Prevalence of depression and associated outcomes for patients with acute coronary syndromes

Major depression is common among people with coronary heart disease. Most research has focused on patients with acute coronary syndromes (ACS), among whom prevalence rates for depression are around 20 % as determined by studies using rigorous clinically structured research interviews [1]. Rates of depression have also been shown to be elevated in individuals following coronary artery bypass grafting [2], patients with unstable angina [3] and patients with chronic heart failure [4]. These rates greatly exceed those seen in the UK general population (2.6 % [5]), suggesting that the associations between coronary disease and depression may be causal (direct or indirect).

The nature of the association between depression and coronary disease is complex. Depression can predate an ACS, approximately doubling the risk of subsequent incident ACS [6, 7], and worsen associated heart failure [8] or cardiac mortality [9]. Depression that predates an ACS is predicted by younger age, female sex, lack of social support, ongoing life difficulties and a past psychiatric history [10]; these are similar to risk factors for depression in the general population. Depressive symptoms may occur after an ACS, so-called ‘new onset’ depression [10]; approximately 20 % of individuals after a recent myocardial infarct (MI) develop depressive symptoms in the 12 months following their cardiac event. ‘New onset’ depression is not associated with the usual risks for depression, but is predicted by negative illness representations relating to the ACS and ongoing cardiac symptoms [10, 11]. Mechanisms underpinning the association between depressive symptoms and poor cardiovascular outcomes may include biological and behavioural processes, or may be confounded by shared genetic vulnerability, environmental stresses, or perseverative negative cognitive processes [12].

Depression among people with an established ACS is an important predictor of negative medical outcomes including poorer health-related quality of life [13, 14], greater morbidity and mortality [15–18], greater use of routine and unscheduled health care [19, 20] and greater health care costs [21]. Some studies have indicated that the timing of onset of depressive symptoms with regards to cardiac-related hospitalisation may be important in determining health outcomes. In particular, ‘new onset’ depression that develops following an MI has the greatest association with subsequent mortality [21–24]. It remains unclear, however, whether ‘new onset’ depression is particularly ‘cardiotoxic’ or whether its apparent associations with poor cardiac outcomes is confounded [23] by, for example, the severity of the underlying cardiac disease or due to a retention bias, with patients suffering with premorbid depression dying before reaching follow-up [9].

Usual care for patients with cardiac disease and depression

In the UK, the NHS routinely offers multidisciplinary cardiac rehabilitation (CR) to patients who experience an acute cardiac event. CR follows a seven-stage standard patient care pathway (stages 0–6, Fig. 1) [25, 26]. Guidance on the recommended content of standard care is published by the British Association for Cardiovascular Prevention and Rehabilitation (BACPR) [26]. Core components include: education; exercise and physical activity; diet and weight management; medical management; and psychological support. In 2010–2011 a national CR audit [27] identified 290 operationally distinct, locality-based comprehensive cardiac rehabilitation programmes (CCRPs; stages 2–5). These teams undertake patient assessments (including mental health status), then generate and implement CR care plans.

Patient attrition across the CR pathway is high. Although around 17 % of patients screen positive for depressive symptoms when attending an initial, locality-based CCRP assessment (stages 2–3), around half of these will not proceed to CCRP. Despite the burden of depressive symptoms, only 10 % of CR services report direct psychology input [27] and patients’ depression usually remains untreated [28]. Locally agreed referral protocols providing for access to psychological care at either the tertiary (stage 1) or community (stages 2–5) level may be agreed. However, the precise content of such protocols and the consistency of their implementation remain unclear from audit data.

While it would appear that structured management of depressive symptoms is not routinely provided in CR, patients can access mental health care through existing care pathways for depression [29–31]. Effective care includes mental health care coordination, which is often managed in primary care and involves the use of stepped care algorithms, and access to psychological or pharmacological interventions of proven effectiveness.

In general populations, cognitive behavioural therapy (CBT) and antidepressant medication (ADM) are the two treatments with most evidence of effectiveness, and both are recommended by the National Institute for Clinical Excellence (NICE) [29, 30]. However, there are problems with ADM, which include side-effects, poor patient adherence and relapse risk on ADM discontinuation. Service-user organisations and policy think tanks advocate greater availability of psychological therapies, which many people prefer [32]. CBT, which is of similar efficacy to ADM [33], has several advantages: it is consistent with many service users’ preferences for non-pharmacological treatment, and it modifies the illness trajectory as its benefits continue after the end of treatment by teaching skills to prevent depressive relapse in the long term. However, CBT has several potential disadvantages. Not all patients may engage or adhere to CBT, due to a multiplicity of reasons (e.g. burden of homework, feelings of confusion or upset at revisiting painful or difficult emotions and situations during therapy) [34]. CBT requires extensive training to deliver competently, and is typically offered only by specialist CBT therapists. The high costs of training and employing sufficient therapists may limit attempts to access CBT. The recent ‘Improving Access to Psychological Therapies’ (IAPT) [35, 36] programme in England has done much to enhance access and recovery rates which are at approximately 50 %. However, IAPT does not reach into specialist CR settings where brief and accessible psychological treatments may have much to offer.

One such psychological treatment is that of Behavioural Activation (BA). BA is postulated to alleviate depression by focusing directly on changing behaviour based on behavioural theory [37]. This theory states that depression is maintained by avoidance of normal activities. As people withdraw and disrupt their basic routines, they become isolated from positive reinforcement opportunities in their environment. They may then end up stuck in a cycle of depressed mood, decreased activity and avoidance [37]. BA systematically disrupts this cycle, initiating action in the presence of negative mood, when people’s natural tendency is to withdraw or avoid [38]. Although CBT incorporates some behavioural elements, these focus on initiating behavioural experiments to test specific beliefs. In contrast, BA targets avoidance from a contextual and functional approach not found in CBT, focusing on understanding the function of behaviour and replacing it accordingly. BA also explicitly prioritises the treatment of negatively reinforced avoidance and rumination. Furthermore, the BA rationale is easier to understand and operationalise for both patients and mental health workers than CBT, where activity is also increased but the primary techniques focus on changing maladaptive beliefs [39]. Its focus on context and functioning is also closely aligned to the ethos of CR services. The relative simplicity of BA treatment makes it relatively straightforward to train nurses without mental health training in its application [40–42]. The study team includes the expertise in respect of the design, training, and delivery of a BA-based intervention [41–43].

Rationale for current research

There is a lack of clear evidence of efficacy for conventional treatments for depression in patients with ACS. Trials of the antidepressants sertraline, citalopram and mirtazapine have shown small or no effect on depression among patients with ACS [44–46]. Efficacy of psychological treatments, which are usually preferred by patients, remains unclear. Recent systematic reviews [47, 48] report modest but significant reductions in depression for patients with coronary disease receiving psychological treatment, although the methodological quality of studies selected is such that it precludes firm conclusions regarding which treatments are most effective. Several high-quality randomised controlled trials (RCTs) in patients with ACS and depression have not confirmed the benefits of psychological therapy in this population. In the large ENRICHD trial, CBT plus citalopram led to very small improvements in depression that were not sustained [49]. Similarly, the CREATE trial found that interpersonal psychotherapy was no better than standard care [44]. In contrast, the CODIACS Vanguard trial RCT [50, 51] found that a patient preference intervention (management options available included problem-solving therapy delivered by a centralised service offered via phone or the web, ADM, both or neither) combined with a stepped care algorithm significantly improved depressive symptoms at 6-months post randomisation. However, these results must be interpreted with caution as the sample size was small (n = 150), and no conclusions can be drawn regarding the effectiveness of individual therapeutic options available as part of the preference intervention. No trials to date have evaluated the effectiveness of BA in patients with an ACS and ‘new onset’ depression.

Most intervention studies have recruited participants immediately following an acute cardiac event, and the complexity of depression in that period may have contributed to the lack of treatment response. The reasons for the limited benefits of conventional depression treatments in patients with coronary disease are not clear. First, depression that starts after an ACS is different from depression in the general population. Post-ACS depression does not have the usual risk factors as seen in the general population, but is associated with ongoing cardiac symptoms, and increased concerns about health [10, 11], which may act to reduce the response to conventional treatment [45]. Second, conventional psychological treatments, such as CBT, that encourage recall of past experience and that challenge maladaptive thoughts, may be too traumatic for people who have suffered a recent, serious threat to life. Third, conventional psychological therapies available through IAPT are considered expensive and may not be widely available to patients with CHD. Indeed, a recent qualitative study of patients [52] concluded that management of depression should be embedded within CR teams rather than as another source of referral. UK CR programmes experience significant patient attrition at each stage of the rehabilitation pathway, with over half of patients dropping out before locality-based CCRP commences. Given this attrition, for the 17 % of patients with depressive symptoms who actually attend at least one assessment with a CCRP, ‘another outward referral’ for psychological care may simply be a further barrier to accessing timely care. If a low-intensity psychological treatment, such as BA, has the potential to be safely and effectively [38, 40–42, 53, 54] embedded within the CCRP, this could holistically tackle the depressive symptoms at the same time as physical rehabilitation as part of patient case management. Similarly, acknowledging that attrition from rehabilitation is high even in patients who attend an initial CCRP assessment, we also believe that any attempt to enhance psychological care should include training CR nurses (who routinely screen for depressive symptoms) to apply evidence-based referrals for those who elect not to attend rehabilitation. Such mental health care coordination will also be in place for patients completing CCRP (including BA), but whose symptoms do not respond.

Study aims and objectives

Pre-pilot feasibility study

Although the focus of this paper is to report the design of the pilot trial, a brief summary of the feasibility study is provided here. The feasibility study (completed March 2015 prior to commencing the pilot trial) employed a mixed-method design to develop and assess an EPC intervention and to undertake preliminary testing of its implementation. Observations of usual care, a before and after observational study, and qualitative interviews with staff and service users were undertaken. The EPC intervention was developed working with four nurses from three NHS CCRP services (stages 2–5; see Fig. 1) from South West England. Nine eligible patients (i.e. individuals with ‘new onset’ depression) were recruited, and both staff and patients were invited to comment on the feasibility and acceptability of implementing and/or experiencing EPC. Additional CR process data was recorded, including participant attendance at, and adherence with the CCRP with embedded EPC. The findings from this feasibility study were used to refine and develop the EPC intervention and the pilot trial methods. Specifically, qualitative and observational data, considered along with findings arising from discussions with lay representatives, identified the need to reduce the intensity of the BA component of the EPC delivered by CR nurses operating within the context of routine care. The EPC intervention to be delivered in the pilot study will thus retain the nurse acting as a mental health care coordinator, using clearly defined clinical decision-making points and applying evidence-based referral pathways, with the BA component delivered as a participant-led BA intervention, actively supported by the CR nurse.

Pilot cluster randomised controlled trial

An external pilot cluster RCT [56, 57] will be undertaken, including the piloting of economic data collection, and a qualitative interview study. A Consolidated Standards of Reporting Trials (CONSORT) diagram describing the flow of participants through the study is presented in Fig. 2.

Trial interventions

Randomisation and allocation concealment

An external pilot cluster RCT [56, 57] will be undertaken, seeking to recruit and randomise eight CCRPs (clusters) to a treatment or a control arm in a 5:3 ratio. The randomisation ratio was informed by data emerging from our feasibility study, including the need to ensure that sufficient nurses and patients have EPC exposure to support the aims of the qualitative process evaluation. Randomisation will be conducted using the stratifying variables of CR team setting (hospital-based, community-based, or mixed hospital and community), and monthly throughput of new patients assessed for CR at stages 2–3, facilitating division into small and large teams. Team setting has been selected as a stratifying variable because our feasibility study suggested that teams working in hospital and community settings may encounter different resource issues that could affect the delivery of EPC. Throughput of new patients into CR services has been selected as a stratifying variable, as this is an indicator of team workload, and will ensure that sufficient participants are recruited into each trial arm.

Randomisation will be carried out by a statistician, independent from the researchers recruiting CR teams, using computer-generated random numbers. A cluster randomised design, as opposed to individual participant randomisation, is essential to avoid contamination between trial arms (i.e. intervention participants coming into direct contact with controls and sharing aspects of their treatment). Our EPC intervention involves training CR nurses to apply mental health care coordination with embedded participant-led BA. Once trained, it would be very difficult operationally for the nurse to apply structured care coordination to only a subset of eligible participants (as would be required with individual randomisation).

Settings and study population

Sample size

Using UK national audit data (2010–2011), 55,452 patients (for MI, PCI, CABG) undertook phase 3 CR from 280 teams: an average of 200 patients per team per year. Assuming 17 % have depressive symptoms [27], this equates to 35 eligible patients per team each year. The participant consent rate will be established through piloting as no relevant UK data, applicable to cluster trials, are available. Two RCTs (individual randomisation) from the US, exploring psychological/drug therapy in cardiac rehabilitation settings, observed highly variable consent rates of 85 % (150/177 – Vanguard CODIACS study) [51] and 37 % (2481/6854 – ENRICHD study) [49]. Based on the patient throughput and rates of depressive symptoms observed in our feasibility study, and an assumed participation rate of 50 %, we aim to recruit 64 patients through the eight teams in 6 months. This sample size is sufficient to estimate a follow-up percentage as low as 50 % with margin of error ±12.8 % based on the width of the 95 % confidence interval (CI), and as high as 90 % with a margin of error of ±9.3 % based on the lower bound of the 95 % CI. We do not plan to use estimates from the pilot of the intra-cluster (intra-CR team) correlation coefficients (ICCs) for key outcomes to plan the sample size for the definitive trial as the pilot sample is small and estimates will be imprecise. Using national audit data (2010–2011; 6272 patients; 119 CR teams), we estimate the ICC for depression to be 0.047 (95 % CI: 0.034 to 0.062). This ICC estimate and CI will be used to inform the sample size calculations for the definitive trial.

Data collection

Participants in both arms will complete baseline measures prior to commencing CCRP, and then two face-to-face follow-up interviews with a researcher at 5 and 8 months post randomisation (Fig. 2). Blinding of patients, practitioners or researchers extracting data on study outcomes is not possible in this cluster design, but the final analysis will be carried out by a statistician who is blind to treatment allocation. Data will be collected on process measures, patient-reported outcomes, and resource use and costs.

Economic evaluation

The analytical perspective of NICE’s decision-making is a societal costing perspective. The pilot study will test methods of resource and service use data collection enabling estimation of the costs to the NHS, costs to social care and PSS, and relevant costs to patients and their carers/families (including NHS and privately funded mental health care). Wherever feasible, these will distinguish use of services for (1) depression or anxiety; (2) for other mental health problems; (3) for other health reasons or social needs. A preliminary assessment of the cost of providing EPC within CR will be undertaken. Service use data will be collected from routine/administrative sources (e.g. hospital records, GP records, community mental health team records, social care records) and participant self-report using the Service and Resource Use Questionnaire (SRUQ). The SRUQ will be adapted from the Client Services Receipt Inventory [76], with input from our lay advisors. The completeness, validity and reliability of participant-reported versus routine administrative data will be compared in relation to the types/amounts of health care/service used over the follow-up periods planned for a definitive trial.

Data collection

Several methods of data collection will be used. The researcher will observe staff training to identify what issues nurses appear to struggle with and what practical concerns they have about EPC. Observations will be recorded through extensive field notes. Nurses trained in EPC will be invited to take part in an interview towards the end of EPC delivery (once they have gained experience in delivering the intervention), to explore their views on the nurse manual, and to assess their views and experiences of delivering EPC within existing programmes. These interviews will be held by an experienced qualitative interviewer (RW) following a topic guide. Interviews will be conducted either by telephone or on a face-to-face basis, as the teams will be based across a large geographical area and telephone interviews can be used to gather the same material as those held face-to-face [80]. Written consent will be secured from those interviewed in person and verbal consent will be gained from those interviewed by telephone. It is predicted that up to 15 nurses will be involved in delivery of EPC in the five CCRPs allocated to the intervention arm. The aim will be to interview around 10 of these nurses.

In-depth interviews will be conducted with patients recruited to the trial who subsequently agree to take part in qualitative interviews. When sampling these patients we will aim for maximum variation in relation to trial arm, age, CR team, gender, socio-economic background, depression score at baseline and adherence to the intervention. Participants will be interviewed shortly after they have completed their 5-month follow-up measurements in case the interview process influences their views of the intervention or trial. Participants will be given an opportunity to ask questions before the interview takes places, and written informed consent will be obtained prior to commencing. All interviews will be conducted by RW following a topic guide. Individuals will be interviewed by telephone or on a face-to-face basis, and verbal or written consent secured respectively. It is predicted that about 30 participants recruited to the trial will be interviewed (10 usual care, 12 completers and 8 non-completers of EPC).

Interviews will also be held with patients who declined to take part in the trial to identify reasons for their decision. These interviews will usually be held by telephone to encourage participation. The data gathered will indicate ways to maximise recruitment and to reflect upon how representative individuals in the trial are of other CR patients. About 10 ‘decliners’ will be interviewed early on in the trial.

Qualitative analysis plan

Data collection and analysis will proceed in parallel. All interview data will be audio-recorded, transcribed verbatim and analysed thematically with the aid of NVivo, and using an approach based on a framework approach [81]. Analysing the data thematically will enable comparisons to be made within and across the interviews, and for the views of staff and patients to be compared and contrasted regarding specific topics, such as intervention acceptability.

Data management

All personal information obtained about patients or staff for the purposes of recruitment or data collection will be held in accordance with the UK Data Protection Act, 1998. Each participant will be assigned a research number and all outcome data will be encrypted and stored without the participant’s name or address. Electronic study records will be stored in a SQL server database managed by the Peninsula Clinical Trial Unit (PenCTU), hosted on a secure server maintained by Plymouth University. Access to electronic data will be permission-based, with access to identifiable information limited to those processing questionnaires and performing initial screening activities. Copies of study data retained at participating sites will be securely stored for the duration of the study prior to archiving. Electronic copies of any letters or e-mails sent to study participants will be stored securely on a password-protected computer at the University of Exeter, and paper-based information held in a locked filing cabinet in the research team offices. Names and participant details will not be passed onto any third parties and no named individuals will be included in the write-up of the results. The only time personal information would be passed on to a third party (i.e. the patient’s GP) would be if we considered there to be risk of serious harm to a research participant and safety protocols need to be activated.

All study data will be kept for 10 years under secure conditions on University of Plymouth and University of Exeter servers. We will seek consent from participants for core outcome data from the pilot study to be released in an anonymised form to an independent data repository (for example, the UK Data Archive) following publication of the key planned outcome papers.

Safety of participants and researchers

While we believe the study has minimal implications for health care staff, participants will have been found to have depressive symptoms and it is, therefore, appropriate to have a safety policy in place regarding the management of potentially serious adverse events (e.g. self-injury or suicidality). The Participant Information Sheet will let the person know that if we are very concerned about their safety or someone else’s safety we may need to break confidentiality and inform their GP.

Involvement in research interviews where participants are asked to reflect on their health issues can, in some cases, cause distress. Should any such difficulties occur during a research interview, the researcher will offer support to the person involved. Should a participant appear significantly upset and at risk as a result of the interview, the researcher will (with permission) advise the individual’s GP of this distress and encourage the person to seek further support from the support network available to them. Should there be any concern that a participant is likely to cause harm either to themselves or another person, their GP will be notified immediately by a senior clinician from the study team. Since researchers will be conducting interviews alone with participants, potentially in the participant’s own home, it will be important to have safeguards in place to protect both participant and researcher. Disclosure and Barring Service checks will be performed on any researcher taking part to ensure that they are an appropriate person to be working with vulnerable adults. To ensure the safety of researcher and patient, a lone-worker policy will be applied, providing a mechanism for ensuring that the exact whereabouts of researchers and patients engaged in research activities is known.