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(Circulation. 2004;110:3452-3456.)
© 2004 American Heart Association, Inc.

Heart Failure

Prognostic Value of Anxiety and Depression in Patients With Chronic Heart Failure

Wei Jiang, MD; Maragatha Kuchibhatla, PhD; Michael S. Cuffe, MD; Eric J. Christopher, MD; Jude D. Alexander, MD; Greg L. Clary, MD; Michael A. Blazing, MD; Laura H. Gaulden, MS; Robert M. Califf, MD; Ranga R. Krishnan, MD; Christopher M. O’Connor, MD

From the Department of Psychiatry and Behavioral Sciences (W.J., E.J.C., G.L.C., R.R.K.), Aging Center (M.K.), and Department of Medicine (W.J., M.S.C., E.J.C., G.L.C., M.A.B., L.H.G., R.M.C., C.M.O.), Duke University Medical Center, Durham, NC, and Medicine/Psychiatry Services (J.D.A.), Shady Grove Adventist Hospital, Rockville, Md.

Correspondence to Wei Jiang, MD, Box 3366, Duke University Medical Center, Durham, NC 27710. E-mail jiang001{at}mc.duke.edu

Received May 20, 2004; revision received September 20, 2004; accepted September 30, 2004.

	Abstract

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Background— Anxiety is often present with depression and may be one of its manifestations. Although the adverse effects of depression in patients with chronic heart failure (CHF) have been well studied, the relation between anxiety and CHF prognosis has not been addressed. In a secondary analysis of data collected for a published study of depression and prognosis in patients with CHF, we examined the relations among anxiety, depression, and prognosis.

Methods and Results— We measured symptoms of anxiety with the Spielberger State-Trait Anxiety Inventory (STAI) scale and symptoms of depression with the Beck Depression Inventory (BDI) scale in 291 patients with CHF hospitalized as a result of cardiac events. We followed up these patients for all-cause mortality over 1 year. The mean scores for state anxiety (State-A) and trait anxiety (Trait-A) were identical at 33.5; the mean BDI score was 8.7±7.6. State-A and Trait-A scores correlated highly with each other (r=0.85; P<0.01) and with BDI score (State-A, r=0.52; Trait-A, r=0.59; P<0.01). Cox proportional-hazards model with and without confounding variables showed no relation between State-A or Trait-A and 1-year mortality. BDI scores, however, significantly predicted increased mortality during 1-year follow-up (hazard ratio, 1.04 for each 1-unit increase; P<0.01).

Conclusions— Although anxiety and depression are highly correlated in CHF patients, depression alone predicts a significantly worse prognosis for these patients.

Key Words: anxiety • depression • heart failure • prognosis

	Introduction

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The roles of depression and anxiety in patients with ischemic heart disease (IHD) have become the focus of extensive studies.^1,2 Although many have suggested a link between depression, anxiety, or both and the development and prognosis of IHD independently of conventional cardiac risk factors, the cumulative evidence is greatest for depression. Evidence supporting an impact of anxiety is less consistent.

Anxiety has been characterized as a strongly negative emotion with a component of fear, and such fear has cognitive, neurobiological, and behavioral manifestations. It often is present concurrently with depression, especially in elderly and in medically ill populations.³ Symptoms of anxiety may be adversely associated with a high risk of IHD, and it has been associated with increased risks of myocardial infarction (MI) and fatal IHD.^4,5 One study reported an 6-fold-higher rate of sudden death among men with than in men without anxiety.⁵ Other studies, however, have not produced similar results.^6–8 In patients with known IHD, anxiety has not been consistently associated with poor prognosis.^9–12 Two studies of the effects of depression and anxiety in the IHD population found that unfavorable outcomes may be independently associated with depression but not anxiety.^13,14

Examination of the role of these emotions has recently expanded into the area of chronic heart failure (CHF).¹ We have reported that depression is an independent risk factor for mortality and morbidity in patients with CHF regardless of cause (ischemic or nonischemic).¹⁵ Few studies, however, have explored the role of anxiety in the prognosis of CHF patients.^13,14 We conducted a prespecified secondary analysis of our original data set,¹⁵ examining the prognostic value of anxiety and its interaction with depression in patients with CHF.

	Methods

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The methods for this study have been reported.¹⁵ Briefly, patients 18 years of age admitted to the cardiology service at Duke University Medical Center between March 1, 1997, and June 30, 1998, were approached for the study if they had clinically diagnosed CHF, defined as NYHA classification II, left ventricular ejection fraction (LVEF) 35%, or both. The institutional review board approved the protocol; all study procedures were in accord with ethics standards outlined in the Helsinki Declaration of 1975 as revised in 1983. All participants provided informed consent according to review-board guidelines. Exclusion criteria included pregnancy, active suicidal ideation, planned major surgery, life expectancy <1 year, and inability to provide consent.

Assessments
Participants were asked to complete a self-administered, 21-item questionnaire, the Beck Depression Inventory (BDI), an established tool for depression screening in various populations. Patients then were asked to complete the Spielberger State-Trait Anxiety Inventory (STAI) scale to measure anxiety symptoms. The STAI has 2 scales for measuring self-reported state anxiety (State-A) and trait anxiety (Trait-A). A person can experience an emotional status at a given moment, with a particular level of intensity, as predisposed by his or her diathesis of emotional vulnerability. The emotional status evoked by a condition is considered State-A, which is transitory, lasting for minutes, hours, or days. Trait-A refers to relatively enduring individual differences in anxiety proneness, ie, diathesis of emotional vulnerability, which accounts for differences between people in the tendency to perceive stressful situations as dangerous or threatening and to respond to such situations with an increase in intensity of their State-A. For 40 years, the STAI has been extensively used and refined to assess State-A and Trait-A in various populations, healthy and ill. The sensitivity of State-A scale to external stress has been shown repeatedly in research on emotional reactions to surgery and other circumstances.¹⁶ Trait-A scores, however, remain essentially unchanged before and after such external changes. Another unique feature of STAI is its "purer" measure of anxiety independent of depression. Its better differentiation between anxiety and depression makes it especially useful in research on depressed patients.¹⁷ A cutoff value of 40 for State-A or Trait-A score has been used to dichotomize cardiac patients into low- and high-anxiety groups.¹⁰

Other Data Collection
Detailed demographic data were collected from medical records, including age, race, sex, primary reason for admission, concomitant illnesses, vital signs, physical examination results, NYHA class, baseline LVEF, and discharge medications.

Follow-Up
All participants were contacted by mail 12 months after initial assessment to collect data on mortality. We telephoned patients if information was not received 4 to 6 weeks after the mailing or to clarify the information received. The Duke Databank for Cardiovascular Disease was used to obtain missing data and contact information. Follow-up 1-year data were 99.7% complete; only 1 patient was lost.

All patients received routine care during index admissions. After discharge, the patients’ primary care physicians and cardiologists provided care. If patients met the modified DSM-IV criteria for major depressive disorder during the initial diagnostic interview schedule interview, we reported these results to the inpatient primary care team. Further intervention for depression was left to their clinical judgment. We specified no particular treatment for depression because no evidence exists for the safety or efficacy of its treatment in this population.

Statistical Analysis
The primary analyses used continuous measures of anxiety and depression to assess correlations with each other. The Pearson coefficient was used to examine the correlation of State-A and Trait-A and their correlation with BDI scores. Characteristics of the patients who completed both the BDI and STAI and the BDI alone were summarized by mean±SD and percentages and compared with t tests and ² tests, respectively. Cox proportional-hazards model was used to examine the associations of anxiety and depression with mortality over time. We first examined unadjusted associations between mortality and each of the following variables: BDI scores, State-A and Trait-A, age, baseline LVEF, NYHA class, and ischemic CHF origin. We then examined the association between mortality and each of the anxiety measures separately after controlling for BDI scores, age, baseline LVEF, NYHA class, and ischemic CHF origin. All analyses were performed with SAS software (version 8.0, SAS). Statistical significance was defined as P<0.05.

	Results

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Study Population
In all, 374 patients provided informed consent for participation, and 357 patients completed the BDI. No patient had active suicidal ideation or refused further psychiatric assessment after the BDI, but 66 patients could not complete the STAI because of hospital discharge or interruption of or exhaustion from assessments related to their admission. Thus, 291 patients completed both the BDI and STAI questionnaires, constituting the analysis population. All the results in Tables 2 through 5 are based on this sample of 291 subjects.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics

View this table: [in this window] [in a new window]   TABLE 2. Mean Measures of Anxiety and Depression by Vital Status at 1 Year

View this table: [in this window] [in a new window]   TABLE 3. Mean Measures of Anxiety and Depression by Origin of Heart Failure

View this table: [in this window] [in a new window]   TABLE 4. Unadjusted Relations of Anxiety, Depression, and Conventional Cardiac Risks With 1-Year Mortality

View this table: [in this window] [in a new window]   TABLE 5. Relation Between Anxiety and Depression and 1-Year Mortality, Adjusted for Conventional Cardiac Risk Factors

Patients who completed the BDI alone were older, less often white, less often married, and in higher NYHA classes than those who completed both tests (Table 1). More of them also had been admitted for chest pain or arrhythmia, which would have required more in-hospital procedures. They had a higher death rate at 1 year (17.9% versus 15.7% for those completing both questionnaires), but none of these differences was statistically significant.

Anxiety and Depression Measures
The mean State-A and Trait-A scores were identical (33.5±12.8 and 33.5±11.7, respectively). In all, 29% of patients had a State-A score 40, and 28% had a Trait-A score 40. The mean BDI score was 8.7±7.6. State-A and Trait-A scores were highly correlated (r=0.85, P<0.01). Likewise, State-A and Trait-A scores each correlated highly with BDI scores (r=0.52 and r=0.59, respectively; both P<0.01). Patients who had died by 1 year had higher BDI scores than survivors (P=0.03) (Table 2), but State-A and Trait-A scores did not differ by vital status at 1 year.

Relation of Anxiety and Depression and Conventional Cardiac Risk Factors
Age related inversely to State-A and Trait-A scores, ie, the younger the patient, the greater the anxiety (r=–0.18, P<0.01; r=–0.13, P=0.03; respectively). However, anxiety was not associated with baseline LVEF (State-A, P=0.45; Trait-A, P=0.60), NYHA class (P=0.71 and P=0.70), or CHF origin (Table 3).

Although depression measures correlated highly with anxiety measures and anxiety was inversely associated with age, depression was not associated with age (r=–0.07, P=0.27). Depression likewise was not associated with baseline LVEF (P=0.77), NYHA class (P=0.25), or CHF origin (P=0.30).

Prognostic Ability of Anxiety and Depression
Neither State-A nor Trait-A scores were associated with unadjusted 1-year mortality. BDI scores, however, significantly predicted mortality (Table 4). Consistent with previous studies,^18–20 age, NYHA class, and ischemic CHF origin were significantly associated with mortality (Table 4). In a Cox proportional-hazards model adjusted for BDI scores, age, baseline LVEF, NYHA class, and ischemic CHF origin, Trait-A was not associated with mortality, and BDI scores remained significantly associated with increased mortality (hazard ratio, 1.045; 95% CI, 1.008 to 1.084) (Table 5). In a similar model adjusted for BDI scores, age, baseline LVEF, NYHA class, and ischemic CHF origin, State-A was not associated with mortality; however, BDI scores were no longer significantly associated with mortality (Table 5).

	Discussion

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This is the first study to examine the extent and impact of anxiety, alone and with depression, on prognosis in CHF patients. Although anxiety and depression were positively and highly correlated in these patients, only depression was associated with increased mortality at 1 year independently of conventional cardiac risk factors and Trait-A. The BDI, an easily self-administered questionnaire, appears to be a useful, reliable tool for identifying CHF patients at high risk of death related to depression or negative affect; for every 1-unit increase in BDI, 1-year mortality was increased by 4%. State-A, in contrast, appears to attenuate the prognostic association between depression and mortality.

Only one other study has examined the relation between anxiety and mortality in CHF patients. Konstam and colleagues²¹ assessed self-reported depression and anxiety in the Studies of Left Ventricular Dysfunction (SOLVD) while studying the ability of several psychological factors to predict readmission and death. In multivariate analyses, neither depression nor anxiety was associated with poorer outcomes. The authors did not reveal the details of the questionnaires used to assess depression and anxiety.

Self-reported anxiety symptoms according to the Crown-Crisp Index have been related to the risk of IHD.^4,22 Studies using other self-reported anxiety measures, however, have yielded inconsistent results in healthy subjects²³ and in patients with established IHD. For example, Frasure-Smith et al¹⁰ reported that an STAI score 40 was associated with a >3-fold increase in cardiac events 1 year after MI (P<0.01) compared with an STAI score <40. In our study, an STAI score 40 did not translate into a higher risk of dying. Moser and Dracup⁹ found that high anxiety levels, measured by the Brief Symptom Inventory <2 days after MI, were associated with 4.9 times the rate of in-hospital complications compared with lower anxiety levels. Denollet and Brutsaert,¹³ however, reported that the adverse association of anxiety and mortality after MI was not independent from type D personality in multiple regression analysis. Lane et al¹¹ reported that neither depression nor anxiety predicted mortality or cardiac events after MI, although both were significantly associated with poorer quality of life. None of these studies examined CHF patients, nor did they assess whether depression and anxiety interact.

Although anxiety and depression are highly comorbid^23–26 and tend to share risk factors,²⁷ anxiety is a discrete emotional experience. Anxiety is typically defined as a future-oriented, negative affective state with a component of fear, resulting from perception of threat and typified by a perceived inability to predict, control, or obtain desired results in upcoming situations.^23,28 Depression also reflects a highly negative affective state, but it uniquely features a very low level of positive affect.²⁹ The different mental components may play different roles in coping and, later, in prognosis. In an investigation of the effects of depression and anxiety on 5-year cardiac mortality among 896 MI survivors, both states were significantly associated with mortality, but only depression remained significant after adjustment for cardiac disease severity.¹⁴ The Montreal Heart Attack Readjustment Trial (M-HART)³⁰ results indicated that highly anxious men might significantly increase their long-term survival by modifying their coping styles. In a study of 5000 individuals undergoing exercise testing, Herrmann et al³¹ found that higher anxiety levels were associated with significantly reduced 5-year mortality after testing; in contrast, depression was associated with significantly higher mortality. Clinical characteristics differed substantially between patients in that study and ours; in particular, 50% of their patients had no known IHD.

Why anxiety was not associated with increased mortality in our patients despite its high correlation with depression is unclear. Phobic anxiety or panic disorder has been consistently associated with IHD, but the association between nonphobic anxiety and IHD has been inconsistent. Our study did not assess the phobic anxiety component. Panic symptoms may represent the more severe spectrum of anxiety or reflect somatic responses, especially of the cardiovascular system, to negative emotions, ie, fear of future uncertainties. Phobic anxiety and panic disorder are rarer than general anxiety, and the STAI may be less sensitive to these disorders.

Some have hypothesized a link between anxiety and IHD via stress-induced increases in sympathetic nervous system activities and catecholamine release. Although anxiety has been associated with increased levels of plasma norepinephrine,^32,33 this potential link has not been tested explicitly. Others have suggested a link between anxiety and electrical instability of the myocardium; electrophysiology studies have shown that ventricular premature beats increase with stimulation from certain psychological stressors^34,35 and decrease with a reduction in sympathetic neural inputs.^36,37 An association between chronic anxiety and arrhythmia has not been established, however.

The most definitive mechanistic finding was the association of anxiety with reduced heart rate variability.^38–41 Patients with depression, however, also have reduced heart rate variability.^2–46 Assessments of anxiety separate from depression and the prognosis of cardiac patients may provide definitive answers.

Depression must be recognized and treated to provide good care for patients with CHF. Patients tend to show symptoms of anxiety rather than depression, however. Given the strong correlation of these states, caregivers must screen for depression when patients report anxiety or appear anxious. Selective serotonin reuptake inhibitors should be considered to treat anxiety, given their anxiolytic effects,^47–50 antidepressant effects, relatively safe profile, and possible cardiac protectiveness.^50,51 Tricyclic antidepressants, although quite efficacious for anxiety, are not recommended for IHD and CHF patients because of their cardiac effects.^52,53 Conventional anxiolytics, such as benzodiazepines and antihistamines, may need to be avoided altogether because of potential side effects. Structured psychotherapies such as cognitive-behavioral therapy and exercise training are nonpharmacological approaches to improving symptoms of anxiety and depression.^54–56

In summary, although anxiety and depression were highly correlated, only depression was related to increased mortality risk in our CHF patients. Given how disease management has evolved since our data were collected in 1998, whether depression remains a risk factor for mortality in these patients is uncertain. Given the significant impact of depression on quality of life, however, and its potential relation to mortality, its treatment in CHF patients must improve. Future studies assessing the relations between different emotional states, cardiac diseases, and their potential mechanisms are required.

	Acknowledgments

 
This study was partly supported by a grant from NIMH, Bethesda, Md.

Disclosure

Dr Krishnan has received grants and/or research support from Novartis and has served as a consultant to the following: Abbott, Amgen, GlaxoSmithKline, Johnson&Johnson, Merck, NPS, Organon, Otsuka, Pfizer, Somerset, Synaptic, Vela, and Wyeth.

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