been identified previously by other investigators and in
analyses of years before 1988 in the experience in this center.
Extrapolation of these results to other experiences may be limited by
varying intensities of medical therapy between centers. In addition,
referral biases related to perceptions about transplantation affect the
complexion of a heart failure population at a transplant center. In a
primary care setting, some patients with similar objective criteria may
have less clinical compromise. In addition, almost all patients were
younger than 70 years, while older patients may be considered for
procedures other than transplantation.
Implications
This analysis of an advanced heart failure
population
provides guidance for the design of future trials in which high early
event rates should allow assessment of alternative therapies that carry
their own risks.27 While the specific criteria suggested
here include ejection fraction, serum sodium, and left
ventricular dimension, the results emphasize the general
importance of choosing inclusion criteria specific for each desired
study population rather than those generalized from other populations
and historical therapies. In addition, the frequency of urgent
transplantation as an end point in advanced heart failure mandates
careful consideration regarding inclusion of potential transplant
candidates in a randomized study.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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24.
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26.
Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr,
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