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European Journal of Heart Failure 2008 10(7):714-721; doi:10.1016/j.ejheart.2008.05.011
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© 2008 European Society of Cardiology

Depression worsens outcomes in elderly patients with heart failure: An analysis of 48,117 patients in a community setting

Alejandro Macchiaa, Simona Montea, Fabio Pellegrinia, Marilena Romeroa, Antonio D'Ettorrea, Luigi Tavazzib, Gianni Tognonia and Aldo P. Maggionic,*

a Consorzio Mario Negri Sud, Santa Maria Imbaro Chieti, Italy
b IRCCS Policlinico San Matteo Pavia, Italy
c Centro Studi ANMCO Firenze, Italy

* Corresponding author. ANMCO Research Center, Via A. La Marmora 34, 50121 Firenze, Italy. Tel.: +39 055 5001703; fax: +39 055 583400. E-mail addresses: maggioni{at}anmco.it, centrostudi{at}anmco.it (A.P. Maggioni).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims: To assess the relationship between depression and clinical outcomes among elderly patients with heart failure (HF) in a community setting.

Methods and results: To identify patients with HF and depression we used record linkage analysis of hospital discharge records, prescription databases and vital statistics. All consecutive patients aged ≥ 60 years in 6 Local Health Authorities in Italy were included. HF was defined as either: 1) hospital discharge with HF diagnosis (ICD-9: 428) and/or 2) chronic treatment for HF identified as concomitant (within 45days) prescription of any combination of ACE inhibitors, digoxin, furosemide, bisoprolol, carvedilol, spironolactone, ARB-blockers. Depression was identified from exposure to psychotropic drugs before HF diagnosis. Cox proportional hazards models adjusted for major confounders were used. To adjust for potential residual known confounders, a propensity score analysis was performed. Sensitivity and subgroup analysis were used to demonstrate the consistency or robustness of the results.

48,117 patients with HF were identified. Of these, 3328 (6.9%) were treated for depression. Among patients with HF, those with depression were significantly older, and more likely to be women with a previous stroke. Depression significantly worsened major outcomes including all cause mortality [HR (95%CI); 1.20 (1.08–1.33)] and the composite of stroke/TIA/AMI [1.23 (1.13–1.34)]. Patients with depression had no increased risk of rehospitalisation for HF. Propensity scores and subgroup analysis confirmed these findings.

Conclusion: Among elderly patients with HF, depression was independently associated with poor clinical outcomes mostly due to an increase in vascular events.

Key Words: Heart failure • Depression • Prognosis

Received November 29, 2007; Revised April 17, 2008; Accepted May 21, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Several prognostic factors have been identified as independent predictors of mortality among patients with heart failure (HF) enrolled in clinical trials [1,2]. Most of these risk stratification models however largely disregarded comorbidities which are very prevalent in a community context [3-5]. Although depression is a relatively common condition among individuals with HF [6], relatively few studies [7-11] have assessed the impact of depression on mortality among patients with heart failure (HF). Moreover, these studies have reported conflicting results, with some [7-9] identifying depression as an independent prognostic marker and others [10,11] suggesting a neutral or non-significant effect. Reasons for these discrepancies could be related to the different definitions of depression used across studies. The different groups used a variety of different instruments for assessing depression, including the Zung Self Rating Depression Scale [7], Beck Depression Index (BDI) [8,9] and the Geriatric Depression Scale [10]. Moreover, these instruments are not validated as diagnostic tools but as prognostic indicators [12]. Additionally the number of patients and events in each study was relatively small. Overall, the most important limitation is that the majority of these studies included patients from a single institution, which is not necessarily representative of the burden of HF in a community setting.

The present study was undertaken to examine the prevalence and the prognostic impact of depression among elderly patients with heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
Record linkage analysis is increasingly recognized as a reliable research tool to assess the interplay between different clinical conditions to evaluate outcomes in large, unselected populations which better represent the real context of life and care [13].

We carried out a record linkage analysis of hospital discharge records, prescription databases and mortality registers, which included data on 521,586 subjects aged ≥60 years. The analysis was performed in six Local Health Authorities (LHAs) from Northern and Southern Italy between January 1st 2000 and December 31st 2004.

2.1. Data sources
Hospital discharge records included information on primary diagnoses and up to five coexisting conditions, diagnostic and therapeutic interventions, date of admission, discharge and in-hospital death. All diagnoses were coded according to the International Classification of Disease, Ninth Revision [ICD-9 CM] [14].

The prescription database documented all prescriptions reimbursed by the National Health System with drugs coded according to the Anatomical Therapeutic Chemical (ATC) Classification [15] and qualified with respect to dosages, date of first prescription as well as duration and intensity of exposure.

Mortality statistics were available as death certificates from each LHA.

A linkage of these three databases was carried out and pharmacological history for each patient was obtained. The reliability of this strategy to produce an epidemiological survey has been previously validated and reported [16,17]. All security and protection measures for patient's data were performed according to national law.

2.2. Identification of HF patients
Patients were classified as HF patients if they were (a) discharged, between January 1st and December 31st 2003 with a primary or secondary diagnosis of HF (ICD-9 code: 428) or (b) chronically exposed to specific medications for HF over the previous two years. Repeated prescriptions of any combination of the following drugs: ACE inhibitors, digoxin, furosemide, carvedilol, bisoprolol, spironolactone, and angiotensin receptor blockers (ARBs) were considered as specific treatments for HF. Combination therapy was defined as prescription of at least one other specified drug within 45 days of the prescription date for the first drug, which was repeated at least three time over one year, as reported elsewhere [16,17]

The index date was either the first occurrence of hospital admission for HF or the date of the second prescription of the aforementioned specific drug combination. For those patients who fulfilled both conditions (specific prescription pattern and hospitalisation) the first chronological event was considered the index date.

2.3. Identification of depression
We identified the HF patients with depression from their exposure to specific drugs within the 12-month period preceding the index date. The drugs used for the identification of depression were: selective serotonin-reuptake inhibitors (SSRIs; Fluoxetine, Paroxetine, Sertraline, Fluvoxamine, Citalopram, Escitalopram); selective norepinephrine-reuptake inhibitors (NRIs; Reboxetine); non-selective norepinephrine-reuptake inhibitors (Desipramine; Nortryptiline); Mixed or dual-actions reuptake inhibitors (Amitriptyline; Clomipramine; Imipramine; Venlafaxine); serotonin antagonists and reuptake inhibitors (Mirtazapine; Mianserin; Nefazodone; Trazodone).

We used two different approaches for qualifying patients with depression: an "occasional exposure criteria" (at least one prescription of anti-depressants) or a "chronic exposure criteria" (at least three prescriptions of anti-depressants).

2.4. Cardiovascular and non-cardiovascular comorbid conditions
Cardiovascular (CV) and non-cardiovascular conditions that are known indicators of additional CV risk were included in the analysis, if documented over the 24-month period preceding the index date. Detailed descriptions of these procedures have been reported elsewhere [16,17]. Briefly, CV comorbidities include previous presence of hypertension, CHD, atrial fibrillation, diabetes, TIA, stroke and peripheral vascular disease. Hypertension and diabetes were identified from hospitalisations and/or chronic exposure to pharmacological treatments. For all other CV conditions for which a specific prescription pattern was not identifiable, only hospitalisation-associated diagnoses were considered.

Non-cardiovascular conditions included malignancy and chronic obstructive lung disease (COPD). Cancer was identified from hospital data. A patient was classified as having COPD if chronically exposed to specific treatments or if hospitalised for any COPD related condition.

For conditions in which prevalence estimation relied only on hospitalisations, the denominator used referred to those patients who had previous hospitalisations (e.g. overall 21,200 persons, 19,646 without depression and 1554 with depression).

2.5. Treatments and compliance during follow up
The daily definite dose (DDD) established by the Nordic Council on Medicines [18], and adopted by the WHO was used to categorize patients during follow up in terms of degree of exposure time (≥50%) to these recommended doses.

2.6. Follow up assessment
Follow up for each patient extended from the index date to day 360 or until the occurrence of the following events: a) All cause mortality or b) non-fatal AMI, non-fatal stroke, non-fatal TIA; c) hospitalisation for HF or d) hospitalisation for any reason.

2.7. Statistical analysis
Characteristics of the HF patients with and without depression are reported as percentages and mean±standard deviation (SD), and were compared with Pearson {chi}2 and Mann-Whitney U test for categorical and continuous variables respectively.

The association of depression at time of discharge with 1-year all cause mortality and major events was assessed using a multivariate Cox proportional hazards model. Results are expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). All multivariate analyses were adjusted for the following covariates: age, sex, diabetes, hypertension, CHD, peripheral vascular disease, stroke, atrial fibrillation, malignancy, COPD and previous hospitalisation.

Furthermore, in order to adjust for potential residual confounding, we also performed a propensity score (PS) analysis [19,20] to predict the probability to be assigned to anti-depressant treatment. The logistic model for PS score assessment included the same covariates used in the multivariate Cox model, plus quadratic terms and a set of two- and three-term interactions between the same covariates.

PS logistic model was selected in a stepwise fashion, and model-building stopped when adequate covariate balance within PS quintiles was reached. Covariate residual imbalances within PS quintiles were assessed at each step with a two-way analysis of variance, in which each confounder was considered as outcome and PS quintiles and treatment as factors. Overlapping of the PS distribution between treatment and control groups was also checked.

PS quintiles were then introduced in the Cox model to allow an adjusted comparison between patients treated with anti-depressant agents and controls for all cause mortality and major events.

Additionally we assessed the association of depression with outcomes in different subsets of patients identified with diverse definitions of HF and depression. Specifically, for HF we considered subjects identified only by prescriptions, those only by hospitalisations and patients who had both criteria. For depression we considered those exposed occasionally to anti-depressants as well as those who had a chronic exposure to treatment. Other clinically relevant subgroups were also identified including age (above or below median) and presence of previous CHD.

Finally, since PS methodology addresses only imbalances due to measured confounders, we also performed a sensitivity analysis to account for potential residual confounding deriving from the effect of an unmeasured binary covariate [21].

P-values <0.05 were considered significant. All the analyses were performed using SAS Statistical Package Release 9.1 (SAS Institute, Cary, NC, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Forty-eight thousand one hundred and seventeen patients with HF were identified. In 41,545 patients, HF was identified only due to chronic exposure to specific treatments. Additionally, 3756 patients were identified from a hospitalisation for HF only. Finally, 2816 patients had both hospitalisation and chronic exposure to treatments. Among patients hospitalised for HF, 76% had HF as the principal diagnosis.

Among patients with HF, 3328 (6.9%) received anti-depressant treatment and 1632 (3.4%) were exposed to at least 3 anti-depressant prescriptions/year. Considering that both of these identification criteria for depression identified patients with similar outcomes (Table 1), all results presented hereafter refer to the population that received anti-depressant agents at least once. Mean duration of follow up was 1 year.


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  		Table 1 Baseline characteristics of HF patients with and without depression

 
3.1. Characteristics of patients
Table 1 describes the main characteristics of HF patients with and without depression.

The clinical profile of the population with HF is typical of epidemiological surveys, with 63% of patients being 75 years or older. Patients had an important burden of CV comorbidities, with three out of four patients having hypertension, one out of four diabetes and nearly 20% atrial fibrillation. A previous hospitalisation with a diagnosis of coronary heart disease was present in 27.1%, peripheral vascular disease in 7% and stroke in 7.2% of patients.

Similarly, an important burden of non-cardiovascular conditions was observed: nearly 21% of subjects had COPD and 8% any malignancy.

Depressive patients were significantly older with a higher proportion of females. Patients with depression had a significantly higher proportion of hospitalisation for stroke (12.7% vs. 6.8%, p<0.0001) and TIA (3.9% vs. 2.4%, p=0.001) and less frequently had atrial fibrillation.

3.2. Treatment of HF and depression
Table 2 shows baseline treatments for the HF patients with and without depression.


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  		Table 2 Baseline treatments for HF and depression

 
The use of evidence based treatments for HF shows a pattern of under-treatment in agreement with other epidemiological studies: 64% of patients received ACE inhibitors (63.5% of patients with HF vs. 64.5% of patients with HF and depression) and 21% beta-blockers (20.7% vs. 20.0). Additionally, 67% received diuretics, 67% digoxin and 5% ARBs. Anticoagulants were prescribed to 14% of the patients. Depressed patients were less likely to be treated with anticoagulants and more likely to receive diuretics and digoxin. Most patients (43.9%) with depression were treated with SSRIs followed by serotonin antagonists and reuptake inhibitors (34%).

3.3. Outcomes
Four thousand seven-hundred and twenty (4720) patients died during the one year follow up period. The adjusted risk of death among patients with depression was 1.20 (1.08-1.33) (p=0.0006) (Table 3). The composite outcome of myocardial infarction, stroke or TIA occurred in 6278 patients. The adjusted risk of the composite end point among patients with HF and depression was 1.23 (1.13-1.34) (p<0.0001) (Fig. 1).


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  		Table 3 Predictors of all cause death during follow up

 


Figure 01
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  		Fig. 1 Survival free of Stroke/TIA/AMI.

 
The risk of hospitalisation for HF was similar between depressed and non-depressed patients. The adjusted risk for HF hospitalisation was 1.06 (0.93-1.20) (p=0.399). Similarly the probability of being hospitalised for any reason was the same for both groups. The adjusted HR was 1.00 (0.94-1.06) (p=0.997). These results were confirmed by the PS methodology: the adjusted risk of death and the composite of myocardial infarction, stroke or TIA was respectively 1.22 [1.10-1.35] and 1.25 [1.15-1.37].

The sensitivity analysis showed that to affect these findings, an unmeasured binary confounder should have a HR of 1.20 and a difference in prevalence between patients with and without depression of at least 40% for mortality and a HR of 1.30 with a difference in prevalence of 50% for the composite outcome.

Neither the different subsets of patients with HF/different criteria for the identification of HF nor the magnitude of exposure to anti-depressants (occasionally treated vs. chronically treated) changed the main results (Fig. 2).


Figure 02
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  		Fig. 2 Subgroup analysis for all cause mortality (A) and survival free of Stroke/TIA/AMI (B).

 
3.4. Treatment and events
To clarify a possible mechanism of impaired survival and survival free of events in patients with depression, we examined both the exposure to evidence based treatments during follow up as well as the compliance to treatments (Fig. 3).


Figure 03
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  		Fig. 3 Prescriptions and compliance with ACE inhibitors and beta blockers among patients with/without depression.

 
Patients with depression were significantly less often exposed to ACE inhibitors during follow up but not to beta blockers. The exposure time to the prescribed treatments was significantly lower among patients with depression. The rate of patients receiving these treatments for at least 50% of their follow up time was lower among depressed patients for both ACE inhibitors and beta blockers (Fig. 3).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The findings of this analysis can be summarized under four main headings: a) among elderly patients with HF in a community setting, depression is independently associated with impaired survival; b) the mechanism is likely related to an increased risk of vascular events during follow up, with no differences in HF-related events; c) depressive patients are less likely to be prescribed evidence based treatments for HF and more likely to be less adherent with these treatments and d) the magnitude of exposure to anti-depressants is not related to major clinical outcomes.

HF is a condition associated with an ominous prognosis, particularly among elderly patients in a community setting. Several prognostic factors have been identified as independent predictors of mortality among patients enrolled in clinical trials. Most of these risk stratification models however largely disregarded comorbidities which are very prevalent in a community context. Further, even in an epidemiological perspective [3], depression is usually ignored by the risk stratification models. This is particularly troublesome because depression is a very prevalent condition. Recent estimates indicate that the prevalence of depression in the general population is close to 5% and that only 28% of these patients are taking anti-depressants [22]. The gap between the presence of depression and the physician's perception/treatment for depression is particularly prevalent among elderly patients [22]. The implications of failure to recognize depression among the elderly suggests a serious public health problem.

Estimates of the prevalence of depression among HF patients are scarce and vary hugely from 13% to 77% [6]. However these estimates are based generally on small groups of patients, who are often hospitalised.

Using a very large registry of community patients with HF, we found that nearly 7% of patients had been treated with anti-depressant agents. The methodology that we used for identification of depression (prescription based) is very specific, albeit relatively insensitive, which allowed us to speculate that at least 7% of patients with HF had depressive symptoms that lead to a specific pharmacological treatment. A similar prevalence has also been reported in other studies using different methods for the identification of depression [6]. Considering that in the general population only one out of four patients with depression is pharmacologically treated, it is also reasonable to speculate that, among our cohort, a higher proportion of patients could have less severe forms of depression. Moreover, considering that elderly patients are those who are less likely to receive appropriate care, the profile of our population reinforces this hypothesis.

We found that depression was associated with a 20% increased risk of death over a relatively short follow up period. Although this observation is consistent with previous reports [7-9], these studies recruited only 600 patients (with 150 deaths) from single centres. Our study which describes 4720 deaths in 48,117 patients not only confirms but extends these findings in an epidemiological perspective.

Although our study was not designed to assess the mechanisms which determine the adverse prognosis associated with depression, we observed that increased mortality was entirely driven by an excess risk (23%) of vascular events. Experimental [23-27] and clinical studies [28-43] have demonstrated that patients with depression have increased markers of inflammation and platelet aggregation that make them more vulnerable to ischaemic events. Our results reinforce the hypothesis that a major proportion of the attributable risk of depression is driven by an excess of vascular events. However, other mechanisms seem to play a role. Access to large prescription datasets allowed us to determine patterns of and compliance with treatments in these patients. In a general context of suboptimal treatment, common in epidemiological surveys [44], depressive patients were less likely to receive evidence based treatments. Additionally, we also found that patients with depression were less often treated for at least 50% of their follow up time. This could reflect either that they were prescribed lower doses of recommended therapies or that they were less adherent to prescribed treatments. Whatever the reason, these two mechanisms could have played a role in the impaired prognosis of depressive patients.

4.1. Study limitations
Some advantages of using administrative data are the breadth of population coverage, the ability to perform lifetime follow up and the capture of mortality data. Additionally, this type of study provides important information about daily practice in a "real-life" population, in our case elderly patients with HF and several comorbidities. Nonetheless, our results should be considered in light of a number of study limitations.

Particular disadvantages are the lack of some baseline clinical measurements, such as ejection fraction and psychiatric diagnosis, and the potential for diagnostic inaccuracy when prescription patterns are used. Reliance on prescription patterns could potentially result in under or over-estimations of the real burden of disease. In this study we used a very specific, albeit relatively insensitive, criterion to classify patients as depressive. This system of identification may have resulted in an under-estimation of the burden of disease, particularly when we consider that elderly patients are usually under treated. Additionally we did not formally validate this identification system.

Also it could be speculated that it is not depression but treatment for depression that confers the excess risk of mortality and outcomes. Although this could not be definitely ruled out, our data suggest that disease and not treatment is associated with poor outcomes, since the magnitude of the treatment (occasionally exposed vs. chronically treated) conferred identical risk.

In conclusion, our analysis of administrative databases in a large cohort of patients with HF shows that depression is associated with a worse outcome in patients with HF. Specific studies should be planned to confirm these observations in populations of patients with more detailed diagnostic procedures for both depression and HF.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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