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Specificity of depression following an acute coronary syndrome to an adverse outcome extends over five years
Psychiatry Research 185 (2011) 347–352
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Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s
Specificity of depression following an acute coronary syndrome to an adverse outcome extends over five years Gordon Parker a,b,⁎, Matthew Hyett a,b, Warren Walsh c, Catherine Owen a,b, Heather Brotchie a,b, Dusan Hadzi-Pavlovic a,b a b c
School of Psychiatry, University of New South Wales, Randwick, NSW 2031, Australia Black Dog Institute, Hospital Road, Prince of Wales Hospital, Randwick, NSW 2031, Australia Department of Cardiac Services, Prince of Wales Hospital, Randwick, NSW 2031, Australia
a r t i c l e
i n f o
Article history: Received 18 February 2010 Received in revised form 13 July 2010 Accepted 14 July 2010 Keywords: Acute coronary syndrome Myocardial infarction Angina Depression Morbidity
a b s t r a c t Many studies have demonstrated that depression is associated with a worse cardiovascular outcome and increased risk of death in those experiencing an acute coronary syndrome (ACS). Recent studies have suggested, however, that any association is strongly influenced by the timing of the depression, with postACS depression providing the greatest risk. Establishing any timing impact should assist etiological clarification. We initially recruited 489 subjects hospitalized for an ACS, assessed lifetime and current depression, and then – at 1 and 12 months – assessed subsequent depression. Subjects were followed for up to 5 years to assess cardiovascular outcome and the impact of depression at differing time points, with three defined poor outcome categories (i.e. cardiac admission and/or cardiac rehospitalization). While outcome was associated with a number of non-depression variables, a poor outcome was most clearly associated with depressive episodes emerging at the time of the ACS but with some risk affected by episodes that commenced prior to the ACS and being persistent. Neither lifetime depressive episodes nor transient depressive episodes occurring around the baseline ACS event appeared to provide any risk. Study findings indicate that any differential deleterious impact of post-ACS depression has both short-term and longer-term outcomes, and, by implicating the centrality of post-ACS depression, should assist studies seeking to identify causal explanations. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction As overviewed earlier (Parker et al., 2008), a revisionist position is emerging in regard to links between depression and cardiovascular disease. For some two decades, studies generally quantified (i) lifetime depression as a risk factor for subsequent cardiovascular disease and (ii) state depression during an ischemic cardiac event as a predictor of a poorer cardiac outcome. However, in the last few years, studies of these associations have generated a number of inconsistent findings. Such inconsistencies may reflect how ‘depression’ has been measured (i.e. dimensionally by severity, or categorically by ‘caseness’ status), use of self-report depression questionnaires as against structured clinical interviews, the period allowed for cardiac-eventrelated depression (i.e. from cardiac admission through to several months after discharge) and the length of the follow-up period. Additionally, many studies have not specified whether depression commencing before, during, or following an acute cardiac event contributed to any differential outcome risk. ⁎ Corresponding author. Black Dog Institute, Prince of Wales Hospital, Randwick, NSW 2031, Australia. Tel.: + 61 2 9382 4372; fax: + 61 2 9382 4343. E-mail address: [email protected] (G. Parker). 0165-1781/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2010.07.015
The last issue is emerging as of key importance, with several recent studies indicating that any association may be dependent on establishing both the time of onset of any depressive episode associated with the cardiac event, and whether it is a first-ever (often called incident depression) or, alternately, a recurrent or ongoing (i.e. a non-incident depression) episode. Several representative studies will be noted. Lesperance et al. (1996) reported that those with a recurring depressive episode during a cardiac admission had a higher mortality rate over the following 18 months than those with incident depression. By contrast, both Grace et al. (2005) (using a 5-year follow-up based on hospital linkage data) and de Jonge et al. (2006) (using a mean follow-up of 2.5 years) reported that those with post-MI (myocardial infarct) depression had increased mortality and morbidity risks, while those who had a prior history of depression were not at increased risk. The Grace et al. (2005) study was limited in terms of the definition of depression, however, in that while a standard self-reported two-week criterion of depressed mood was used, participants were not asked to rate further symptomatology. For current depression, their study used a dimensional scale of depression severity. Such measurement may not accurately reflect clinical depressive symptomatology and may instead detect mild and inconsequential ‘depressive’ periods.
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To clarify such issues, we undertook a study focusing on clinical depression and examined the impact of (i) the onset time of any clinical depressive episode, and (ii) the incident/non-incident onset status of post-cardiac depression on subsequent cardiovascular outcome, quantifying depression status with a case-finding measure. A large sample of subjects hospitalized with an acute coronary syndrome (ACS) – defined as an acute myocardial infarct or unstable angina pectoris – were recruited and interviewed shortly following their hospitalization. Lifetime and current episodes of major depression and/or dysthymia (defined by the Diagnostic and Statistical Manual for Mental Disorders or DSM-IV; American Psychiatric Association [APA], 2000) were quantified and subjects reassessed (by telephone interview) one month after baseline assessment to determine if they met DSM-IV symptom and duration criteria. Outcome was initially standardized around their progress from the one-month assessment to 12 months following initial hospitalization. The study endpoint was readmission for another ACS and/or cardiac mortality in that 12-month period. In a resulting publication (Parker et al., 2008), we quantified that 12-month outcome was not associated with either (i) any preceding lifetime depressive episode or (ii) existing depression at initial hospitalization. However, a poor 12-month outcome was predicted by depression (recurrent or a first-ever episode) developing in the month following the ACS event. This suggested that it was the timing that conveys poor cardiac outcome risk, irrespective of the depressive episode being an initial or newly recurrent one. If such a ‘timing’ issue determines risk, it is capable of several explanations, including the psychosocial impact of an ACS-associated depression; or a biological explanation, for example, that post-ACS depression may reflect and/or result in “inflammation and low heart rate variability” (Carney et al., 2002; de Jonge, 2009; Frasure-Smith et al., 2009b). If such ‘state’ factors are determinants, it then remains to be established whether they preferentially compromise short-term outcome or whether they provide an ongoing risk. The latter issue dictated our current extension study. In this report we examine the impact of depression timing over an extended follow-up period. As only 22% of the participants followed up at our one-year review had experienced a cardiac-related death or readmission, the lengthier follow-up increased the numbers of poor outcome subjects and so increased statistical power which allowed associations to be quantified with greater confidence. 2. Method 2.1. Initial patient selection Eligible subjects were those admitted to hospital with an ACS diagnosis, whether an acute MI and/or unstable Angina Pectoris (UAP). Of the 904 eligible subjects, 299 were excluded if non-English speaking or cognitively or significantly physically impaired, 19 were deceased soon after being approached and could not complete the study, and a further 9 patients started the study but withdrew consent soon after, while another 88 refused informed consent, generating a sample of 489 eligible subjects (MI = 316, UAP = 173). 2.2. Study protocol Eligible subjects received a semi-structured clinical baseline interview from a research assistant at a mean of 3.8 days (S.D. ± 3.0 days) following admission, including the depression section of the Composite International Diagnosis Interview (CIDI version 2.14; WHO, 1997), to establish whether subjects met current or lifetime DSM-IV (APA, 2000) criteria for Major Depression and/or Dysthymia (i.e. clinical depression). Four weeks following baseline interview, subjects were contacted by phone to determine whether they then met criteria for clinical depression, reflecting the emergence of a post-baseline onset episode, or a baseline episode only then meeting the two-week duration criterion required for a DSM-IV major depressive episode. Study subjects were contacted by phone after both three years and five years to determine outcome, while as noted below, outcome details were pursued with family members, managing primary physicians and review of hospital records as needed. Here we report data on the extended five-year follow-up.
2.3. Depression ‘timing’ variables In comparison to our earlier report, we examine outcome at five years (specifically 260 weeks following baseline admission) in relation to an increased number of sample sub-sets, in order to examine the impact of timing of any depressive episode even more specifically. Sub-sets were defined as: (i) ‘nil’ — subjects who had no history of depression at any time; (ii) ‘prior’ — subjects who had had at least one episode of depression prior to (but were not depressed at) the baseline admission; (iii) ‘incident’ — subjects who developed their first-ever episode of depression in the month subsequent to baseline admission (this includes those whose depression started shortly prior to their index ACS, but which did not meet the DSM two-week duration criterion at baseline assessment); (iv) ‘recurrent’ — subjects who had had at least one episode of depression prior to (but were not depressed at) the baseline admission, and who then developed an episode of depression in the subsequent month (again, this includes those whose depression may have started shortly before their index ACS); (v) ‘continuing’ — subjects who were depressed at the baseline admission and remained depressed at the end of the first month; and (vi) ‘non-continuing’ — subjects depressed at the baseline admission but no longer depressed at the end of the first month. 2.4. Other key study variables At baseline – and as detailed previously (Parker et al., 2008) – we collected data on cardiac symptoms and cardiac history, medical and/or psychiatric co-morbidities, cardiac and psychotropic medications, interventions received in hospital, biochemical results, and a range of other variables. Data on both left ventricular ejection fraction (LVEF) and the number of diseased vessels on angiography were recorded at baseline as measures of disease severity. In all our one-year outcome analyses (Parker et al., 2008), depressed sub-sets were generally younger than non-depressed sub-sets, so age was judged as a key covariate. Current analyses also included a variable reflecting the date of first hospitalization in order for any improvement or worsening in cardiac outcomes over the extended recruitment interval to be tested. To that end, the 118-week recruitment period was divided into five intervals (four of 24 weeks and one of 22 weeks) and each patient's date of recruitment was coded 0–4, with 4 being the earliest period. 2.5. Outcome measures We defined three possible primary outcomes over the five years subsequent to the one-month assessment following baseline hospitalization: (i) cardiac admission; (ii) cardiac death; and (iii) cardiac event (either cardiac admission and/or cardiac death). A cardiac admission was defined as hospitalization as a consequence of a cardiac condition, and a cardiac death as death from a cardiac condition. A ‘cardiac admission’ was defined as admission to hospital (not merely attendance at a Casualty Emergency department) for an acute myocardial infarct, angina, ischemic heart disease or heart failure — but not for atrial fibrillation alone, while we also excluded those who were admitted for a cardiac procedure alone (such as insertion of a pacemaker). We sought initially to obtain cardiac admission details from the patient or from a relative. If such information was unclear, we then contacted their managing practitioner and/or accessed any available hospital records. Details on any ‘cardiac death’ were obtained principally by obtaining the death certificate but, if insufficiently precise, information was sought from relatives, managing practitioners and review of any available hospital records. As death precludes subsequent events, subjects who died from whatever cause without a preceding admission over the follow-up period were included in the analyses and treated statistically as censored for the survival analyses in relation to cardiac admission outcome status. Subjects who died from a non-cardiac cause were similarly treated in relation to the second and third outcome definitions. 2.6. Follow-up assessments As described, an assessment (following baseline admission) was undertaken at four weeks to capture any baseline depressive episode that met duration criteria. At 12 months, the first outcome status follow-up occurred, with assessment by a research assistant (not necessarily blind to baseline depression status) including clinical status, medication adherence, cardiac procedures and hospital readmissions. If a patient could not be interviewed, contact was made with family members or the patient's physician. The names of all untraced individuals were submitted to the NSW Registry of Births, Deaths and Marriages and the Australian National Death Index to clarify their outcome status. At five years, the second outcome status follow-up occurred, and, as for the 12month review, if the patient could not be interviewed, we sought to interview a relative and/or managing medical practitioner to determine their outcome and, if no such contacts could be established, we again submitted patients' names to the NSW Registry and National Index to determine if the patient had died, and their listed cause of death. 2.7. Statistical analyses Descriptive statistic analyses used SPSS V17. Survival curves were estimated using the Kaplan–Meier method and modeling of survival used the discrete-time approach in which a regression model (in this case, a logit model) was fitted to person–period structured data (Singer and Willett, 2003). For the latter, the time–period used was one
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month, with all events coded to the month, not the day that they occurred. Survival analyses used R (version 2.9.2) software (R Core Development Team, 2009).
3. Results 3.1. Study overview At baseline, 489 subjects were assessed (70.3% male) and with a mean age of 65.7 (S.D. 12.2) years. At the five-year review, 53 (10.8%) subjects had been lost to the study. Of these, 12 (2.5%) subjects had withdrawn consent; 11 (2.2%) subjects had died in the first month; 9 (1.8%) subjects could not be contacted at one month and consequently for whom we again had no follow-up data; 19 (3.9%) subjects had insufficient primary (17 subjects) or covariate data (2 subjects) for analysis; and 2 (0.4%) subjects had missing files. Data on the remaining 436 subjects (89.2% of the original sample) are now analyzed. 3.2. Depression ‘timing’ and outcome Table 1 quantifies the number of subjects within each of the study outcome sub-sets in relation to any depressive experience. Of the total 436 subjects, 159 had experienced a single or recurrent major depressive episode, 12 met criteria for dysthymia and 37 met criteria for dysthymia and major depression. Fig. 1 plots the survival curves for any cardiac event (37% of the sample) and it is apparent that the differential outcome at five years was emerging (albeit less distinctively evident) at the earlier one-year review. In comparison to those who had never experienced any depressive episode, the greatest chance of experiencing any cardiac event was for the incident and recurrent depression sub-sets, and with those in the continuing sub-set having an intermediate outcome. Fig. 2 plots the trajectories of those assigned to the cardiac death outcome — with the lack of any suggested differentiation (other than for incident depression) perhaps reflecting the small sub-set numbers for this outcome group. 3.3. Possible study covariates
Fig. 1. Survival curves for any cardiac event for those with (i) no lifetime depression, (ii) prior depression only, (iii) incident depression, (iv) recurrent depression, (v) continuing depression and (vi) non-continuing depression.
admission, diabetes, smoking, any past admission, low LVEF, cerebrovascular event such as a transient ischemic attack [TIA] or cerebrovascular accident [CVA]), and any current treatment with a broadaction (i.e. Monoamine Oxidase Inhibitor or MAOI and/or a Tricyclic Antidepressant or TCA) or narrow-action (i.e. Selective Serotonin Reuptake Inhibitor or SSRI) antidepressant drug. Inspection suggests that the mean age was differentially low in the recurrent depression group, that there were quite varying rates of CABGs (high in the incident and low in the recurrent group), that smoking was distinctly higher in the recurrent group, and with other instances of variable prevalences of such factors encouraging examination of their
In our earlier paper (Parker et al., 2008), we reported that those in any depressed group sub-set were generally younger than those never depressed, but that such sub-set membership was not associated with measures of disease severity (e.g. LVEF less than 35%, number of diseased vessels, first admission for ACS, number of previous admissions for an ACS). In our current study we examined (and document in Table 2) for associations between depression classification and a number of risk factors or confounders (e.g. age, gender, any coronary artery bypass graft surgery [CABG] following the index
Table 1 Impact of timing of depression onset and depressive sub-set status on cardiac death and/or cardiac rehospitalization rates. Cardiac-related event Subjects
Admission
Death
Admission and/or death
Depression status
N
%
N
%
N
%
N
%
Nil Prior Incident Recurrent Continuing Non-continuing Total
265 77 24 20 27 23 436
60.8 17.7 5.6 4.6 6.2 5.3 100
72 17 10 12 10 7 128
27.2 22.1 41.7 60.0 37.0 30.4 29.4
27 6 4 2 3 2 44
10.2 7.8 16.7 10.0 11.1 8.7 10.1
92 23 13 12 13 9 162
34.7 29.9 54.2 60.0 48.1 39.1 37.2
Study sub-set considered in analyses. Percentages in bold differ significantly (P b 0.05) from the “Nil” group.
Fig. 2. Survival curves for any cardiac death for those with (i) no lifetime depression, (ii) prior depression only, (iii) incident depression, (iv) recurrent depression, (v) continuing depression and (vi) non-continuing depression.
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Table 2 Association of risk factors with depression status. Depression status
Nil Prior Incident Recurrent Continuing Non-continuing Total
Age (S.D.)
68.4 10.7 63.3 13.1 68.3 11.6 50.0 8.4 62.4 11.9 64.1 12.7 66.1 12.0
Sex (male)
Any CABG
Diabetes
Past admission
Smoking
LVEF b35%
TIA/CVA ever
Current antidepressant MAOI/TCA SSRI
195 73.6% 53 68.8% 15 62.5% 13 65.0% 17 63.0% 16 69.6% 309 70.9%
77 29.1% 13 16.9% 11 45.8% 2 10.0% 8 29.6% 5 21.7% 116 26.6%
48 18.1% 11 14.3% 7 29.2% 3 15.0% 6 22.2% 4 17.4% 79 18.1%
105 39.6% 25 32.5% 10 41.7% 11 55.0% 11 40.7% 9 39.1% 171 39.2%
35 13.2% 9 11.7% 6 25.0% 8 40.0% 7 25.9% 5 21.7% 70 16.1%
16 6.0% 3 3.9% 1 4.2% 0 0.0% 0 .0% 2 8.7% 22 5.0%
35 13.2% 12 15.6% 4 16.7% 1 5.0% 4 14.8% 2 8.7% 58 13.3%
6 2.3% 2 2.6% 0 0.0% 0 0.0% 4 14.8% 0 0.0% 12 2.8%
4 1.5% 6 7.8% 1 4.2% 0 0.0% 2 7.4% 2 8.7% 15 3.4%
Numbers and percentages quantity those within differing sample sub-sets that had the risk factor. CABG = Coronary artery bypass graft, LVEF = left ventricular ejection fraction, TIA = Transient ischemic attack; CVA = cerebro-vascular accident; MAOI = monoamine oxidase inhibitor; TCA = tricyclic; SSRI = selective seretonin reuptake inhibitor. Italics denote the S.D.'s of age across depression status and percentages for all other variables.
individual impact and their possible inclusion in multivariate analyses. Table 3 analyses the impact of cardiac risk factors on outcome. Data indicate that gender, smoking and baseline exposure to antidepressant medication were of no impact, that older age was linked only to an increased chance of cardiac death and not to hospital readmission, that diabetes increased the risk of a poor composite outcome, that a low LVEF and a previous cerebrovascular event (CVA and/or TIA) increased the chance of cardiac death, and that having a CABG was associated with a lower risk of all three outcomes. Each of these variables was included as covariates in our multivariate analyses.
3.5. Smoothed hazard functions for any cardiac event We repeated the survival analyses, examining prediction of cardiac death only. While recognizing that low cell numbers reduced power, significant findings were that a poor outcome was associated only with recurrent depressive sub-set status (OR = 5.88, 95% CI 1.09– 31.70, P = 0.039); and with a number of covariates: older age (OR = 1.08, 95% CI 1.04–1.12, P b 0.001), lower LVEF (OR = 3.21, 95% CI 1.36–7.58, P = 0.008), a previous CVA/TIA (OR = 2.52, 95% CI 1.26– 5.08, P = 0.009), and diabetes (OR = 2.07, 95% CI 1.01–4.25, P = 0.048). A lower risk was associated with having received a CABG (OR = 0.36, 95% CI 0.14–0.95, P = 0.040). Plots of the hazard functions were broadly similar to those depicted for any cardiac event.
3.4. Modeling survival
4. Discussion
In Table 4, we quantify the impact of other variables in our survival analysis examining predictors of any cardiac event. The discrete-time model survival analysis in Table 4 incorporates the time that people survived or were followed up and allowed hazard functions to be calculated. A worse outcome was associated with the following covariates – older age, diabetes, a CVA or TIA and a low LVEF – and a better outcome with having had a CABG. In relation to depression variables, recurrent, incident and continuing sub-set membership were associated with a worse outcome, while non-continuing depression provided no increased risk over nil depression. An assessor suggested that, instead of explicitly coding the depressive sub-sets, three binary variables (i.e. the presence or absence of a depressive episode pre-ACS, at the time of the ACS, and in the one-month period following an ACS — post-ACS) and their interactions be used. When we repeated the survival analysis using these dummy variables, the effects of other covariates were unchanged. Of the main effects and their interactions, only post-ACS depression was significant, with a risk of 2.37 (95% CI 1.53–3.67), consistent with the findings in Table 4 which loculated depression impact to a new episode (incident or recurrent). We calculated the hazard function for the six levels of the depression factor while keeping the covariates at their means. The spline smoothed hazards are graphed in Fig. 3. The hazards for the nil depression and non-continuing depressive sub-set are indistinguishable. As might be expected, the hazard functions were initially high but declined rapidly over the first two years, with increased peaks at the end of three years, and prior to the fifth year — the two extended follow-up review periods.
Our one-year follow-up – indicating that what we here call incident and recurrent depression appeared to provide the greatest risk to a poor outcome – raised two key questions. Firstly, as numbers experiencing a poor cardiac outcome were small, could this finding have reflected a lack of statistical power and risked invalid interpretation? Secondly, if a valid finding, might the impact of any etiological factor have not only been temporary — compromising short-term outcome but attenuating and not having any impact on extended outcome? We therefore report their five-year outcome. Obtaining full data sets on 89% of the original cohort was important in strengthening the likely integrity of the analyses. Relatively few subjects had experienced a cardiac death indicating their cardiac management had clearly been of a high level (for a group whose mean age had been 66 years at baseline recruitment). Nevertheless management changes rapidly and thus we included time of recruitment as a study covariate and demonstrated that outcome improved further over time. A poorer outcome was significantly associated with older age, having diabetes, a low LVEF and having previously experienced a cerebrovascular event, while having coronary artery bypass surgery (a CABG) was associated with an improved outcome. Such findings indicated the importance of including such variables as covariates in key analyses, to ensure that the independent contribution of depression timing could be quantified. As cardiac death was a rare event (being experienced by only 10% of the subjects), the principal outcome variable was having a ‘cardiac event’, and experienced by 162 subjects (or 37%). The consolidation of such events into one composite outcome variable needs to be
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Table 3 Outcome by risk factor. Outcome experienced
Risk factor Age (median) Sex (male) Any CABG Diabetes Past admission Smoker LVEF b35% CVA/TIA ever TCA/MAOI SSRI
Below Above No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes
Risk
Admission
Cardiac death
N
N
%
221 215 127 309 320 116 357 79 265 171 366 70 414 22 378 58 424 12 421 15
69 59 37 91 106 22 100 28 71 57 104 24 120 8 107 21 124 4 124 4
31.2 27.4 29.1 29.4 33.1 19.0 28.0 35.4 26.8 33.3 28.4 34.3 29.0 36.4 28.3 36.2 29.2 33.3 29.5 26.7
P
0.004
N
%
12 32 10 34 38 6 31 13 18 26 40 4 36 8 28 16 44 0 40 4
5.4 14.9 7.9 11.0 11.9 5.2 8.7 16.5 6.8 15.2 10.9 5.7 8.7 36.4 7.4 27.6 10.4 0.0 9.5 26.7
Any cardiac P 0.001
0.047
0.005
0.001 b0.001
N
%
76 86 46 116 135 27 124 38 86 76 135 27 148 14 128 34 158 4 154 8
34.4 40.0 36.2 37.5 42.2 23.3 34.7 48.1 32.5 44.4 36.9 38.6 35.7 63.6 33.9 58.6 37.3 33.3 36.6 53.3
P
b 0.001 0.029 0.015
0.012 b 0.001
CABG = Coronary artery bypass graft; LVEF = Left ventricular ejection fraction; TIA = Transient ischemic attack; CVA = Cerebrovascular accident; MAOI = monoamine oxidase inhibitor; TCA = Tricyclic; SSRI = Selective serotonin reuptake inhibitor.
recognized as a potential limitation to the current study. In comparison to our one-year review (Parker et al., 2008), the consolidation increased the percentages of ‘events’ and allowed us to broaden the sample sub-sets to create five variably ‘timed’ depressive trajectories. While lifetime depression has been demonstrated to increase the risk of a poor post-ACS outcome (Herbst et al., 2007), negative findings have also been reported. For example, Dickens et al. (2007) reported that depression increased risk only in incident cases. Glassman et al. (2009) reported that there was no difference in mortality rates between patients with a 30-day diagnosis of major depression — with or without a prior history of major depression. Those findings could be interpreted as indicating that lifetime depression provides a risk to poor outcome but are also equally interpreted (and perhaps more parsimoniously) by viewing the risk as coming from ‘baseline’ depression – independent of any prior lifetime history of depression – and further supported by those
authors quantifying increased mortality as being associated with more severe depression at baseline. Importantly, we also found no evidence of lifetime depression having any impact on five-year outcome — alone, and, of key relevance, in comparison to those who had experienced any episode of clinical depression over their life. As noted earlier, inconsistencies in the literature may reflect differing definitions of ‘depression’ — ranging from a dimensional trait or emotional state through to clinical depression. Our study has focused on DSM-IV-defined ‘clinical depression’, where biological factors may be expected to make a greater contribution than would personality or life event stressors. It should be noted, however, that while we
Table 4 Impact of covariates on discrete-time survival analysis for any cardiac event. Risk 95% CI
Nil depression Prior depression Incident depression Recurrent depression Continuing depression Non-continuing depression Study entry time Age Sex (male) Any CABG Diabetes Past admission Smoker LVEF b 35% CVA/TIA ever TCA/MAOI SSRI
B
S.E.
z
P
Risk
Lower
Upper
– − 0.26 0.80 1.02 0.61 0.08 0.13 0.02 0.16 − 0.85 0.42 0.10 0.03 0.86 0.52 − 0.08 0.27
– 0.24 0.31 0.36 0.32 0.36 0.06 0.01 0.19 0.22 0.20 0.17 0.23 0.30 0.21 0.54 0.39
– − 1.07 2.56 2.83 1.92 0.22 2.08 2.10 0.84 − 3.82 2.11 0.60 0.14 2.83 2.43 − 0.14 0.71
– 0.29 0.01 0.01 0.06 0.82 0.04 0.04 0.40 0.00 0.04 0.55 0.89 0.01 0.02 0.89 0.48
– 0.77 2.23 2.78 1.83 1.08 1.13 1.02 1.17 0.43 1.52 1.11 1.03 2.37 1.68 0.93 1.32
– 0.48 1.21 1.37 0.99 0.54 1.01 1.00 0.81 0.28 1.03 0.79 0.66 1.30 1.11 0.33 0.61
– 1.24 4.11 5.65 3.40 2.18 1.28 1.03 1.70 0.66 2.23 1.56 1.63 4.29 2.56 2.65 2.82
Items in bold represent significant risk. CABG = Coronary artery bypass graft; LVEF = Left ventricular ejection fraction; TIA= Transient ischemic attack; CVA = Cerebrovascular accident; MAOI= Monoamine oxidase inhibitor; TCA= Tricyclic; SSRI = Selective serotonin reuptake inhibitor.
Fig. 3. Smoothed hazard functions for any cardiac event (evaluated at covariate means) for those with (i) no lifetime depression, (ii) prior depression, (iii) incident depression, (iv) recurrent depression, (v) continuing depression and (vi) non-continuing depression.
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assessed depressive symptoms (via structured interview), response biases (e.g. denial, over-reporting) may lead to misclassification. Any increased chance of a cardiac event in the five-year review period being associated with depression was most clearly associated with a depression which commenced post-ACS, and with the impact over five years being most distinct for those with a new episode of depression — whether a first-ever (incident) depression or a ‘recurrent’ episode; while any ‘continuing’ episode (i.e. present during the post-ACS period but having been present prior to the index ACS admission) had a less distinctive association. Further, despite the relatively small numbers meeting criteria for ‘cardiac death’, a consolidated (i.e. incident or recurrent) post-ACS depression variable was a significant predictor of that outcome, whether examined in relation to all initial study sub-sets or with the sub-sets condensed to three principal groups. Another key finding was that non-continuing depression (i.e. depression that had been experienced previously and during the time of the ACS admission — but not persisting through to the one-month review) was unassociated with a poor outcome. It might be expected that members of this sub-set would be more likely to have depression for reasons unrelated to their cardiac condition — a differential finding of distinct importance. Thus, any deleterious impact of clinical depression on cardiac functioning appeared most weighted to episodes of depression that commenced at the time of the acute coronary syndrome (be the depression an incident or recurrent episode — but with some risk effected from episodes that commenced prior to the ACS and being persistent (i.e. ‘continuing depression’) and with the episode's risk impact continuing at least over the next five years. Narrowing the type of depression (i.e. ‘clinical depression’), its timing and its persistence of risk (both influencing one-year and five-year outcome) should narrow the candidate etiological factors. Findings may also have clinical implications in arguing for those developing depression following any ACS event to receive more assertive depression management, be it a drug or non-drug based approach. In our earlier paper (Parker et al., 2008), we overviewed research indicating that depression commencing post-ACS may be a signal marker of autonomic system dysfunction, and that the link might be mediated by reduced heart rate variability, and in line with recent speculation by Frasure-Smith et al. (2009a,b) of perturbed parasympathetic/sympathetic balance. de Jonge (2009) has argued for low heart rate variability and inflammation as candidates, noting that both are associated with the severity of underlying heart disease, depression and cardiovascular prognosis. Not only will future studies need to examine for phenomenological distinctions between incident and recurrent depression and (ideally) continuing and non-continuing depression experienced by those
with a cardiac condition, but there is a need to undertake studies pursuing inflammatory and immunological mechanisms that might explain why – at least in regard to the depression/heart disease nexus – it would appear that ‘timing is everything’. Acknowledgements We thank Penny Sawdy and Bianca Blanch for assistance with data entry necessary for our analysis, and Kerrie Eyers, who assisted with the preparation and proof-reading of the manuscript. This study was supported by a National Health and Medical Research Council Program Grant (510135) and an Infrastructure Grant from the New South Wales Department of Health.
References American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders, Text Revision, 4th ed. American Psychiatric Association, Washington. Carney, R.M., Freedland, K.E., Miller, G.E., Jaffe, A.S., 2002. Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. Journal of Psychosomatic Research 53 (4), 897–902. de Jonge, P., 2009. The importance of incident depression in myocardial infarction patients. Biological Psychiatry 65 (4), e7–8. de Jonge, P., van den Brink, R.H., Spijkerman, T.A., Ormel, J., 2006. Only incident depressive episodes after myocardial infarction are associated with new cardiovascular events. Journal of the American College of Cardiology 48 (11), 2204–2208. Dickens, C., McGowan, L., Percival, C., Tomenson, B., Cotter, L., Heagerty, A., Creed, F., 2007. Depression is a risk factor for mortality after myocardial infarction: fact or artifact? Journal of the American College of Cardiology 49 (18), 1834–1840. Frasure-Smith, N., Lesperance, F., Habra, M., Talajic, M., Khairy, P., Dorian, P., Roy, D., 2009a. Elevated depression symptoms predict long-term cardiovascular mortality in patients with atrial fibrillation and heart failure. Circulation 120 (2), 134–140. Frasure-Smith, N., Lesperance, F., Irwin, M.R., Talajic, M., Pollock, B.G., 2009b. The relationships among heart rate variability, inflammatory markers and depression in coronary heart disease patients. Brain, Behavior, and Immunity 23 (8), 1140–1147. Glassman, A.H., Bigger Jr., J.T., Gaffney, M., 2009. Psychiatric characteristics associated with long-term mortality among 361 patients having an acute coronary syndrome and major depression: seven-year follow-up of SADHART participants. Archives of General Psychiatry 66 (9), 1022–1029. Grace, S.L., Abbey, S.E., Kapral, M.K., Fang, J., Nolan, R.P., Stewart, D.E., 2005. Effect of depression on five-year mortality after an acute coronary syndrome. The American Journal of Cardiology 96 (9), 1179–1185. Herbst, S., Pietrzak, R.H., Wagner, J., White, W.B., Petry, N.M., 2007. Lifetime major depression is associated with coronary heart disease in older adults: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Psychosomatic Medicine 69 (8), 729–734. Lesperance, F., Frasure-Smith, N., Talajic, M., 1996. Major depression before and after myocardial infarction: its nature and consequences. Psychosomatic Medicine 58 (2), 99–110. Parker, G.B., Hilton, T.M., Walsh, W.F., Owen, C.A., Heruc, G.A., Olley, A., Brotchie, H., Hadzi-Pavlovic, D., 2008. Timing is everything: the onset of depression and acute coronary syndrome outcome. Biological Psychiatry 64 (8), 660–666. R Core Development Team, 2009. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna. Singer, J.D., Willett, J.B., 2003. Applied Longitudinal Data Analysis: Modeling Change and Event Occurrence. Oxford University Press, New York. World Health Organization, 1997. Composite International Diagnostic Interview 2.14: CIDI Interview Manual. WHO, Geneva.
Contents lists available at ScienceDirect
Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s
Specificity of depression following an acute coronary syndrome to an adverse outcome extends over five years Gordon Parker a,b,⁎, Matthew Hyett a,b, Warren Walsh c, Catherine Owen a,b, Heather Brotchie a,b, Dusan Hadzi-Pavlovic a,b a b c
School of Psychiatry, University of New South Wales, Randwick, NSW 2031, Australia Black Dog Institute, Hospital Road, Prince of Wales Hospital, Randwick, NSW 2031, Australia Department of Cardiac Services, Prince of Wales Hospital, Randwick, NSW 2031, Australia
a r t i c l e
i n f o
Article history: Received 18 February 2010 Received in revised form 13 July 2010 Accepted 14 July 2010 Keywords: Acute coronary syndrome Myocardial infarction Angina Depression Morbidity
a b s t r a c t Many studies have demonstrated that depression is associated with a worse cardiovascular outcome and increased risk of death in those experiencing an acute coronary syndrome (ACS). Recent studies have suggested, however, that any association is strongly influenced by the timing of the depression, with postACS depression providing the greatest risk. Establishing any timing impact should assist etiological clarification. We initially recruited 489 subjects hospitalized for an ACS, assessed lifetime and current depression, and then – at 1 and 12 months – assessed subsequent depression. Subjects were followed for up to 5 years to assess cardiovascular outcome and the impact of depression at differing time points, with three defined poor outcome categories (i.e. cardiac admission and/or cardiac rehospitalization). While outcome was associated with a number of non-depression variables, a poor outcome was most clearly associated with depressive episodes emerging at the time of the ACS but with some risk affected by episodes that commenced prior to the ACS and being persistent. Neither lifetime depressive episodes nor transient depressive episodes occurring around the baseline ACS event appeared to provide any risk. Study findings indicate that any differential deleterious impact of post-ACS depression has both short-term and longer-term outcomes, and, by implicating the centrality of post-ACS depression, should assist studies seeking to identify causal explanations. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction As overviewed earlier (Parker et al., 2008), a revisionist position is emerging in regard to links between depression and cardiovascular disease. For some two decades, studies generally quantified (i) lifetime depression as a risk factor for subsequent cardiovascular disease and (ii) state depression during an ischemic cardiac event as a predictor of a poorer cardiac outcome. However, in the last few years, studies of these associations have generated a number of inconsistent findings. Such inconsistencies may reflect how ‘depression’ has been measured (i.e. dimensionally by severity, or categorically by ‘caseness’ status), use of self-report depression questionnaires as against structured clinical interviews, the period allowed for cardiac-eventrelated depression (i.e. from cardiac admission through to several months after discharge) and the length of the follow-up period. Additionally, many studies have not specified whether depression commencing before, during, or following an acute cardiac event contributed to any differential outcome risk. ⁎ Corresponding author. Black Dog Institute, Prince of Wales Hospital, Randwick, NSW 2031, Australia. Tel.: + 61 2 9382 4372; fax: + 61 2 9382 4343. E-mail address: [email protected] (G. Parker). 0165-1781/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2010.07.015
The last issue is emerging as of key importance, with several recent studies indicating that any association may be dependent on establishing both the time of onset of any depressive episode associated with the cardiac event, and whether it is a first-ever (often called incident depression) or, alternately, a recurrent or ongoing (i.e. a non-incident depression) episode. Several representative studies will be noted. Lesperance et al. (1996) reported that those with a recurring depressive episode during a cardiac admission had a higher mortality rate over the following 18 months than those with incident depression. By contrast, both Grace et al. (2005) (using a 5-year follow-up based on hospital linkage data) and de Jonge et al. (2006) (using a mean follow-up of 2.5 years) reported that those with post-MI (myocardial infarct) depression had increased mortality and morbidity risks, while those who had a prior history of depression were not at increased risk. The Grace et al. (2005) study was limited in terms of the definition of depression, however, in that while a standard self-reported two-week criterion of depressed mood was used, participants were not asked to rate further symptomatology. For current depression, their study used a dimensional scale of depression severity. Such measurement may not accurately reflect clinical depressive symptomatology and may instead detect mild and inconsequential ‘depressive’ periods.
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To clarify such issues, we undertook a study focusing on clinical depression and examined the impact of (i) the onset time of any clinical depressive episode, and (ii) the incident/non-incident onset status of post-cardiac depression on subsequent cardiovascular outcome, quantifying depression status with a case-finding measure. A large sample of subjects hospitalized with an acute coronary syndrome (ACS) – defined as an acute myocardial infarct or unstable angina pectoris – were recruited and interviewed shortly following their hospitalization. Lifetime and current episodes of major depression and/or dysthymia (defined by the Diagnostic and Statistical Manual for Mental Disorders or DSM-IV; American Psychiatric Association [APA], 2000) were quantified and subjects reassessed (by telephone interview) one month after baseline assessment to determine if they met DSM-IV symptom and duration criteria. Outcome was initially standardized around their progress from the one-month assessment to 12 months following initial hospitalization. The study endpoint was readmission for another ACS and/or cardiac mortality in that 12-month period. In a resulting publication (Parker et al., 2008), we quantified that 12-month outcome was not associated with either (i) any preceding lifetime depressive episode or (ii) existing depression at initial hospitalization. However, a poor 12-month outcome was predicted by depression (recurrent or a first-ever episode) developing in the month following the ACS event. This suggested that it was the timing that conveys poor cardiac outcome risk, irrespective of the depressive episode being an initial or newly recurrent one. If such a ‘timing’ issue determines risk, it is capable of several explanations, including the psychosocial impact of an ACS-associated depression; or a biological explanation, for example, that post-ACS depression may reflect and/or result in “inflammation and low heart rate variability” (Carney et al., 2002; de Jonge, 2009; Frasure-Smith et al., 2009b). If such ‘state’ factors are determinants, it then remains to be established whether they preferentially compromise short-term outcome or whether they provide an ongoing risk. The latter issue dictated our current extension study. In this report we examine the impact of depression timing over an extended follow-up period. As only 22% of the participants followed up at our one-year review had experienced a cardiac-related death or readmission, the lengthier follow-up increased the numbers of poor outcome subjects and so increased statistical power which allowed associations to be quantified with greater confidence. 2. Method 2.1. Initial patient selection Eligible subjects were those admitted to hospital with an ACS diagnosis, whether an acute MI and/or unstable Angina Pectoris (UAP). Of the 904 eligible subjects, 299 were excluded if non-English speaking or cognitively or significantly physically impaired, 19 were deceased soon after being approached and could not complete the study, and a further 9 patients started the study but withdrew consent soon after, while another 88 refused informed consent, generating a sample of 489 eligible subjects (MI = 316, UAP = 173). 2.2. Study protocol Eligible subjects received a semi-structured clinical baseline interview from a research assistant at a mean of 3.8 days (S.D. ± 3.0 days) following admission, including the depression section of the Composite International Diagnosis Interview (CIDI version 2.14; WHO, 1997), to establish whether subjects met current or lifetime DSM-IV (APA, 2000) criteria for Major Depression and/or Dysthymia (i.e. clinical depression). Four weeks following baseline interview, subjects were contacted by phone to determine whether they then met criteria for clinical depression, reflecting the emergence of a post-baseline onset episode, or a baseline episode only then meeting the two-week duration criterion required for a DSM-IV major depressive episode. Study subjects were contacted by phone after both three years and five years to determine outcome, while as noted below, outcome details were pursued with family members, managing primary physicians and review of hospital records as needed. Here we report data on the extended five-year follow-up.
2.3. Depression ‘timing’ variables In comparison to our earlier report, we examine outcome at five years (specifically 260 weeks following baseline admission) in relation to an increased number of sample sub-sets, in order to examine the impact of timing of any depressive episode even more specifically. Sub-sets were defined as: (i) ‘nil’ — subjects who had no history of depression at any time; (ii) ‘prior’ — subjects who had had at least one episode of depression prior to (but were not depressed at) the baseline admission; (iii) ‘incident’ — subjects who developed their first-ever episode of depression in the month subsequent to baseline admission (this includes those whose depression started shortly prior to their index ACS, but which did not meet the DSM two-week duration criterion at baseline assessment); (iv) ‘recurrent’ — subjects who had had at least one episode of depression prior to (but were not depressed at) the baseline admission, and who then developed an episode of depression in the subsequent month (again, this includes those whose depression may have started shortly before their index ACS); (v) ‘continuing’ — subjects who were depressed at the baseline admission and remained depressed at the end of the first month; and (vi) ‘non-continuing’ — subjects depressed at the baseline admission but no longer depressed at the end of the first month. 2.4. Other key study variables At baseline – and as detailed previously (Parker et al., 2008) – we collected data on cardiac symptoms and cardiac history, medical and/or psychiatric co-morbidities, cardiac and psychotropic medications, interventions received in hospital, biochemical results, and a range of other variables. Data on both left ventricular ejection fraction (LVEF) and the number of diseased vessels on angiography were recorded at baseline as measures of disease severity. In all our one-year outcome analyses (Parker et al., 2008), depressed sub-sets were generally younger than non-depressed sub-sets, so age was judged as a key covariate. Current analyses also included a variable reflecting the date of first hospitalization in order for any improvement or worsening in cardiac outcomes over the extended recruitment interval to be tested. To that end, the 118-week recruitment period was divided into five intervals (four of 24 weeks and one of 22 weeks) and each patient's date of recruitment was coded 0–4, with 4 being the earliest period. 2.5. Outcome measures We defined three possible primary outcomes over the five years subsequent to the one-month assessment following baseline hospitalization: (i) cardiac admission; (ii) cardiac death; and (iii) cardiac event (either cardiac admission and/or cardiac death). A cardiac admission was defined as hospitalization as a consequence of a cardiac condition, and a cardiac death as death from a cardiac condition. A ‘cardiac admission’ was defined as admission to hospital (not merely attendance at a Casualty Emergency department) for an acute myocardial infarct, angina, ischemic heart disease or heart failure — but not for atrial fibrillation alone, while we also excluded those who were admitted for a cardiac procedure alone (such as insertion of a pacemaker). We sought initially to obtain cardiac admission details from the patient or from a relative. If such information was unclear, we then contacted their managing practitioner and/or accessed any available hospital records. Details on any ‘cardiac death’ were obtained principally by obtaining the death certificate but, if insufficiently precise, information was sought from relatives, managing practitioners and review of any available hospital records. As death precludes subsequent events, subjects who died from whatever cause without a preceding admission over the follow-up period were included in the analyses and treated statistically as censored for the survival analyses in relation to cardiac admission outcome status. Subjects who died from a non-cardiac cause were similarly treated in relation to the second and third outcome definitions. 2.6. Follow-up assessments As described, an assessment (following baseline admission) was undertaken at four weeks to capture any baseline depressive episode that met duration criteria. At 12 months, the first outcome status follow-up occurred, with assessment by a research assistant (not necessarily blind to baseline depression status) including clinical status, medication adherence, cardiac procedures and hospital readmissions. If a patient could not be interviewed, contact was made with family members or the patient's physician. The names of all untraced individuals were submitted to the NSW Registry of Births, Deaths and Marriages and the Australian National Death Index to clarify their outcome status. At five years, the second outcome status follow-up occurred, and, as for the 12month review, if the patient could not be interviewed, we sought to interview a relative and/or managing medical practitioner to determine their outcome and, if no such contacts could be established, we again submitted patients' names to the NSW Registry and National Index to determine if the patient had died, and their listed cause of death. 2.7. Statistical analyses Descriptive statistic analyses used SPSS V17. Survival curves were estimated using the Kaplan–Meier method and modeling of survival used the discrete-time approach in which a regression model (in this case, a logit model) was fitted to person–period structured data (Singer and Willett, 2003). For the latter, the time–period used was one
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month, with all events coded to the month, not the day that they occurred. Survival analyses used R (version 2.9.2) software (R Core Development Team, 2009).
3. Results 3.1. Study overview At baseline, 489 subjects were assessed (70.3% male) and with a mean age of 65.7 (S.D. 12.2) years. At the five-year review, 53 (10.8%) subjects had been lost to the study. Of these, 12 (2.5%) subjects had withdrawn consent; 11 (2.2%) subjects had died in the first month; 9 (1.8%) subjects could not be contacted at one month and consequently for whom we again had no follow-up data; 19 (3.9%) subjects had insufficient primary (17 subjects) or covariate data (2 subjects) for analysis; and 2 (0.4%) subjects had missing files. Data on the remaining 436 subjects (89.2% of the original sample) are now analyzed. 3.2. Depression ‘timing’ and outcome Table 1 quantifies the number of subjects within each of the study outcome sub-sets in relation to any depressive experience. Of the total 436 subjects, 159 had experienced a single or recurrent major depressive episode, 12 met criteria for dysthymia and 37 met criteria for dysthymia and major depression. Fig. 1 plots the survival curves for any cardiac event (37% of the sample) and it is apparent that the differential outcome at five years was emerging (albeit less distinctively evident) at the earlier one-year review. In comparison to those who had never experienced any depressive episode, the greatest chance of experiencing any cardiac event was for the incident and recurrent depression sub-sets, and with those in the continuing sub-set having an intermediate outcome. Fig. 2 plots the trajectories of those assigned to the cardiac death outcome — with the lack of any suggested differentiation (other than for incident depression) perhaps reflecting the small sub-set numbers for this outcome group. 3.3. Possible study covariates
Fig. 1. Survival curves for any cardiac event for those with (i) no lifetime depression, (ii) prior depression only, (iii) incident depression, (iv) recurrent depression, (v) continuing depression and (vi) non-continuing depression.
admission, diabetes, smoking, any past admission, low LVEF, cerebrovascular event such as a transient ischemic attack [TIA] or cerebrovascular accident [CVA]), and any current treatment with a broadaction (i.e. Monoamine Oxidase Inhibitor or MAOI and/or a Tricyclic Antidepressant or TCA) or narrow-action (i.e. Selective Serotonin Reuptake Inhibitor or SSRI) antidepressant drug. Inspection suggests that the mean age was differentially low in the recurrent depression group, that there were quite varying rates of CABGs (high in the incident and low in the recurrent group), that smoking was distinctly higher in the recurrent group, and with other instances of variable prevalences of such factors encouraging examination of their
In our earlier paper (Parker et al., 2008), we reported that those in any depressed group sub-set were generally younger than those never depressed, but that such sub-set membership was not associated with measures of disease severity (e.g. LVEF less than 35%, number of diseased vessels, first admission for ACS, number of previous admissions for an ACS). In our current study we examined (and document in Table 2) for associations between depression classification and a number of risk factors or confounders (e.g. age, gender, any coronary artery bypass graft surgery [CABG] following the index
Table 1 Impact of timing of depression onset and depressive sub-set status on cardiac death and/or cardiac rehospitalization rates. Cardiac-related event Subjects
Admission
Death
Admission and/or death
Depression status
N
%
N
%
N
%
N
%
Nil Prior Incident Recurrent Continuing Non-continuing Total
265 77 24 20 27 23 436
60.8 17.7 5.6 4.6 6.2 5.3 100
72 17 10 12 10 7 128
27.2 22.1 41.7 60.0 37.0 30.4 29.4
27 6 4 2 3 2 44
10.2 7.8 16.7 10.0 11.1 8.7 10.1
92 23 13 12 13 9 162
34.7 29.9 54.2 60.0 48.1 39.1 37.2
Study sub-set considered in analyses. Percentages in bold differ significantly (P b 0.05) from the “Nil” group.
Fig. 2. Survival curves for any cardiac death for those with (i) no lifetime depression, (ii) prior depression only, (iii) incident depression, (iv) recurrent depression, (v) continuing depression and (vi) non-continuing depression.
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Table 2 Association of risk factors with depression status. Depression status
Nil Prior Incident Recurrent Continuing Non-continuing Total
Age (S.D.)
68.4 10.7 63.3 13.1 68.3 11.6 50.0 8.4 62.4 11.9 64.1 12.7 66.1 12.0
Sex (male)
Any CABG
Diabetes
Past admission
Smoking
LVEF b35%
TIA/CVA ever
Current antidepressant MAOI/TCA SSRI
195 73.6% 53 68.8% 15 62.5% 13 65.0% 17 63.0% 16 69.6% 309 70.9%
77 29.1% 13 16.9% 11 45.8% 2 10.0% 8 29.6% 5 21.7% 116 26.6%
48 18.1% 11 14.3% 7 29.2% 3 15.0% 6 22.2% 4 17.4% 79 18.1%
105 39.6% 25 32.5% 10 41.7% 11 55.0% 11 40.7% 9 39.1% 171 39.2%
35 13.2% 9 11.7% 6 25.0% 8 40.0% 7 25.9% 5 21.7% 70 16.1%
16 6.0% 3 3.9% 1 4.2% 0 0.0% 0 .0% 2 8.7% 22 5.0%
35 13.2% 12 15.6% 4 16.7% 1 5.0% 4 14.8% 2 8.7% 58 13.3%
6 2.3% 2 2.6% 0 0.0% 0 0.0% 4 14.8% 0 0.0% 12 2.8%
4 1.5% 6 7.8% 1 4.2% 0 0.0% 2 7.4% 2 8.7% 15 3.4%
Numbers and percentages quantity those within differing sample sub-sets that had the risk factor. CABG = Coronary artery bypass graft, LVEF = left ventricular ejection fraction, TIA = Transient ischemic attack; CVA = cerebro-vascular accident; MAOI = monoamine oxidase inhibitor; TCA = tricyclic; SSRI = selective seretonin reuptake inhibitor. Italics denote the S.D.'s of age across depression status and percentages for all other variables.
individual impact and their possible inclusion in multivariate analyses. Table 3 analyses the impact of cardiac risk factors on outcome. Data indicate that gender, smoking and baseline exposure to antidepressant medication were of no impact, that older age was linked only to an increased chance of cardiac death and not to hospital readmission, that diabetes increased the risk of a poor composite outcome, that a low LVEF and a previous cerebrovascular event (CVA and/or TIA) increased the chance of cardiac death, and that having a CABG was associated with a lower risk of all three outcomes. Each of these variables was included as covariates in our multivariate analyses.
3.5. Smoothed hazard functions for any cardiac event We repeated the survival analyses, examining prediction of cardiac death only. While recognizing that low cell numbers reduced power, significant findings were that a poor outcome was associated only with recurrent depressive sub-set status (OR = 5.88, 95% CI 1.09– 31.70, P = 0.039); and with a number of covariates: older age (OR = 1.08, 95% CI 1.04–1.12, P b 0.001), lower LVEF (OR = 3.21, 95% CI 1.36–7.58, P = 0.008), a previous CVA/TIA (OR = 2.52, 95% CI 1.26– 5.08, P = 0.009), and diabetes (OR = 2.07, 95% CI 1.01–4.25, P = 0.048). A lower risk was associated with having received a CABG (OR = 0.36, 95% CI 0.14–0.95, P = 0.040). Plots of the hazard functions were broadly similar to those depicted for any cardiac event.
3.4. Modeling survival
4. Discussion
In Table 4, we quantify the impact of other variables in our survival analysis examining predictors of any cardiac event. The discrete-time model survival analysis in Table 4 incorporates the time that people survived or were followed up and allowed hazard functions to be calculated. A worse outcome was associated with the following covariates – older age, diabetes, a CVA or TIA and a low LVEF – and a better outcome with having had a CABG. In relation to depression variables, recurrent, incident and continuing sub-set membership were associated with a worse outcome, while non-continuing depression provided no increased risk over nil depression. An assessor suggested that, instead of explicitly coding the depressive sub-sets, three binary variables (i.e. the presence or absence of a depressive episode pre-ACS, at the time of the ACS, and in the one-month period following an ACS — post-ACS) and their interactions be used. When we repeated the survival analysis using these dummy variables, the effects of other covariates were unchanged. Of the main effects and their interactions, only post-ACS depression was significant, with a risk of 2.37 (95% CI 1.53–3.67), consistent with the findings in Table 4 which loculated depression impact to a new episode (incident or recurrent). We calculated the hazard function for the six levels of the depression factor while keeping the covariates at their means. The spline smoothed hazards are graphed in Fig. 3. The hazards for the nil depression and non-continuing depressive sub-set are indistinguishable. As might be expected, the hazard functions were initially high but declined rapidly over the first two years, with increased peaks at the end of three years, and prior to the fifth year — the two extended follow-up review periods.
Our one-year follow-up – indicating that what we here call incident and recurrent depression appeared to provide the greatest risk to a poor outcome – raised two key questions. Firstly, as numbers experiencing a poor cardiac outcome were small, could this finding have reflected a lack of statistical power and risked invalid interpretation? Secondly, if a valid finding, might the impact of any etiological factor have not only been temporary — compromising short-term outcome but attenuating and not having any impact on extended outcome? We therefore report their five-year outcome. Obtaining full data sets on 89% of the original cohort was important in strengthening the likely integrity of the analyses. Relatively few subjects had experienced a cardiac death indicating their cardiac management had clearly been of a high level (for a group whose mean age had been 66 years at baseline recruitment). Nevertheless management changes rapidly and thus we included time of recruitment as a study covariate and demonstrated that outcome improved further over time. A poorer outcome was significantly associated with older age, having diabetes, a low LVEF and having previously experienced a cerebrovascular event, while having coronary artery bypass surgery (a CABG) was associated with an improved outcome. Such findings indicated the importance of including such variables as covariates in key analyses, to ensure that the independent contribution of depression timing could be quantified. As cardiac death was a rare event (being experienced by only 10% of the subjects), the principal outcome variable was having a ‘cardiac event’, and experienced by 162 subjects (or 37%). The consolidation of such events into one composite outcome variable needs to be
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Table 3 Outcome by risk factor. Outcome experienced
Risk factor Age (median) Sex (male) Any CABG Diabetes Past admission Smoker LVEF b35% CVA/TIA ever TCA/MAOI SSRI
Below Above No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes
Risk
Admission
Cardiac death
N
N
%
221 215 127 309 320 116 357 79 265 171 366 70 414 22 378 58 424 12 421 15
69 59 37 91 106 22 100 28 71 57 104 24 120 8 107 21 124 4 124 4
31.2 27.4 29.1 29.4 33.1 19.0 28.0 35.4 26.8 33.3 28.4 34.3 29.0 36.4 28.3 36.2 29.2 33.3 29.5 26.7
P
0.004
N
%
12 32 10 34 38 6 31 13 18 26 40 4 36 8 28 16 44 0 40 4
5.4 14.9 7.9 11.0 11.9 5.2 8.7 16.5 6.8 15.2 10.9 5.7 8.7 36.4 7.4 27.6 10.4 0.0 9.5 26.7
Any cardiac P 0.001
0.047
0.005
0.001 b0.001
N
%
76 86 46 116 135 27 124 38 86 76 135 27 148 14 128 34 158 4 154 8
34.4 40.0 36.2 37.5 42.2 23.3 34.7 48.1 32.5 44.4 36.9 38.6 35.7 63.6 33.9 58.6 37.3 33.3 36.6 53.3
P
b 0.001 0.029 0.015
0.012 b 0.001
CABG = Coronary artery bypass graft; LVEF = Left ventricular ejection fraction; TIA = Transient ischemic attack; CVA = Cerebrovascular accident; MAOI = monoamine oxidase inhibitor; TCA = Tricyclic; SSRI = Selective serotonin reuptake inhibitor.
recognized as a potential limitation to the current study. In comparison to our one-year review (Parker et al., 2008), the consolidation increased the percentages of ‘events’ and allowed us to broaden the sample sub-sets to create five variably ‘timed’ depressive trajectories. While lifetime depression has been demonstrated to increase the risk of a poor post-ACS outcome (Herbst et al., 2007), negative findings have also been reported. For example, Dickens et al. (2007) reported that depression increased risk only in incident cases. Glassman et al. (2009) reported that there was no difference in mortality rates between patients with a 30-day diagnosis of major depression — with or without a prior history of major depression. Those findings could be interpreted as indicating that lifetime depression provides a risk to poor outcome but are also equally interpreted (and perhaps more parsimoniously) by viewing the risk as coming from ‘baseline’ depression – independent of any prior lifetime history of depression – and further supported by those
authors quantifying increased mortality as being associated with more severe depression at baseline. Importantly, we also found no evidence of lifetime depression having any impact on five-year outcome — alone, and, of key relevance, in comparison to those who had experienced any episode of clinical depression over their life. As noted earlier, inconsistencies in the literature may reflect differing definitions of ‘depression’ — ranging from a dimensional trait or emotional state through to clinical depression. Our study has focused on DSM-IV-defined ‘clinical depression’, where biological factors may be expected to make a greater contribution than would personality or life event stressors. It should be noted, however, that while we
Table 4 Impact of covariates on discrete-time survival analysis for any cardiac event. Risk 95% CI
Nil depression Prior depression Incident depression Recurrent depression Continuing depression Non-continuing depression Study entry time Age Sex (male) Any CABG Diabetes Past admission Smoker LVEF b 35% CVA/TIA ever TCA/MAOI SSRI
B
S.E.
z
P
Risk
Lower
Upper
– − 0.26 0.80 1.02 0.61 0.08 0.13 0.02 0.16 − 0.85 0.42 0.10 0.03 0.86 0.52 − 0.08 0.27
– 0.24 0.31 0.36 0.32 0.36 0.06 0.01 0.19 0.22 0.20 0.17 0.23 0.30 0.21 0.54 0.39
– − 1.07 2.56 2.83 1.92 0.22 2.08 2.10 0.84 − 3.82 2.11 0.60 0.14 2.83 2.43 − 0.14 0.71
– 0.29 0.01 0.01 0.06 0.82 0.04 0.04 0.40 0.00 0.04 0.55 0.89 0.01 0.02 0.89 0.48
– 0.77 2.23 2.78 1.83 1.08 1.13 1.02 1.17 0.43 1.52 1.11 1.03 2.37 1.68 0.93 1.32
– 0.48 1.21 1.37 0.99 0.54 1.01 1.00 0.81 0.28 1.03 0.79 0.66 1.30 1.11 0.33 0.61
– 1.24 4.11 5.65 3.40 2.18 1.28 1.03 1.70 0.66 2.23 1.56 1.63 4.29 2.56 2.65 2.82
Items in bold represent significant risk. CABG = Coronary artery bypass graft; LVEF = Left ventricular ejection fraction; TIA= Transient ischemic attack; CVA = Cerebrovascular accident; MAOI= Monoamine oxidase inhibitor; TCA= Tricyclic; SSRI = Selective serotonin reuptake inhibitor.
Fig. 3. Smoothed hazard functions for any cardiac event (evaluated at covariate means) for those with (i) no lifetime depression, (ii) prior depression, (iii) incident depression, (iv) recurrent depression, (v) continuing depression and (vi) non-continuing depression.
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assessed depressive symptoms (via structured interview), response biases (e.g. denial, over-reporting) may lead to misclassification. Any increased chance of a cardiac event in the five-year review period being associated with depression was most clearly associated with a depression which commenced post-ACS, and with the impact over five years being most distinct for those with a new episode of depression — whether a first-ever (incident) depression or a ‘recurrent’ episode; while any ‘continuing’ episode (i.e. present during the post-ACS period but having been present prior to the index ACS admission) had a less distinctive association. Further, despite the relatively small numbers meeting criteria for ‘cardiac death’, a consolidated (i.e. incident or recurrent) post-ACS depression variable was a significant predictor of that outcome, whether examined in relation to all initial study sub-sets or with the sub-sets condensed to three principal groups. Another key finding was that non-continuing depression (i.e. depression that had been experienced previously and during the time of the ACS admission — but not persisting through to the one-month review) was unassociated with a poor outcome. It might be expected that members of this sub-set would be more likely to have depression for reasons unrelated to their cardiac condition — a differential finding of distinct importance. Thus, any deleterious impact of clinical depression on cardiac functioning appeared most weighted to episodes of depression that commenced at the time of the acute coronary syndrome (be the depression an incident or recurrent episode — but with some risk effected from episodes that commenced prior to the ACS and being persistent (i.e. ‘continuing depression’) and with the episode's risk impact continuing at least over the next five years. Narrowing the type of depression (i.e. ‘clinical depression’), its timing and its persistence of risk (both influencing one-year and five-year outcome) should narrow the candidate etiological factors. Findings may also have clinical implications in arguing for those developing depression following any ACS event to receive more assertive depression management, be it a drug or non-drug based approach. In our earlier paper (Parker et al., 2008), we overviewed research indicating that depression commencing post-ACS may be a signal marker of autonomic system dysfunction, and that the link might be mediated by reduced heart rate variability, and in line with recent speculation by Frasure-Smith et al. (2009a,b) of perturbed parasympathetic/sympathetic balance. de Jonge (2009) has argued for low heart rate variability and inflammation as candidates, noting that both are associated with the severity of underlying heart disease, depression and cardiovascular prognosis. Not only will future studies need to examine for phenomenological distinctions between incident and recurrent depression and (ideally) continuing and non-continuing depression experienced by those
with a cardiac condition, but there is a need to undertake studies pursuing inflammatory and immunological mechanisms that might explain why – at least in regard to the depression/heart disease nexus – it would appear that ‘timing is everything’. Acknowledgements We thank Penny Sawdy and Bianca Blanch for assistance with data entry necessary for our analysis, and Kerrie Eyers, who assisted with the preparation and proof-reading of the manuscript. This study was supported by a National Health and Medical Research Council Program Grant (510135) and an Infrastructure Grant from the New South Wales Department of Health.
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