Interventions for improving outcomes in patients with multimorbidity in primary care and community setting: a systematic review

We searched MEDLINE, EMBASE, CINAHL, The Cochrane Library’s five databases and two trials registers up to 9 September 2019. We also searched grey literature, in particular, the comprehensive database of the International Research Community in Multimorbidity and abstracts from annual meetings of the Society of Academic Primary Care and the North American Primary Care Research Group. We also consulted experts in the field for completed or ongoing studies, over a number of years. Search strategies are available in Additional file 1: Search Strategy.

Study designs eligible for inclusion were randomised controlled trials (RCTs), non-randomised clinical trials (nRCTs), controlled before-after studies (CBAs), and interrupted time series analyses (ITS), meeting Cochrane Effective Practice and Organisation of Care (EPOC) quality criteria [20]. We included studies of adults with multimorbidity receiving care in a primary or community care setting. We adopted the most widely used definition of multimorbidity, that is, the co-existence of multiple chronic conditions in the same individual, usually defined as two or more conditions. We used the WHO definition of chronic disease, which is ‘health problems that require ongoing management over a period of years or decades’ [21]. Studies in which inclusion was based on comorbidity with a specific index condition [22] or only the age of participants (e.g. older patients) were excluded. We also excluded professional educational interventions where no care was delivered to an identified group of people with multimorbidity.

We included any type of intervention based in primary care and community settings that was specifically directed towards a group of people defined as having multimorbidity. Primary healthcare was defined as providing ‘integrated, easy to access, healthcare services by clinicians who are accountable for addressing a large majority of personal healthcare needs, developing a sustained and continuous relationship with patients, and practising in the context of family and community’ [23]. We anticipated that all interventions would be multifaceted given the nature of multimorbidity. We considered and reported complex interventions using the TIDIER checklist [24]. We categorised interventions based on their predominant intervention focus into the following groupings: (i) care coordination plus support for self-management; (ii) support for self-management, and (iii) medicines management. The comparison was usual primary healthcare as provided in that setting.

One author undertook an initial screen of abstracts to remove those clearly ineligible. Two authors (SS, EW) then independently screened remaining abstracts and identified full texts for screening, screened full texts and selected studies for inclusion. No automated tools were used in the process. Two authors (SS, EW) undertook data abstraction and cross-checked data abstraction forms. Disagreements about data abstraction were resolved by consensus between the authors. If data were missing, we contacted authors and have reported this where applicable. Two authors assessed and cross-checked the risk of bias in all included studies using Cochrane criteria (SMS and EW or BC), including allocation (sequence generation and concealment); baseline characteristics; incomplete outcome data; contamination; blinding; selective outcome reporting and other potential sources of bias. We assessed the certainty of the evidence for health-related quality of life (HRQoL), mental health, clinical, psychosocial, health service utilisation, medicines and provider behaviour outcomes using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria including risk of bias, consistency of effect, imprecision, indirectness and other potential criteria such as publication bias [25].

We based our main outcomes for this review on the core outcome set for multimorbidity [26] and these were health-related quality of life (HRQoL) and mental health outcomes. Additional outcomes included clinical outcomes, other psychosocial outcomes such as self-efficacy, health behaviours, healthcare utilisation, medicines outcomes, provider behaviour, including quality of care, patient satisfaction, harms and economic outcomes. Where data from multiple timepoints was reported, we extracted the data from the designated study end-point.

Due to the clinical heterogeneity relating to the wide variation in participants, interventions and outcomes assessed, the main synthesis of the results is narrative. This decision was made by all authors on reviewing the range of participants and interventions as presented in the Table of Included studies. We undertook meta-analysis where it was appropriate to combine studies in terms of participants, interventions or outcomes and in these cases we used risk ratios or mean differences in the synthesis. We did not impute any missing data, and clustering in original studies was already incorporated in included study estimates within the meta-analyses. Meta-analysis was undertaken in the Revman software for the main outcome HRQoL using a random-effects model with generic inverse variance, which incorporates cluster effects within estimates for each included study. We also conducted a random effects meta-analysis of mean difference in two studies for the additional outcome of self-efficacy using.

From a total of 38,489 original citations (after duplicates were removed) (Fig. 1), 205 full texts were reviewed. Of these, 189 articles were excluded and a total of 16 RCTs were included. Sixteen studies contributed data for inclusion in the narrative synthesis and 7 provided data for meta-analyses.

A total of 16 RCTs with 4753 participants were included. Eight had a parallel design [27‐34], and eight had a cluster design [35‐42], with one of these having a cluster stepped wedge design [37]. Intervention duration varied from 6 weeks to 18 months, with the majority lasting 6 to 12 months. Most studies collected follow-up data at intervention completion. The studies were conducted in Germany (n = 4), UK (n = 3), USA (n = 3), Canada (n = 2), Ireland (n = 2) and one study each in Spain and Australia. All studies were funded publicly by government agencies or through charitable or university foundations. The definition of multimorbidity varied across studies though all used some additional measure of complexity beyond the standard multimorbidity definition of 2 or more conditions. These included higher numbers of conditions or additional factors such as high health service use or polypharmacy. The mean number of conditions in patients in the 14 studies that reported this, ranged from 3 to 12.7 conditions (see Table 1), suggesting that included studies were targeting those with more complex multimorbidity. Whilst six of the 16 studies targeted older patients, the mean age of included patients ranged from 50 to 80.5 years with 10 of the 16 included studies having participants with a mean age > 70 years indicating that most studies included older patients (see Table 1).

The interventions were all multifaceted (Table 1). Few studies specifically reported patient involvement in intervention design though this was becoming more common in later studies [38, 40]. Studies were grouped into three broad groupings of care-coordination plus self-management support (CC/SMS), self-management support (SMS) and medicines management. Eight of the 16 included studies examined CC/SMS type interventions and involved multifaceted interventions that targeted the coordination of care, healthcare providers and also provided self-management support for patients [27, 30, 31, 35, 38, 40‐42]. Four studies reported on SMS interventions that did not have a clear link to the patients’ healthcare provision [28, 29, 33, 34]. Three of these were group-based programmes based on the Chronic Disease Self-Management Support programme and the fourth involved health promoters working from community clinics to provide individual self-management support [28]. Four studies focused primarily on medicines management but specifically targeted patients with multimorbidity [32, 36, 37, 39]. In the majority of included studies, the comparator was usual primary healthcare.

The studies were all RCTs and overall there was low or unclear risk of bias with only one study having a high risk of bias in two of the eight risk of bias domains, blinding and protection against contamination [32] (see Fig. 2). The most common issue leading to a judgement of unclear risk of bias was lack of clarity around blinding, which can be a challenge in these types of interventions. The risk of bias for individual studies is presented in Additional file 2: Figure 1.

In general, whilst all the included studies were RCTs, the main concerns related to inconsistency and imprecision. For all intervention types, we downgraded the evidence for all outcomes to low certainty due to serious concerns about inconsistency and imprecision (see Additional file 3: Grade Working Sheets). This reflects the clinical heterogeneity of participants, interventions and outcomes assessed and the likelihood that future studies may change our review findings.

The effects of intervention on the main and additional outcomes are presented in Table 2.

Overall, the results suggest that all intervention types targeting patients with multimorbidity probably make little or no difference to the main outcomes of HRQoL (n = 10) [29, 30, 32, 33, 37‐42] or mental health outcomes (n = 6) [11, 29, 33, 40‐42]. Five of the 10 studies with HRQoL outcomes reported EQ-5D scores that could be included in a meta-analysis [11, 33, 39‐41], with a mean difference of 0.03 (95% CI −0.01 to 0.07, I² = 39%) (see Fig. 3), consistent with the overall effect suggesting no difference in this outcome. The five studies included in the HRQoL meta-analysis had low risk of bias overall.

For additional outcomes, there was little or no effect on clinical outcomes (n = 2) or on the majority of other psychosocial outcomes (n = 11), including self-efficacy (n = 4). A meta-analysis of studies with available data for self-efficacy (n = 2) found a mean difference in self-efficacy scores of 0.92, 95% CI −0.04 to 1.88, I² = 63% (see Additional file 4: Figure 2). There were mixed effects on function and activity (n = 4) and patient health behaviours (n = 2). There was little or no effect on healthcare utilisation (n = 9), though numbers of hospital admissions in most studies were small. There was also little or no effect on medicine outcomes (n = 9). Five of the care coordination/self-management support studies reported little or no effect on numbers of medicines or medication adherence. There were mixed effects on medicine outcomes in the four studies with a medicines management type intervention, which reported mixed results in medication appropriateness and potentially inappropriate prescribing. There was some improvement in healthcare provider behaviours in two of the three care coordination/self-management support studies reporting these outcomes but mixed effects on patient satisfaction with services (n = 3). Only one of the 16 included studies reported a potential adverse event relating to prescribing of analgesics but no other studies reported harms. Only two of the 16 studies reported full cost-effectiveness analyses to date with one reporting cost-effectiveness [38] and the other reporting equivocal results [40].

Multimorbidity is a complex area because the characteristics of participants can vary depending on definitions used. This limits the potential to combine study results reasonably for meta-analysis. This clinical heterogeneity has led some to question whether defined interventions can be developed for this population. Despite this challenge, there are increasing numbers of interventions being developed and evaluated. The review was carried out using the updated Cochrane Handbook for Systematic Reviews of Interventions [49]. Potential limitations in the search process for this review related to the lack of a MeSH term for multimorbidity, though this has now been addressed. This meant that we originally had to use broad search terms which led to a high yield of citations to be searched. Given the very high number of titles screened this was done by only one author and this is a limitation of the review. However, the authors are active researchers in the field of multimorbidity and are unaware of any potentially eligible studies that were missed by the search. We were also unable to retrieve some missing data from authors. However, as limited meta-analyses were undertaken this did not lead to any appreciable measurement bias. The usual limitations relating to publication bias apply, but we have searched the grey literature and contacted experts in the field to try to identify published and ongoing trials in this area. A further limitation of the review is that the last full comprehensive search update was conducted in September 2019. In view of this limitation, we reviewed the comprehensive database of the International Research Community in Multimorbidity to review potential studies published between 2019 and 2021 [50]. Only two potentially eligible trials [51, 52] were identified and the results of these studies would not change the conclusions of the current systematic review.

The variation in definitions in the included studies included highlights the need for clear reporting of participant characteristics. Without these definitions, the generalisability or applicability of studies for people with multimorbidity will be uncertain [53]. When designing interventions, researchers need to be clear about the theoretical assumptions underlying the intervention, consider its individual components and the evidence base behind each, and then link these to outcomes. There is a specific framework to support the development of interventions for multimorbidity, which highlights the potential for other study designs, such as stepped-wedge designs that may be more suited to multimorbidity intervention initiatives and that can be undertaken within service/research partnerships [54]. There is also room to improve patient and public participation (PPI) in multimorbidity trials with only a few of the more recent studies in this review incorporating PPI [38, 40]. People with multimorbidity are more likely to experience what is referred to as ‘treatment burden’, that is, the effort needed to engage in the multiple treatments offered to them can actually make their lives more difficult [14]. Only one study included a treatment burden measure and reported little or no difference in this outcome [40]. Outcomes for this review were based on the core outcome set for multimorbidity, which can also inform outcome selection for future studies so that we can more easily compare interventions across different studies [26].