Download Psychiatric Evaluations of Heart Transplant Candidates: Predicting

Psychiatric Evaluations of Heart Transplant Candidates:
Predicting Post-Transplant Hospitalizations,
Rejection Episodes, and Survival
JASON E. OWEN, PH.D., M.P.H.
CURLEY L. BONDS, M.D.
DAVID K. WELLISCH, PH.D.
The authors assessed the validity of psychiatric evaluations for orthotopic heart transplant candidates with respect to predicting adverse post-transplant outcomes. A group of 108 transplant recipients were followed for an average of 970 days, and pre-transplant evaluations were retrospectively coded for psychiatric risk factors. Previous suicide attempts, poor adherence to
medical recommendations, previous drug or alcohol rehabilitation, and depression significantly
predicted attenuated survival times. Also, past suicide attempt was associated with a greater risk
for post-transplant infection. Assessment and early treatment for these risk factors may reduce
post-transplant morbidity and mortality.
(Psychosomatics 2006; 47:213–222)
A
lthough medical risk factors for postcardiac transplant
morbidity and mortality have been relatively welldefined,1,2 psychiatric risk factors have received less attention in the literature.3 Psychosocial risk factors do currently
play a role in determination of eligibility for listing on heart
transplant waiting lists. However, the validity of these factors for predicting post-transplant outcomes remains less
than certain.
Expert opinions are commonly used, but may not accurately reflect risk of adverse post-transplant outcomes.
In a 1991 survey of 204 cardiac transplant centers, 92.3%
of United States and 89.2% of non-United States centers
viewed active schizophrenia as an absolute contraindication to transplantation.4 More recently, evidence of successful transplant outcomes in patients with active psychotic symptoms has been reported.5 In a consensus report
of the American Society of Transplant Physicians, successful predictors of good post-transplant outcomes were
defined as the absence of substance abuse, active psychosis, suicidal behavior, and personality disorder and the
presence of good adherence to medical regimens, good
cognitive functioning, adequate social support, and ade-
Psychosomatics 47:3, May-June 2006
quate financial resources.6 Currently, the most commonly
agreed-upon relative or absolute psychosocial contraindications to transplantation are active schizophrenia, multiple
past or recent suicide attempts, dementia, suicidal ideation,
severe mental retardation, Axis I or Axis II psychiatric disorder, drug or alcohol abuse within the past 6 months, medication noncompliance, and current cigarette-smoking.4,7
The presence of any one of these factors should not in and
of itself constitute a contraindication for transplantation
without consideration of a broader context (e.g., family
support sufficient to maintain medical adherence in a psychotic patient) or in the absence of predictive validity.
Few studies have examined the validity of such psychosocial risk factors for predicting actual post-transplant
complications and death. To date, results supporting the
Received July 12, 2004; revised June 1, 2005; accepted June 23, 2005.
From the Dept. of Psychology, Loma Linda University and the Dept. of
Psychiatry and Behavioral Sciences, University of California, Los Angeles. Send correspondence and reprint requests to Jason E Owen, Ph.D.,
M.P.H., Dept. of Psychology, Loma Linda University, 11130 Anderson
St., Loma Linda, CA 92350. e-mail: [email protected]
Copyright 䉷 2006 The Academy of Psychosomatic Medicine
http://psy.psychiatryonline.org
213
Heart Transplant Candidates
validity of these risk factors have been mixed. With regard
to episodes of post-transplant infection and rejection, several studies have reported no association between psychosocial factors or psychiatric disorders and post-transplant
mortality or infection.8–10 However, Paris et al.11 reported
that the presence of global psychiatric problems and a history of limited adherence to medical regimens are associated with a greater risk for infection and rehospitalization.
Only one published study to-date has prospectively examined the impact of all psychiatric risk factors included
in a typical psychiatric pre-transplant evaluation on posttransplant outcomes. Shapiro and colleagues12 found that
several pre-transplant psychiatric risk factors were associated with post-transplant adherence problems (substance
abuse, personality disorder, unstable living arrangements,
and high estimated global psychiatric risk) and rejection
episodes (high estimated global psychiatric risk). None of
the assessed variables in that study were significant predictors of post-transplant infection episodes or survival.
Identification of valid psychosocial risk factors for
poor transplant outcomes is imperative in order to match
at-risk patients with appropriate treatments or services before transplantation. Olbrisch et al.13 have suggested that
the high prevalence of psychiatric disorder among transplant candidates warrants the provision of mental health
services such as relaxation-training procedures, skill-building and problem-solving exercises, and cognitive-behavior
therapy. Also, pharmacologic management of depression
and anxiety symptoms are thought to be well-tolerated, efficacious, and cost-effective in this clinical population.14,15
This study used survival analysis to capture timedependent patterns occurring over a nearly 3-year followup period. The primary aim of the present study was to
characterize the predictive validity of pre-transplant psychiatric evaluations of cardiac patients relative to posttransplant hospitalizations, rejections episodes, and survival. We hypothesized that greater risk, as identified
through the psychiatric evaluation, would be associated
with attenuated survival, time to post-transplant hospitalization, and time to infection/rejection. A secondary aim of
the study was to evaluate the predictive capacity of each
of the individual psychiatric risk factors for post-transplant
outcomes and to develop a multivariate model to determine
the relative importance of potential risk factors. We hypothesized that previously-identified psychiatric risk factors (i.e., recent substance abuse, history of suicide attempt,
having a personality disorder, low levels of social support,
and poor past adherence to medical regimens) would be
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associated with a greater likelihood of post-transplant hospitalizations, infections, and death.
METHOD
Subjects
All patients who received a psychiatric pre-transplant
evaluation between January 1, 1997 and December 31,
2000 and who underwent subsequent orthotopic heart
transplant were eligible for inclusion in the present study.
Those patients who were not listed for transplant on the
United Network for Organ Sharing (UNOS) cardiac transplant list were excluded. Also, patients who were members
of a large HMO and received all subsequent follow-up outside of our transplant program and patients who were less
than 18 years old at the time of the pre-transplant evaluation were excluded from this analysis.
Procedure
All cardiac patients being considered for transplants at
UCLA received a pre-transplant evaluation that was
conducted by a psychiatrist or a psychologist using a semistructured interview. Retrospective chart review was performed on each of these pre-transplant psychiatric evaluations to extract and quantify all relevant variables. All
pre-transplant psychiatric evaluations were conducted with
a four-page structured evaluation form, and evaluation reports were dictated as patient notes, using this form as a
template. In most cases, patients were interviewed directly,
but in cases in which the patient was too medically ill to
participate in an interview, spouses or other immediate
family members provided information about the patient.
For all patients, medical records and lab tests were also
reviewed for evidence of poor adherence to medical regimens. Also, in July of 2003, medical records were reviewed for all patients who had undergone pre-transplant
psychiatric evaluation and cardiac transplantation between
1997 and 2000. Date of last follow-up with the patient,
death, post-transplant hospitalization, or suspected/confirmed episodes of infection or rejection were recorded for
each eligible subject.
Pre-Transplant Psychiatric Evaluation
At the time of evaluation, the clinician recorded basic
demographic characteristics of each patient, including age,
gender, ethnicity, educational attainment, and indication for
transplant. Clinicians also obtained a brief psychiatric hisPsychosomatics 47:3, May-June 2006
Owen et al.
tory, consisting of previous psychiatric diagnoses and
symptoms; history of alcohol, tobacco, and substance use;
social history; and medical history. A mental status examination and psychiatric interview were also conducted
in order to assess for current Axis I and Axis II conditions.
For each patient, level of understanding of their medical
condition and understanding of the risks and benefits associated with heart transplantation were rated by clinicians
using a 3-point Likert scale anchored by “poor,” “good,”
and “excellent.” Clinicians also noted whether or not each
patient exhibited a history of positive adherence to past
medical management. An extensive documentation of current social support was conducted to assess for the presence
of supportive others who would be available to assist the
patient in the post-transplant period. Finally, on the basis
of each patient’s current psychiatric status, abstinence from
alcohol/tobacco and other drugs of abuse, understanding of
their medical condition and risks/benefits associated with
transplantation, positive past history of medical adherence,
and level of social support, the patient was classified as to
degree of overall psychiatric risk. Overall psychiatric risk
was assessed with a 3-point Likert scale, with Lowest risk
level associated with being a “good candidate,” Moderate
risk level associated with being an “acceptable candidate,”
and High risk level associated with being a “high-risk candidate.” All evaluation reports were made available to the
transplant team, and any areas of concern were identified
as targets for intervention before the transplantation procedure.
number of days between transplant and the last known
medical follow-up visit. Age, gender, marital status, and
transplant indication were considered as covariates, but
none of these variables were associated with post-transplant hospitalization, infection/rejection, or survival. Thus,
we report results from unadjusted Cox models.
With respect to overall psychiatric risk classification
(i.e., Good, Acceptable [moderate], versus High-Risk candidates for transplant), we sought to determine which psychiatric and demographic variables assessed during the
transplant evaluation were associated with risk categories.
To accomplish this aim, we performed chi-square analyses
to test the relationship between each categorically-coded
psychiatric risk variable and membership in one of the
three risk categories. For continuous variables (i.e., age
at interview), analysis of variance was used to detect possible differences between levels of psychiatric risk. We
then sought to compare survival outcomes as a function
of psychiatric risk classification, while controlling for
demographic variables that might influence survival. Cox
proportional-hazards regression was also used for this purpose. Finally, we used hierarchical Cox proportionalhazards models and stepwise forward regression to identify
the strongest set of predictors of post-transplant survival.
We included in these exploratory models only variables
with univariate associations with post-transplant survival
at the p⬍0.1 level.
Statistical Analysis
Demographics of the Sample
All data were analyzed with SAS Version 8.02 and
SPSS Verson 12. In order to characterize relationships between individual psychiatric risk variables hypothesized to
be associated with the timing of post-transplant outcomes,
we used Cox proportional-hazards regression analysis.
Variables were created to account for the occurrence of
post-transplant outcomes (i.e., death, rehospitalization, or
infection) and the timing of each outcome. Patients were
first characterized with regard to the status of each outcome
event (i.e., alive versus dead; no infection episodes versus
one or more; and no post-transplant hospitalizations versus
one or more). Next, if the event had occurred by the time
of the analysis, the number of days between the date of
transplant and the date of the first event was recorded. For
patients who did not experience an event (i.e., death, rehospitalization, or infection) by the time the analysis was
conducted, the time variable was censored to reflect the
Demographic characteristics of the study sample are
shown in Table 1. As shown, patients who were evaluated
were predominantly unemployed (73.7%), male (73.1%),
and married (78.7%). Unemployment ranged from less
than 6 months to more than 5 years, and most patients had
been unemployed for 1 year or longer. Major indications
for transplant were noted, with two categories (ischemic
and idiopathic dilated cardiomyopathy) accounting for
73.2% of these indications. A very small number (4.1%)
had previously undergone orthotopic heart transplantation
and were currently undergoing evaluation before retransplantation. Patients in this study underwent transplantation
an average of 112 days after the date of psychiatric evaluation (range: 1 to 954 days). The mean duration of followup was 971 days (range: 1 to 2,065 days), and 30.6% of
those who received a psychiatric evaluation died during
this period of follow-up.
Psychosomatics 47:3, May-June 2006
RESULTS
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Heart Transplant Candidates
Psychiatric Risk Factors
Psychiatric risk characteristics of the participants are
shown in Table 2. Of note, a large majority (77.8%) show
evidence of a current Axis I disorder, although these conditions were largely accounted for by disorders associated
with alcohol and nicotine abuse and dependence. However,
40.4% of those who were evaluated met criteria for a mood
disorder: 30.8% of all evaluated patients met criteria for a
depression-related diagnosis (i.e., major depression, adjustment disorder with depressed mood, depression due to
a general medical condition, or depression not otherwise
specified), and 14.4% met criteria for an anxiety-related
diagnosis (i.e., posttraumatic stress disorder, anxiety disorder due to a general medical condition, or generalized
anxiety disorder). Also, 6.7% of the sample met criteria for
a sleep disorder due to their general medical condition. A
positive history of alcohol dependence or abuse was noted
in 27.8% of the patients, but only 5.6% could be characterized as actively dependent on alcohol at the time of the
evaluation. A positive history of tobacco dependency was
noted in 55.6%; however 98.3% of those reporting a hisTABLE 1.
tory of tobacco dependence reported abstinence at the time
of evaluation. A large number of patients were found to
currently use at least one class of psychoactive medication
(41.7%), including sedative/hypnotics (27.9%), selective
serotonin-reuptake inhibitors (15.4%), novel antidepressants (3.9%), and tricyclic antidepressants (4.8%). The majority (91.7%) had a good or excellent understanding of
risks and benefits of transplantation. In terms of overall
psychiatric risk assessment for transplantation, a large
number (50.0%) were rated as Good candidates, and a
smaller minority (11.1%) were rated as High-Risk candidates.
Predictors of Transplant Outcomes
Table 3 depicts Cox proportional-hazards analyses of
time to first post-transplant hospitalization, first post-transplant episode of infection, and death. Increasing psychiatric
risk classification (i.e., Acceptable candidates versus Good
candidates or High-Risk candidates versus Acceptable candidates) was associated with a greater hazard of post-transplant mortality (Wald v2[2]⳱6.09; p⳱0.048), but was not
Demographic Characteristics for the Total Sample and for Each Psychiatric Risk Classification
Characteristic
Age, years,* mean (SD)
Gender, %
Male
Female
Married,* %
Employment status, %
Currently employed
Unemployed ⬍6 months
Unemployed 6–12 months
Unemployed 1–5 years
Unemployed ⬎5 years
Transplant indication, %
Dilated cardiomyopathy (ischemic)
Dilated cardiomyopathy (idiopathic)
Re-transplant (graft failure)
Valvular heart disease
Dilated cardiomyopathy (viral)
Dilated cardiomyopathy (other)
Dilated cardiomyopathy (post-partum)
Congenital heart defect
Hypertrophic cardiomyopathy
Dilated cardiomyopathy (adriamycin)
Dilated cardiomyopathy (alcoholic)
Eisenmenger’s syndrome
Other cardiac disease
All Patients
(Nⴔ108)
Good Risk
(Nⴔ54)
Acceptable Risk
(Nⴔ42)
High Risk
(Nⴔ12)
53.3 (12.9)
55.4a (11.0)
53.1ab (14.0)
44.5b (14.0)
73.1
26.9
78.7
70.4
29.6
87.0a
83.3
16.7
76.2ab
50.0
50.0
50.0b
26.7
10.5
4.8
35.2
22.9
31.5
7.4
3.7
35.2
22.2
25.0
10.0
2.5
35.0
27.5
9.1
27.3
18.2
36.4
9.1
41.7
31.5
4.6
3.7
3.7
3.7
2.8
2.8
1.9
0.9
0.9
0.9
0.9
38.9
29.6
7.4
3.7
5.6
5.6
1.9
1.9
3.7
0.0
0.0
1.9
0.0
47.6
33.3
2.4
4.8
2.4
0.0
2.4
2.4
0.0
2.4
0.0
0.0
2.4
33.3
33.3
0.0
0.0
0.0
8.3
8.3
8.3
0.0
0.0
8.3
0.0
0.0
Note: Significant differences among the three risk groups are indicated by *(p⬍0.05). Significant pairwise comparisons are indicated by groups
with different superscripts (i.e., groups sharing a letter did not differ significantly from one another).
SD: standard deviation.
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Psychosomatics 47:3, May-June 2006
Owen et al.
predictive of either post-transplant infection (p⳱0.10) or
hospitalization (p⳱0.62). None of the demographic or psychiatric evaluation variables predicted time to rehospitalization. Past history of suicide attempt was strongly associated with time to infection/rejection episode (p⬍0.001).
Five of the assessed variables were significantly associated
with survival in these analyses. Of the demographic variables, only current employment significantly increased the
hazard of death after transplant in this sample. Among the
variables derived from the psychiatric evaluation, shorter
survival time was associated with history of drug or alcohol
detoxification, a current depressive disorder, history of past
suicide attempt, a history of poor medical adherence, and
an overall clinical estimate of high-risk transplant status.
Predictors of Risk Classification
As shown in Table 2, the following variables were
associated with High-Risk status: poor adherence with previous medical regimens, past psychiatric hospitalization,
presence of a mood disorder, presence of an Axis II disTABLE 2.
order, use of psychiatric medications, history of alcohol or
substance detoxification, current or recent alcohol dependence, history of nicotine dependence, history of any substance abuse, and lack of confirmed social support available to meet practical needs of post-transplant recovery.
Also, three demographic variables were associated with
risk classification. These included age (younger age associated with higher risk status: F[2, 101]⳱3.94; p⳱0.023),
marital status (being unmarried associated with higher risk
status: v2[2]⳱7.4; p⳱0.025), and gender (female gender
associated with higher risk: v2[2]⳱6.3; p⳱0.04). Post-hoc
analyses revealed that female patients were significantly
more likely than male patients in this sample to report undergoing drug or alcohol rehabilitation (v2[2]⳱4.3;
p⳱0.038) and to report a previous suicide attempt
(v2[2]⳱5.0; p⳱0.02). Single patients were significantly
more likely than those with partners to exhibit a current
mood disorder (v2[2]⳱5.2; p⳱0.023), report a previous
suicide attempt (v2[2]⳱7.2; p⳱0.007), or have a history
of poor medical adherence (v2[2]⳱11.5; p⬍0.001). Interestingly, Acceptable candidates waited significantly longer
Psychiatric Risk Characteristics for the Total Sample and for Each Psychiatric Risk Classification
Prevalence, %
Characteristic
History of medical noncompliance
Positive family psychiatric history
Positive history of alcohol dependency or abuse
Drinkers reporting current abstinence
Past history of hallucinogen use
Past history of stimulant use
Past history of opiate use
Positive history of tobacco dependency
Smokers reporting current abstinence
Past history of detox or rehab program for substance abuse/
dependency
Evidence or history of Axis I disorder (including nicotine dependence)
Evidence of a current Axis II disorder
Current use of psychiatric medication (including sedatives/hypnotics)
Confirmed social support at time of evaluation
Past psychiatric hospitalization
Past suicide attempt
Understanding of transplant risks/benefits
Poor
Adequate
Good
Excellent
Overall psychiatric risk assessment
High-risk candidate
Acceptable-risk candidate
Good-risk candidate
All Patients
(Nⴔ108)
Good Risk
(Nⴔ54)
Acceptable Risk
(Nⴔ42)
High Risk
(Nⴔ12)
6.7***
16.7
27.8**
80.0
2.8*
2.8**
0.0
55.6*
98.3
0.0 a
13.0
13.0 a
71.4
0.0 a
0.0 a
0.0
46.3 a
100.0
2.6 a
16.7
38.1 b
87.5
2.4 ab
0.0 a
0.0
59.5 ab
100.0
50.0 b
33.3
58.3 b
71.4
16.7 b
25.0 b
0.0
83.3 b
90.0
3.7***
77.8***
5.6*
41.7*
34.3*
1.9*
1.9
0.0 a
61.1 a
5.6
29.6 a
29.6
0.0 a
0.0
0.0 a
92.9 b
2.4
50.0 ab
35.7
0.0 a
2.4
33.3 b
100.0 b
16.7
66.7 b
50.0
16.7 b
8.3
1.9
6.5
78.7
13.0
1.9
3.7
74.1
20.4
0.0
9.5
83.3
7.1
8.3
8.3
83.3
0.0
11.1
38.9
50.0
0.0
0.0
100.0
0.0
100.0
0.0
100.0
0.0
0.0
Note: Significant differences between the three risk groups are indicated by *p⬍0.05; **p⬍0.01; and ***p⬍0.001. Significant pairwise comparisons are indicated by groups with different superscripts (i.e., groups sharing a letter did not differ significantly from one another).
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217
Heart Transplant Candidates
Survival Analysis
Survival curves, based on a Cox proportional-hazards
model, for the three psychiatric risk categories (i.e., HighRisk, Acceptable, and Good candidates) are shown in Figure 1. The Acceptable and Good candidates were not statistically different from one another in their overall
survival, whereas High-Risk candidates exhibited significantly worse survival relative to both groups over time
(v2[1]⳱8.3; p⳱0.004. By the end of the study, 23.8% of
the Good candidates, 27.8% of Acceptable candidates, and
66.7% of High-risk candidates were deceased. Of note, the
survival curves differentiate High-risk candidates in the
immediate post-transplant period, and the gap widens increasingly over time. To control for the possible effects of
age and employment status on survival, these variables
were entered into the model as covariates. After adjusting
for age and employment, High-Risk candidates continued
to exhibit significantly lower survival than Acceptable or
Good candidates (v2[1]⳱7.0; p⳱0.008). The hazard of
death for High-Risk candidates was over 2.5 times greater
than those who were classified as Acceptable or Good candidates (hazard ratio [HR]: 2.67).
TABLE 3.
Multivariate Survival Models
Upon examining the univariate predictors of survival
in Table 3 (at p⬍0.1), we further sought to evaluate the
relative contributions of the variables related to demographic factors (i.e., current employment), substance
abuse/dependence (i.e., history of tobacco use, past drug
FIGURE 1.
Survival as a Function of Psychiatric Risk
Classification
1.0
0.8
Percent Surviving
for their transplants (mean: 149 days) than did Good
(mean: 89 days) or High-Risk (mean: 66 days) candidates
(F[1, 102]⳱4.76; p⳱0.031).
0.6
0.4
Risk Classification
Good
Acceptable
High risk
0.2
0
500
1,000
1,500
Days Post-Transplant
2,000
Cox Proportional-Hazard Ratios for Post-Transplant Hospitalization, Post-Transplant Infection Episode, and Death (Nⴔ108)
Hazard Ratio (HR)
Variable
Age (HR for each 10-year increase in age)
Gender (male versus female)
Marital status (partnered versus unpartnered)
Currently employed
Family psychiatric history
Current or recent alcohol dependence
History of tobacco dependence
History of illicit substance abuse or dependence
Previous drug or alcohol detoxification program
Current mood disorder
Current depressive disorder
Current anxiety disorder
Current use of psychiatric medications
Confirmed social support
Previous psychiatric hospitalization
Past suicide attempt
History of poor medical compliance
Understanding of risks/benefits of transplant (excellent/good versus adequate/poor)
Clinical estimate of risk (high-risk versus acceptable/good candidates)
Note:
218
†
Hospitalization
Infection
Death
0.88
0.66
0.61
1.26
0.96
1.26
1.32
1.42
2.31
0.88
0.69
0.90
0.79
0.84
2.07
4.08†
0.76
1.18
1.77
0.86
0.93
1.19
1.32
0.76
1.65
1.00
2.68
3.05
1.29
0.96
1.52
1.08
0.66
2.69
13.08***
1.03
1.10
2.17
0.83
0.88
0.70
1.99†
1.25
1.54
1.91†
2.72†
3.14*
1.67
2.52**
0.48
1.02
1.26
3.28
5.44*
3.40*
0.80
2.67*
p⬍0.10; *p⬍0.05; **p⬍0.01; ***p⬍0.001.
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or alcohol rehabilitation, and past substance abuse/dependence), mood disorder (i.e., depression-related disorder,
past suicide attempt), and adherence. We used post-hoc hierarchical Cox proportional-hazards models to evaluate the
unique contribution of each of these four sets of variables.
Results of this analysis are shown in Table 4. Although the
univariate relationship between current employment and
hazard of death only approached significance, employment
was a significant predictor of mortality in the full multivariate model. After adjustment for the effects of employment on survival, sets of variables associated with both
substance abuse/dependence and mood disorder were significantly predictive of mortality. Adherence, however, was
not associated with survival upon adjustment for employment, substance abuse/dependence, and mood disorder. Finally, the independent variables that were significant univariate predictors of survival (at p⬍0.1; see Table 3) were
selected for inclusion in a forward stepwise Cox proportional-hazards analysis. Using the ␣⳱0.05 criterion for entry into the model, only three predictors were retained in
the final model: current employment (v2[1]⳱8.94;
p⳱0.003; HR: 3.58), depression (v2[1]⳱8.84; p⳱0.003;
HR: 3.19), and risk status (High-Risk versus Acceptable/
Good): v2[1]⳱5.88; p⳱0.02; HR: 2.84).
psychiatric risk status, determined by assessment of each
of the individual risk factors listed in Table 3, significantly
predicted survival but failed to predict either time to infection or hospitalization. Of the five variables hypothesized
to most strongly predict these outcomes, none predicted
time to hospitalization, and only past suicide attempt was
associated with time to infection. Three of the five hypothesized variables were significantly predictive of shortened
survival time: past history of substance abuse, past suicide
attempt, and poor adherence to recommended medical regimens. The study results suggest that the variables of concern were more strongly associated with survival than with
hospitalizations or infections.
With respect to the survival curves, we observed several interesting findings. First, differences among risk
groups emerge early in the post-transplant process. Shortly
after transplant, the High-Risk group was already experiencing greater mortality than either of the other two groups.
Second, these effects increased over time. However, given
our current assessment procedures, we were not able to
adequately distinguish survival outcomes between “good”
and “acceptable” candidates. It is noteworthy that our sample is restricted in range with respect to the distribution of
overall psychiatric risk. Those patients deemed to be at
high risk during the pre-transplant evaluations would be
less likely to be UNOS-listed than either acceptable or
good candidates. Similarly, acceptable candidates would be
less likely to be UNOS-listed than good candidates. Those
acceptable and high-risk candidates who were UNOSlisted and subsequently underwent orthotopic heart trans-
DISCUSSION
Hypotheses of the study were largely supported when applied to survival outcomes but disconfirmed with respect
to post-transplant infections and hospitalizations. Overall
TABLE 4.
Hierarchical Cox Proportional-Hazard Analyses of Post-Transplant Survival
Predictor
D v2 [df]
†
Current employment
3.25 [1]
Drug and alcohol use
History of tobacco dependence
7.83 [3]*
v2 [df]
HR (95% CI)
9.70[1]**
4.00
(1.67–9.55)
2.68 [1]
History of substance abuse/dependence
1.74 [1]
Past drug or alcohol rehabilitation
0.00 [1]
Mood disorders
Depression
11.75 [2]**
5.92 [1]*
3.24 [1] †
Past suicide attempt
Adherence to medical regimen
1.96
(0.88–4.39)
2.42
(0.65–9.01)
0.97
(0.23–4.08)
ⳮ0.94 [1]
1.35 [1]
2.74
(1.22–6.15)
4.98
(0.87–28.59)
2.02
(0.62–6.62)
Note: HR: hazard ratio.
†
p⬍0.10; *p⬍0.05; **p⬍0.01; ***p⬍0.001.
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Heart Transplant Candidates
plant very likely exhibited other medical or personal characteristics that may have compensated for their increased
psychiatric risk for a poor transplant outcome. If this is
indeed the case, the power to detect between-group differences among the three risk categories would be attenuated,
and the observed significant findings may be suggestive of
robust effects.
Of the individual risk factors explored in the present
study, depression emerged as an unexpected but consequential predictor of survival. Our study suggests that current depressive disorder increases the hazard of post-transplant mortality, and this finding is consistent with previous
studies of depression and outcomes in heart transplant patients.16 In addition to depression, itself, many of the risk
factors found to be associated with attenuated survival
times commonly co-occur with depression (i.e., tobacco,
alcohol, and substance use; past suicide attempts; and poor
medical adherence).17 These results are not altogether surprising, given the robust associations between depression
and poor prognosis in patients with cardiac disease.18,19
Moreover, depression may be particularly salient, given
evidence-based guidelines for clinical management in this
population. Because depression among those with cardiac
disease is responsive to both pharmacologic20 and nonpharmacologic21,22 interventions, early identification and
treatment of depression has the potential to substantially
improve post-transplant outcomes.
Our results further suggest that adherence may also
play a particularly important role in the prevention of adverse post-transplant outcomes. Dew et al.23 have shown
that poor adherence to post-transplant medical regimens
substantially increases risk of acute graft rejection and cardiac allograft disease. To our knowledge, the present study
is among the first to demonstrate that poor pre-transplant
adherence increases risk of death in this population. Dew
et al.24 have published a structured assessment instrument
for the evaluation of eight unique domains of medical adherence (i.e., exercise, monitoring blood pressure, medications, smoking, diet, having blood work completed,
clinic attendance, and heavy drinking). Systematic evaluation of each of these domains before transplant listing
could assist in the early identification of problem areas so
that clinical services could be matched to patient needs as
early as possible in the transplantation process.
With respect to these individual predictors of mortality, some are more widely prevalent among potential transplant candidates (i.e., current depressive disorder), whereas
others are only rarely observed (i.e., past suicide attempt).
However, uncommon issues, such as past suicide attempt,
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are “red flags” that are associated with a higher hazard of
mortality and should be recognized as indicators of need
for more comprehensive pre-transplant intervention. The
relationship between current employment and greater hazard of mortality, although not significant, unexpectedly approached statistical significance. Those who continue to
work until the time of listing for transplant may show more
Type A personality characteristics and associated cardiac
risks25 or may simply have less time to prepare for the
significant life changes that accompany transplantation. Efforts to address the specific needs of those who remain
employed at the time of evaluation may be warranted (e.g.,
stress-management training or more intensive education
and planning for the post-transplant transition).
Our ultimate goal in this study was to determine the
“best-fit model” to predict the outcomes of survival. Our
multivariate analyses suggest that current employment,
current depression, and high-risk status were the strongest
predictors of post-transplant mortality, with each of these
variables conferring an approximately threefold increase in
hazard of mortality. In other words, the incidence of death
in the post-transplant follow-up period was nearly 300%
higher among individuals who demonstrated any one of
these risk factors. Specifically relating to employment, the
paradox was that, if the patient worked, he or she was more
at risk for death, which perhaps reflects the need for insulation and protection from work-associated stress. For
patients who continue to work despite declining functional
status because of their dependence on income or insurance,
greater efforts to assist patients with meeting these concrete
needs may be warranted. These results also provide initial
validation of the structured psychiatric evaluation applied
in this study and highlight the importance of early identification and intervention for treatable risk factors, such as
clinical depression.
Several limitations of the present study are noteworthy. First, given the limited sample size of the study,
caution should be used in interpreting the observed results.
Larger replication studies will be necessary to provide
more precise estimates of hazard ratios for specific predictors of post-transplant survivors, particularly for observed
characteristics that were rarely reported by those waiting
for transplant (i.e., substance abuse, history of past suicide
attempt, and previous participation in a drug rehabilitation
program). Collaboration across transplant centers and use
of standardized psychiatric assessment procedures would
greatly facilitate such a replication study.26,27 Currently, psychosocial evaluations are not standardized across transplant
centers, which leads to the possibility that patients with simiPsychosomatics 47:3, May-June 2006
Owen et al.
lar risk profiles will receive different overall estimates of
risk from one center to another. Accordingly, results of the
present study may not generalize across centers.
It is also important to note that in addition to the
planned comparisons articulated in our hypotheses, this
study used a number of post-hoc analyses of relationships
between individual psychiatric risk factors and post-transplant survival, hospitalization, and infection. Application
of the Dunn-Bonferroni procedure to correct for possible
inflation of the experiment-wise Type I error rate renders
the post-hoc findings nonsignificant at the ␣⳱0.0038 level
(0.05 divided by 13 for each of the unplanned analyses).
Weighing both the scarcity of organs available for transplant and the potential impact of misclassifying risk factors
for adverse outcomes in this population, it is important to
consider the implications of both Type I and Type II error
rates. In situations of this type, Keppel and Zedeck have
suggested that, rather than risk committing Type I errors at
the expense of Type II errors (or vice versa), researchers
should suspend judgment for those analyses that clearly
exceed the uncorrected alpha level but do not meet the
alpha level specified by a Type I correction procedure.28
We recommend that the reader view the exploratory findings generated in this study with some degree of caution
pending follow-up studies with power sufficient to confirm
our current findings.
Given the life-altering consequences of decisions
made by healthcare professionals with respect to organ allocation, the preliminary nature of these findings warrants
further study, and we caution against using these findings
as the basis for modifying policies related to listing candidates for heart transplantation. This caution is particularly relevant, given that psychiatric evaluation procedures
are not uniform across transplant centers and may vary
substantially from the evaluation procedure used in this
study. However, our results begin to suggest that there are
a number of identifiable and modifiable risk factors that
should be targets for intervention early in the transplant
process. Pharmacologic and nonpharmacologic treatments
should be made routinely available to the relatively high
number of transplant candidates facing symptoms of clinical depression. Such treatment may be particularly important for those candidates who have exhibited signs of major
depression that precede the onset of cardiac disease. Also,
given the inherently stressful nature of the transplant process, counseling focused on issues surrounding substance,
alcohol, and tobacco use should be provided to those with
a history of using these drugs in times of stress. Finally,
more intensive counseling on specific adherence-related issues23 will likely improve clinical outcomes in these patients.
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