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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 214 http://psy.psychiatryonline.org 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 http://psy.psychiatryonline.org 215 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. 216 http://psy.psychiatryonline.org 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). Psychosomatics 47:3, May-June 2006 http://psy.psychiatryonline.org 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. http://psy.psychiatryonline.org Psychosomatics 47:3, May-June 2006 Owen et al. 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. Psychosomatics 47:3, May-June 2006 http://psy.psychiatryonline.org 219 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, 220 http://psy.psychiatryonline.org 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. 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