Summary of findings
Description of the condition
Chronic obstructive pulmonary disease (COPD) is a heterogeneous, systemic condition characterized by restricted airflow which is not fully reversible. It is a major cause of morbidity, due to the ageing of the world's population and the continued use of tobacco and exposure to indoor biomass pollution. The prevalence of COPD is expected to increase substantially in the coming decades (Lopez 2006; GOLD 2009). According to the World Health Organization (WHO), COPD will be the third leading cause of death in 2020 (Lopez 2006; WHO 2008). Given the rise in prevalence, COPD has important financial consequences, with high reported direct costs (healthcare resources, medication prescriptions) and indirect costs (absence from paid work, consequences of disability) (Britton 2003).
Optimal management of COPD is complex, as it is a multi-component disease. Clinical, functional and radiological presentation varies greatly from patient to patient, despite having a similar degree of airflow limitation (Wedzicha 2000; GOLD 2009; Agusti 2010). Evidence suggests that the previous 2007 Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification of disease severity, solely based upon the degree of airflow limitation, is a poor predictor of other important negative features of COPD (Agusti 2010; Burgel 2010).
Health-related quality of life (HRQoL) and exercise tolerance may be more important to people with COPD than the more traditional measure of lung function. This is because COPD has a profound impact on HRQoL and exercise tolerance, even in those with modest airflow limitation (Engstrom 1996). Furthermore, impaired HRQoL (Domingo-Salvany 2002; Fan 2002; Martinez 2006) and exercise tolerance (Gerardi 1996; Pinto-Plata 2004) have been associated with an increased risk of mortality (Cote 2009).
In addition, some people are more prone than others to episodes of acute exacerbations, which are an important cause of morbidity, mortality, hospital admission and impaired health status (Seemungal 1998; Wedzicha 2000; Calverley 2003). Although exacerbations become more severe and occur more frequently with increased severity of COPD, this is not always the case. There is some evidence for a 'frequent-exacerbation' phenotype (or group of people) that exacerbate more often than would be expected given their 'severity' as predicted by lung function testing (Hurst 2010).
Episodes of exacerbations are often not reported by patients to health care providers (Seemungal 2000). An important reason for patients' delay in reporting an increase in symptoms to their doctor is the fear of being sent to hospital. This passive behavior can eventually lead to a respiratory crisis, indeed necessitating urgent referral. In order to break through the self reinforcing negative spiral of dyspnoea, deconditioning and social deprivation doctors need to collaborate with their patients, with a focus on self management skills: "if symptoms increase, you need to let us know rapidly to prevent further worsening" (Chavannes 2008). In viewing COPD as a disease process with a clinical, heterogeneous picture of progressive deterioration, an integrated system of care could be built on a disease management model. Ideally, it is based on active self management to slow down progression of the disease, including daily self care, patient-physician collaboration and exacerbation management. Information should be tailored to the person's needs, knowledge level and clinical profile and be accessible by the patient when they need it most (Tiep 1997; Bourbeau 2013).
Description of the intervention
In the last decade, the concept of integrated disease management (IDM) was introduced as a mean of improving quality and efficiency of care. IDM interventions are aimed at reducing symptoms and avoiding fragmentation of care, while containing costs. Therefore, IDM programs are generally believed to be cost-effective, but the available evidence is inconclusive. Several systematic reviews have shown positive results, at least for some outcomes of chronic IDM, in people with chronic heart failure (Gonseth 2004; Roccaforte 2005), diabetes (Norris 2002; Knight 2005; Pimouguet 2010) and depression (Badamgarav 2003; Neumeyer-Gromen 2004).
However, there is no consensus in the literature about the definition of IDM. Several definitions have been proposed since the introduction of the concept 'disease management'. In order to facilitate the communication between researchers, policy makers and IDM program leaders, Schrijvers proposed a definition, based on earlier reported definitions (Care Continuum Alliance; Dellby 1996; Epstein 1996; Ellrodt 1997; Zitter 1997; Weingarten 2002; Faxon 2004): "Disease management consists of a group of coherent interventions designed to prevent or manage one or more chronic conditions using a systematic, multidisciplinary approach and potentially employing multiple treatment modalities. The goal of chronic disease management is to identify persons at risk for one or more chronic conditions, to promote self-management by patients and to address the illness or conditions with maximum clinical outcome, effectiveness and efficiency regardless of treatment setting(s) or typical reimbursement patterns" (Schrijvers 2009). In addition, Peytremann-Bridevaux and Burnand added more elements, adapting the definition as follows: "Chronic disease prevention and management consists of a group of coherent interventions, designed to prevent or manage one or more chronic conditions using a community wide, systematic and structured multidisciplinary approach potentially employing multiple treatment modalities. The goal of chronic disease prevention and management is to identify persons with one or more chronic conditions, to promote self-management by patients and to address the illness or conditions according to disease severity and patient needs and based on the best available evidence, maximizing clinical effectiveness and efficiency regardless of treatment setting(s) or typical reimbursement patterns. Routine process and outcome measurements should allow feedback to all those involved, as well as to adapt the programme" (Peytremann-Bridevaux 2009).
How the intervention might work
There is great variation in the symptoms, functional limitations and degrees of psychological well-being of COPD patients, as well as the speed of the progression of COPD towards more severe stages (Agusti 2010). This calls for a multi-faceted response, including different elements (e.g. smoking cessation, physiotherapeutic reactivation, self management, optimal medication adherence) targeted at the patient, professional or organizational level. Therefore, IDM programs have been developed to improve effectiveness and economic efficiency of chronic care delivery (Norris 2003) by combining patient-related, professional-directed and organizational interventions (Wagner 2001; Lemmens 2009).
Why it is important to do this review
As health-related quality of life, exercise tolerance and number of exacerbations are the most important patient-related outcomes in COPD, the focus in this review will be on these primary outcomes.
Several systematic reviews have been published that evaluated the effect of IDM in COPD patients (Adams 2007; Niesink 2007; Peytremann-Bridevaux 2008; Lemmens 2009; Steuten 2009). These reviews differ from our review in various ways. Adams' review focused solely on interventions which could be arranged according to the chronic care model of Wagner (Wagner 1996; Adams 2007). Furthermore, Adams included studies between 1966 and 2005. Since then, several studies focusing on IDM in COPD patients have been published. Niesink and colleagues evaluated the quality of life in COPD patients, but did not report outcomes of exacerbations or exercise tolerance. Furthermore, the authors decided not to perform a meta-analysis; reasons for this were not clearly described (Niesink 2007). Peytremann-Bridevaux performed a meta-analysis and focused on quality of life, exacerbations and exercise tolerance. However, they did not take into account the differences in study design (randomised controlled trials (RCT) versus before/after uncontrolled studies) in their conclusions (Peytremann-Bridevaux 2008). Lemmens' review examined the effectiveness of IDM in a mix of patients with COPD, asthma or both (Lemmens 2009). No subgroup analysis was performed for patients with COPD. Furthermore, conclusions were drawn irrespective of the study designs (i.e. RCTs, controlled clinical trials, quasi-experimental, controlled before and after time studies and time series designs; Lemmens 2009). Steuten et al aimed to determine the cost-effectiveness of COPD programs and the authors did not perform a meta-analysis of clinical effects (Steuten 2009).
Overall, all reviews suggested some beneficial effects on health status. However, firm conclusions could not be made regarding the effectiveness of IDM, due to the large heterogeneity in the interventions, study populations, outcome measurements and methodological quality. The literature searches of the aforementioned reviews for relevant RCTs investigating the effectiveness of IDM for patients with COPD were carried out between December 2006 and May 2008. Since then, several studies have been published. Furthermore, none of the former published systematic reviews were carried out according to the latest methods for conducting a systematic review (Higgins 2011). Within the framework of The Cochrane Collaboration, we have systematically and comprehensively evaluated the effectiveness of IDM in people with COPD.
To evaluate the effectiveness of IDM programs or interventions in people with COPD on health-related quality of life, exercise tolerance and the number of exacerbations.
Criteria for considering studies for this review
Types of studies
We included only randomised controlled trials (RCTs) in which IDM programs or interventions were compared to controls in people with COPD. Cluster-randomized trials were also eligible. There were no restrictions regarding the language of the paper.
Types of participants
People with a clinical diagnosis of COPD according to the GOLD criteria were included: people having chronic respiratory symptoms (i.e. coughing, sputum or dyspnoea) and a limited post-bronchodilator forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio of < 0.7. Severity of airflow obstruction was classified using the GOLD stages of 2009 (GOLD 2009). All GOLD stages were accepted. Studies including participants with other diagnoses than COPD were only eligible if the results of participants with COPD were available separately.
Types of interventions
We included studies where the IDM intervention consisted of strategies to improve the care for participants with COPD, including organizational, professional, patient-directed and financial interventions. We classified these according to the Cochrane Effective Practice and Organization of Care Group (EPOC) taxonomy of interventions (EPOC 2008), complemented with patient-directed interventions (i.e. self management and education). Our definitive checklist consisted of the following components of the IDM intervention that could be scored:
- Education/self management: i.e. education, self-management, personal goals and/or action plan, exacerbation management
- Exercise: i.e. (home) exercise training and/or strength and/or endurance training
- Psychosocial: cognitive behavioral therapy, stress management, other psychological assessment and/or treatment
- Smoking cessation
- Medication: optimal medication/prescription of medication adherence
- Nutrition: dietary intervention
- Follow-up and/or communication: structural follow-up and/or communication, case management by nurses, optimal diagnosis
- Multidisciplinary team: active participation and formation of teams of professional caregivers from different disciplines, revision of professional roles, integration of services, local team meetings
- Financial intervention: fees/payment/grants for providing IDM.
As IDM includes different components mentioned above, delivered by different healthcare disciplines, the RCT studies had to include:
- at least two components of interventions as mentioned above;
- active involvement of at least two different categories of healthcare providers; and
- a minimum duration of the IDM intervention of three months.
In all studies, we determined the dominant component of the program.
We compared IDM versus controls (varying from usual care or no treatment to single interventions, mono-disciplinary interventions).
Types of outcome measures
- Health-related quality of life (HRQoL), as reported by one of the following questionnaires: a validated disease-specific questionnaire, e.g. Clinical COPD Questionnaire (CCQ; van der Molen 2003; Kocks 2006), Chronic Respiratory Questionnaire (CRQ; Guyatt 1987), St. George's Respiratory Questionnaire (SGRQ; Jones 1991; Jones 2005), COPD Assessment Test (CAT; Jones 2009) or a generic questionnaire, e.g. Short Form-36 (SF-36; Ware 1992), Euro Qol-5D (EQ-5D; EuroQol Group 1990)).
- Maximal or functional exercise capacity, as reported by one of the following outcomes: the peak capacity measured in the exercise laboratory using an incremental exercise test defined according to the results of timed walk tests e.g. 6- or 12-minute walk test (Redelmeier 1997) or shuttle run test (Singh 1992)).
- Exacerbation-related outcomes, as reported by one of the following: time to first exacerbation, number of exacerbations, duration and/or severity, and measured by reporting of symptoms, antibiotics or prednisolone prescriptions and/or hospital admissions or hospital days related to exacerbations.
- Survival (mortality).
- Lung function (FEV1, FVC).
- Co-ordination of care, e.g. accessibility of care, participation rate in the disease management program, satisfaction of health care providers and participants with regard to the program, or the extent to which disease management was implemented, from the perspective of the patient (PACIC; Glasgow 2005) and the caregiver (Bonomi 2002).
We evaluated outcomes at the following endpoints: a) short-term (12 months or less); b) long-term (longer than 12 months) follow-up, if possible.
Search methods for identification of studies
We identified trials using the Cochrane Airways Group Register of trials, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE and CINAHL. The search was performed without language restrictions, using the highly sensitive Cochrane Collaboration search strategy, which aims to identify all randomised controlled trials (Lefebvre 2009). We used specific MeSH headings and additional keywords to identify all RCTs on IDM in COPD patients. As IDM programs were first described in 1990, our search was restricted to publications from 1990 onwards. The complete search strategies for the database searches are provided in the appendices (MEDLINE Appendix 1; EMBASE Appendix 2; CINAHL Appendix 3; CENTRAL Appendix 4; Airways Register Appendix 5). The search has been conducted up to April 2012. We ran an update search on 12 April 2013, but the results have not been fully incorporated: nine studies have been added as 'ongoing studies' and three studies have been added as 'studies awaiting classification'.
Searching other resources
In order to identify all possible studies, we carried out an additional search for systematic reviews in the Cochrane Database of Systematic Reviews. We screened reference lists of included RCTs and systematic reviews for potential studies for this review. To identify ongoing or new studies, we searched databases of ongoing studies, including ClinicalTrials.gov and other relevant registers.
Data collection and analysis
Selection of studies
Two review authors (AK and NS) independently assessed the title and abstract of all identified citations. We excluded all trials that were not randomised controlled trials or in which participants had no diagnosis of COPD. All studies excluded by the first two review authors because of the nature of the intervention were double-checked by a third review author (NC). Furthermore, if there was any doubt, we retrieved the full-text article and examined it for inclusion eligibility. Disagreements were discussed in a consensus meeting.
Data extraction and management
We collected the following information from included studies in our review: 1) the study design (i.e. randomisation method, sample size, blinding); 2) participant characteristics (i.e. diagnosis COPD according to GOLD criteria, age, sex); 3) interventions (i.e. setting, number of professionals involved, elements of IDM program/intervention, frequency and duration of intervention); 4) outcome measures and timing of outcome assessment; 5) results (i.e. loss to follow-up, outcomes). The outcome data were extracted by one author (AK) and checked by another (NC) using a standardized data extraction form. In case of missing data, we contacted the authors of these studies for additional information or clarification.
Assessment of risk of bias in included studies
Two of us (AK and NC) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), according to the following items:
- Allocation sequence generation
- Concealment of allocation
- Blinding of participants and health care providers, in relation to the intervention
- Blinding of outcome assessment
- Incomplete outcome data
- Selective outcome reporting
As cluster-randomized trials were also considered for inclusion, we added the following design-related criteria for these types of studies:
- Recruitment bias (i.e. individuals are recruited after the clusters have been randomised)
- Baseline imbalance between groups (i.e. the risk of baseline differences can be reduced by using stratified or pair-matched randomisation of clusters)
- Loss of follow-up of clusters (i.e. missing clusters and missing outcomes for individuals within clusters may lead to a risk of bias in cluster-randomized trials)
- Methods of analysis adequate for cluster-randomized controlled trials (i.e. taking clustering into account in the analysis) (Higgins 2011)
We judged all items as high, low or unclear risk of bias. We resolved disagreements in a consensus meeting.
Measures of treatment effect
We analyzed the results of the studies using RevMan 5, using random-effects modeling. We used forest plots to compare results across trials. The results were related to the minimal clinically important difference (MCID).
We expressed the results of each RCT as risk ratios (RR) with corresponding 95% confidence intervals (95% CI) for dichotomous data, and mean difference (MD) or standardized mean difference (SMD) for continuous data, depending on the similarity of outcome measurement scale (i.e. MDs are used when all studies use the same outcome measurement scale and SMDs when studies use different outcome measurement scales). We summarized data in a meta-analysis only if the data are clinically and statistically sufficiently homogenous. If the meta-analysis led to statistically significant overall estimates, we transformed these results (pooled estimate of RR, MD or SMD) back into measures which are clinically useful in daily practice. We planned to use the number needed to treat for an additional beneficial outcome (NNTB) and the absolute and/or relative improvement on the original units in order to report these as the final results of the review.
Unit of analysis issues
In case of a unit of analysis error occurrence in cluster-randomized controlled trials, we adjusted for the design effect by reducing the size of the trial to its "effective sample size" (Rao 1992). The effective sample size of a single intervention group in a cluster-randomized trial is its original sample size divided by a quantity called the 'design effect'. The design effect is 1+ (M-1)* ICC, where M is the average cluster size and ICC is the intra-cluster correlation coefficient. For dichotomous data, both the number of participants and the number experiencing the event were divided by the design effect. For continuous data, only the sample sizes were reduced; means and standard deviations remained unchanged (Higgins 2011).
Dealing with missing data
In case of missing data, we planned to contact the authors for additional information about the missing data for individuals. We sent a reminder if we did not receive a response. Secondly, we planned to assume the missing values to have a poor outcome. For continuous outcomes (i.e. health-related quality of life, exercise capacity) and dichotomous outcomes (i.e. mortality), we planned to calculate the effect size (SMD, MD, RR) based on the number of participants analyzed at the time point. If the number of participants analyzed is not reported for each time point, we planned to use the number of randomised participants in each group at baseline. We planned to perform sensitivity analysis to investigate whether our assumptions have been reasonable (i.e. comparing results using number of participants analyzed with number of participants randomised).
Assessment of heterogeneity
We measured clinical and statistical heterogeneity using the I
- control group: a) no treatment; b) treatment with one health care provider; c) treatment with one component; d) other disease management programs (short duration of therapies);
- intervention group, with regard to a) type of health care providers (i.e. general practitioner, lung specialist, physiotherapist, practice nurse); b) different components as listed by the EPOC classification (EPOC 2008); c) frequency and duration of intervention.
In case of substantial heterogeneity, we explored the data further, including subgroup analyses (see Subgroup analysis and investigation of heterogeneity) in an attempt to explain the heterogeneity.
Assessment of reporting biases
In order to determine whether reporting bias was present, we evaluated whether the protocol for the RCT was published before recruitment of patients of the study was started. For studies published after 1 July 2005, we screened the Clinical Trial Register at the International Clinical Trials Registry Platform of the World Health Organization (http://apps.who.int/trialsearch) (De Angelis 2004). For each study, we evaluated whether selective reporting of outcomes was present (outcome reporting bias). Furthermore, we made a funnel plot to assess the possibility of reporting bias.
We pooled results of the studies using the random-effects model. For continuous data, we recorded the mean change from baseline to endpoint and standard deviation (SD) for each group. For dichotomous data we recorded the number of participants with each outcome event and calculated the odds ratio (OR). We used results reported at three months, as our predetermined inclusion criteria postulated a program of at least three months duration (to ensure sufficient impact). If data at three months were unavailable, we analyzed the data measured most closely to this time point. We evaluated outcomes at short- (3 to 12 months) and long-term (> 12 months) follow-up.
We presented the main results of the review in a 'Summary of findings' table, which includes an overall grading of the evidence using the GRADE approach in accordance with the recommendations laid out in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This involves making separate ratings for quality of evidence for each patient-important outcome and identifies five factors that can lower the quality of evidence, including: study limitations; indirectness of evidence (also called clinical heterogeneity with regard to study population, intervention, control group and outcomes); unexplained heterogeneity or inconsistency of results (i.e. statistical heterogeneity); imprecision of results (i.e. due to small sample sizes and few events); and high probability of publication bias. However, other factors can increase the quality of evidence, such as large magnitude of effect; plausible confounding, which could reduce the demonstrated effect; and dose-response gradient (GRADE Working Group 2004). We presented the short- and long-term outcomes for our primary outcomes in the 'Summary of findings' table if possible.
Subgroup analysis and investigation of heterogeneity
In order to explain heterogeneity between the results of the included studies, we planned the following subgroup analyses a priori (where data were available) to determine if outcomes differed among:
- the setting of the IDM intervention (e.g. primary, secondary or tertiary care);
- design of the studies (individually randomised patients versus cluster-randomized patients (with and without adjusting for design effect));
- control group: a) no treatment; b) treatment with one health care provider; c) treatment with one component; d) other disease management interventions (short duration of therapies);
- intervention group, with regard to a) type of health care provider (i.e. general practitioner, lung specialist, physiotherapist, practice nurse); b) different components as listed by the EPOC classification (EPOC 2008); c) frequency and duration of intervention.
We carried out sensitivity analyses for the primary outcome measurements, in order to explore effect size differences and the robustness of conclusions. We planned sensitivity analysis determined a priori based on:
- studies without study limitations with regard to a) allocation concealment; b) blinding of participants and investigators; c) recruitment bias; d) baseline imbalance between groups; e) loss of follow-up of clusters; f) adequate analysis;
- method of analysis: a) results of studies using number of patients analyzed; b) studies using number of patients randomised.
We presented the main results of the review in a 'Summary of findings' table, which includes an overall grading of the evidence using the GRADE approach (GRADEpro; GRADE Working Group 2004) and a summary of the available data on the main outcomes, as described in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Description of studies
Results of the search
Our literature search identified 6700 titles and abstracts, resulting in 4776 references after de-duplication. Two review authors (AK, NS) screened the title/abstracts of these studies based on the predetermined inclusion criteria. Studies that were excluded because of the IDM intervention were double-checked by a third review author (NC). We retrieved the full-text articles of these studies and they were discussed in a consensus meeting. Finally, we identified 49 potentially relevant articles about IDM in COPD patients. We obtained full-text versions of these papers and data were extracted by one review author (AK) and double-checked by a second review author (NC). Finally, a total of 26 (cluster) randomised controlled trials were included in the review. The PRISMA flow diagram is presented in Figure 1.
|Figure 1. Study flow diagram.|
Twenty-six RCTs met the eligibility criteria for the review, of which two were cluster-randomized trials (Rea 2004; Wood-Baker 2006). One trial was a cross-over trial (Cambach 1997). The studies were published between 1994 and 2011. Five studies originated from the Netherlands (Wijkstra 1994; Strijbos 1996; Cambach 1997; van Wetering 2010; Trappenburg 2011), four studies from Spain (Güell 2000; Farrero 2001; Güell 2006; Fernandez 2009), three studies from Australia (Smith 1999; Boxall 2005; Wood-Baker 2006), three from the United Kingdom (Littlejohns 1991; Dheda 2004; Sridhar 2008) and three from the United States (Aiken 2006; Koff 2009; Rice 2010). Two studies were conducted in Denmark (Bendstrup 1997; Gottlieb 2011), two originated from Sweden (Engstrom 1999; Theander 2009) and one each from Brazil (Mendes 2010), Canada (Bourbeau 2003), Japan (Wakabayashi 2011) and New Zealand (Rea 2004).
A total of 2997 COPD patients were randomised in the 26 studies, with a range of 30 to 713 patients per study. Of these, 2523 (84%) patients completed the studies (range 18 to 725). The mean age of the study population was 68 years (SD 3.7), with 68% being male. Patients had a mean FEV1 % predicted of 44.3% (range 28 to 66).
Patients were treated in all types of healthcare settings: primary care (eight studies), secondary care (12 studies), tertiary care (one study) and a combination of primary and secondary health care (five studies). The number of health care providers involved in the IDM program ranged from two to seven, with a mean number of three. Furthermore, we calculated the number of components per program, which ranged from two to eight, with a mean number of four.
A priori, we planned to arrange the interventions in order to perform subgroup analysis based on type of intervention, according to type of health care providers, different components, and frequency and duration of intervention. However, it was not possible to determine the mean intensity, frequency or duration of all programs, due to lack of data. Furthermore, as the studies were too heterogeneous, it was not possible to arrange programs according to different combinations of components or combinations of health care providers. Therefore, we determined the dominant component of the IDM program in all studies. The main component of the intervention could directly be determined in nine studies (Littlejohns 1991; Smith 1999; Farrero 2001; Bourbeau 2003; Dheda 2004; Aiken 2006; Wood-Baker 2006; Koff 2009; Trappenburg 2011) from the objective or title of the study. For example, in Aiken 2006: "The objective is to document outcomes of a randomised trial of the PhoenixCare demonstration program of palliative care and coordinated care/case management for seriously chronically ill individuals who simultaneously received active treatment from managed care organizations. Intensive home-based case management provided by registered nurse case managers, in coordination with patients’ existing source of medical care, comprised the intervention".
In the remaining 17 studies, the main component was not directly clear from the objective. In 15 studies (Wijkstra 1994; Strijbos 1996; Bendstrup 1997; Cambach 1997; Engstrom 1999; Güell 2000; Boxall 2005; Güell 2006; Fernandez 2009; Theander 2009; Mendes 2010; Rice 2010; van Wetering 2010; Gottlieb 2011; Wakabayashi 2011), we chose the main component of the intervention as the component on which most of the time of the intervention was spent. For example: Bendstrup 1997: "The intervention programme lasted 12 weeks. The programme consisted of the following components. Exercise training: the patients trained together at the hospital for 1h, three times a week for 12 weeks. Occupational therapy: two lessons each group. Education: 12 sessions. Smoking cessation: only for patients wishing to stop smoking."
In one study (Sridhar 2008) there were two components on which most of the time of the intervention was spent (exercise and self management action plan). In another study (Rea 2004) there were two main components: self management action plan and structured follow-up. Therefore we arranged these two studies as separate categories.
We made the following categories:
- IDM exercise and self management action plan (one study: Sridhar 2008).
- IDM self management action plan and structured follow-up (one study: Rea 2004)
- IDM program of educational sessions, follow by a phase of individually tailored education according to scores on the Lung Information Needs Questionnaire score (one study: Wakabayashi 2011).
In two studies, IDM was compared to another IDM intervention and a control group (Strijbos 1996; Mendes 2010). Both studies involved two intervention groups including an IDM program with a focus on exercise training and one control group. In both studies, we combined and pooled data from the two intervention arms as one group. One study had a cross-over design with drug treatment after three months (Cambach 1997). Therefore, we used solely the data for the intervention and control group at baseline and at three months.
Control groups consisted of usual care in 20 studies, in two studies control patients received a mono-disciplinary treatment including optimization of drug treatment (Cambach 1997; Güell 2006) and in four studies control patients received a treatment solely with education (Wood-Baker 2006; Fernandez 2009; Rice 2010; Wakabayashi 2011). Usual care consisted in all studies of regular follow-up visits to health care providers, which depended on the type of setting. There was access to health care providers on a 'need to' basis, without additional treatment or management programs. In all studies, no attempts were made to influence this usual care.
We recorded the number of studies reporting a specific outcome as follows:
- Quality of life (22 studies)
- Exercise capacity (18 studies)
- Exacerbation-related outcomes: measured by number of exacerbations; hospital admissions; hospitalisation days; emergency department (ED) visits; number of prednisolone or antibiotics courses (15 studies)
- Lung function (14 studies)
- Survival, mortality (five studies)
- Depression (four studies)
- Dyspnea, measured by MRC Dyspnea score (three studies) or Borg score (three studies)
- Co-ordination of care (three studies)
Details of the included studies are provided in Characteristics of included studies.
We requested additional data from the authors of 14 studies. Of these, 11 authors responded (79%) and six (43%) could provide us with additional data. Therefore, it was not necessary to impute missing data as described in our research protocol (see Dealing with missing data).
After the first selection based on abstract and title, 49 potentially eligible studies were identified. Finally, after reading the full-text papers, we excluded 23 studies for one of the following reasons:
- not a RCT (n = 1);
- no diagnosis of COPD or no obtainable results reported for COPD as a subgroup (n = 2);
- intervention includes one component of care (n = 3);
- intervention includes one health care provider of different disciplines (n = 4);
- duration of intervention is less than three months (n = 4);
- active treatment as a control group (n = 9).
Risk of bias in included studies
|Figure 2. 'Risk of bias' summary: review authors' judgments about each risk of bias item for each included study.|
Nineteen studies reported full details of adequate sequence generation and we judged them to be of low risk of bias. We judged the remaining seven studies as having unclear risk of bias as they were reported as randomised, but gave no description of the methods used to conceal the sequence. Fourteen studies reported adequate allocation concealment, while we judged four studies as high risk of bias. There were insufficient details for the remaining six studies for us to reach a firm conclusion so we judged them to be at unclear risk of bias. There were 13 studies in which both the sequence generation and concealment of allocation were adequately described, thus selection bias was minimized in these studies.
The nature of the intervention precludes the possibility of blinding patients or health care providers. Therefore, we judged all the studies, except Trappenburg 2011, to be at high risk of performance bias. Trappenburg 2011 made a good attempt in using a modified informed consent procedure (postponed information), which meant that patients were unaware of the major aim of the study (education and an action plan), thereby enabling a single-blind study design (Trappenburg 2011). Therefore, we scored this study as low risk of bias. While blinding of health care providers and patients is impossible with this type of intervention, outcome assessors could be blinded to participants' allocation. This was reported in nine trials indicating a low risk of bias. Outcome assessors were unblinded in seven studies (high risk) and 10 studies provided insufficient information (unclear risk).
Incomplete outcome data
We judged 19 out of the 26 studies as low risk of bias, as they had low drop-out rates, drop-out rates were balanced across groups or trial authors performed an intention-to-treat analysis. We rated seven studies as high risk of bias and they were likely to be subject to attrition bias. Three out of these seven studies (Dheda 2004; Mendes 2010; Gottlieb 2011) had unbalanced drop-out rates, with higher rates in the intervention group compared to the control group. One study had a high drop-out rate balanced in both groups (31%) and the authors performed no intention-to treat-analysis (Bendstrup 1997). Cambach 1997 excluded all patients who did not return for one or more of the assessments from the final analyses. In Farrero 2001, quality of life was only investigated in the first 40 consecutive patients, therefore inducing risk of bias. In Smith 1999, all control participants refused to fill in the quality of life questionnaire and expressed that the burden of participating in a study, including questionnaires, was greater than expected.
We rated 21 studies as low risk of bias and five studies as high risk of bias. Three studies (Rice 2010; van Wetering 2010; Trappenburg 2011) published a study protocol, with which we could compare the results sections. In the other studies, we checked whether the outcomes reported in the methods section of the article were reported in the results section. Five studies (Littlejohns 1991; Smith 1999; Bourbeau 2003; Dheda 2004; Gottlieb 2011) selectively reported outcomes. In two studies (Bourbeau 2003; Dheda 2004) the authors reported no statistically significant difference in the outcome and therefore did not present data, indicating selection bias. In the other three studies (Littlejohns 1991; Smith 1999; Gottlieb 2011), it remained unclear why it was planned to measure an outcome but it was not ultimately published.
Other potential sources of bias
We included two cluster-randomized trials (Rea 2004; Wood-Baker 2006). Unfortunately, both studies introduced noteworthy biases related to cluster-randomization in different ways. In one study (Wood-Baker 2006) recruitment bias remained unclear, as the authors provided insufficient information regarding the cluster-randomization process. In contrast, we judged Rea 2004 to have low risk of bias, as clusters were randomised before patients were recruited. Furthermore, we rated both studies as high risk of bias for baseline imbalance between groups, which could have been reduced when stratified or if pair-matched randomisation of the clusters had been used instead (Higgins 2011). In the Rea 2004 study, there was loss to follow-up of five clusters (four control and one intervention cluster), therefore this study was subject to bias. There was no follow-up of clusters in Wood-Baker 2006 (low risk of bias). Finally, both studies introduced bias as they analyzed data by incorrect statistical methods, not taking the clustering into account. This may account for the over-precise results and can result in much more weight in a meta-analysis (Higgins 2011). Therefore, in our meta-analyses we adjusted for the design effect by reducing the size of the trial to its "effective sample size" (Rao 1992). Based on similar primary care cluster-randomized trials, we used an intra-class correlation coefficient (ICC) of 0.01 (Kerry 1998; Campbell 2001). For dichotomous data, we divided both the number of participants and the number experiencing the event by the design effect. For continuous data, we reduced the sample sizes; means and standard deviations remained unchanged (Higgins 2011).
Effects of interventions
In the majority of the outcomes, heterogeneity was not encountered. However, there was substantial heterogeneity present in SGRQ total score, six-minute walk distance (6MWD), CRQ dyspnoea (long-term), hospital admissions for all causes, hospital days and ED visits. If possible, we performed sensitivity and subgroup analysis on these outcomes to see if the heterogeneity could be explained. Our a priori determined subgroup analysis based on type of health care provider and the frequency and duration of intervention was impossible, as there was large heterogeneity among combinations of health care providers and the exact composition in terms of duration, frequency and intensity of programs was often not clearly reported. In addition, we were not able to perform subgroup analysis on GOLD stage or MRC Dyspnea score, as most studies did not report GOLD stages or MRC Dyspnea score. Furthermore, the definitions and classifications of GOLD stages have been changed over the years, resulting in large variation in severity within subgroups.
Instead, we performed subgroup analysis based on type of setting of the intervention (primary, secondary, tertiary care) and type of control group. Furthermore, we performed subgroup analysis with regard to the dominant component of the IDM program.
1. Quality of life
Of the 26 included studies, 23 measured HRQoL using six different instruments (see Characteristics of included studies):
- St. George's Respiratory Questionnaire (SGRQ) (13 studies);
- Chronic Respiratory Questionnaire (CRQ) (eight studies);
- Short Form-36 (SF-36) (three studies);
- Sickness Impact Profile (SIP) (two studies);
- Dartmouth Primary Care Co-operative Quality of Life questionnaire (COOP) (one study).
The SGRQ and CRQ are both disease-specific quality of life questionnaires. However, a meta-analysis combining CRQ and SGRQ score should not be used as Puhan 2006 has shown that the CRQ is more responsive than the SGRQ. Furthermore, the included generic quality of life questionnaires (SF-36, SIP and COOP) measure other dimensions of generic health quality of life, and therefore combining data in a meta-analysis across tools was not possible.
1.1 Respiratory-specific QoL
18.104.22.168 SGRQ total score - short-term
The SGRQ is a disease-specific, validated questionnaire with a scale from 0 (good health) to 100 (worse health status). A negative sign on this questionnaire indicates improvement, and the minimal clinically important difference (MCID) is -4 points (Jones 1991). Thirteen studies with a total population of 1425 patients provided data on the SGRQ total score with a follow-up of 3 to 12 months (Engstrom 1999; Bourbeau 2003; Dheda 2004; Boxall 2005; Wood-Baker 2006; Koff 2009; Fernandez 2009; Theander 2009; Rice 2010; van Wetering 2010; Gottlieb 2011; Trappenburg 2011; Wakabayashi 2011). The pooled mean difference (MD) on the SGRQ total score was -3.71 in favor of IDM (95% confidence interval (CI) of -5.83 to -1.59; Analysis 1.1; Figure 3; Summary of findings for the main comparison) which reached statistical significance (P < 0.001) and was close to, but did not reach, the MCID of -4 points. In other words, those treated with IDM had 3.71 out of 100 points better quality of life on this questionnaire. Pooling indicated a high degree of heterogeneity (I² = 56%, P = 0.01). Heterogeneity was due to differences in the quality of studies. We were able to reduce heterogeneity if we performed multiple sensitivity analyses based on studies with adequate allocation concealment, adequate blinding of outcome assessment, cluster-randomization bias, or studies analyzing outcomes by intention-to-treat. Sensitivity analysis on studies with adequate allocation concealment (Bourbeau 2003; Boxall 2005; Koff 2009; Theander 2009; van Wetering 2010; Gottlieb 2011; Trappenburg 2011; Wakabayashi 2011) demonstrated that there was still a statistically significant effect in favor of the intervention group (MD -3.16; 95% CI -4.75 to -1.57, P < 0.001). In the same way, in trials (Engstrom 1999; Bourbeau 2003; van Wetering 2010; Rice 2010; Trappenburg 2011; Wakabayashi 2011) with adequate blinding of outcome assessment the effect did not change (MD -3.16; 95% CI -4.81 to -1.51, P < 0.001). A sensitivity analysis excluding the cluster-randomized study of Wood-Baker 2006, in which there was an unclear risk of recruitment bias and a high risk of bias on baseline imbalance, the effect changed to a clinically and statistically significant MD in favor of IDM (-4.22; 95% CI -6.14 to -2.30, P < 0.001). Lastly, a sensitivity analysis on the studies that analyzed the data using the intention-to-treat principle (Bourbeau 2003; Rice 2010) showed a statistically significant and clinically relevant difference in favor of IDM (MD -4.65; 95% CI -6.69 to -2.62, P < 0.0001) compared to controls.
|Figure 3. Forest plot of comparison: 1 Integrated disease management versus control, outcome: 1.1 SGRQ: short-term (3 to 12 months).|
Subgroup analysis based on type of setting
There were six studies conducted in primary care on 456 participants (Boxall 2005; Wood-Baker 2006; Koff 2009; Fernandez 2009; van Wetering 2010; Gottlieb 2011) and seven studies in secondary care on 969 participants (Engstrom 1999; Bourbeau 2003; Dheda 2004; Theander 2009; Rice 2010; Trappenburg 2011; Wakabayashi 2011). No studies were performed in tertiary care. Subgroup analysis based on primary care studies showed a clinically relevant mean difference of -4.68 (95% CI -8.80 to -0.56) in favor of IDM. This result was statistically significant and clinically relevant. Subgroup analysis on secondary care studies showed a statistically significant difference of -3.41 (95% CI -5.97 to -0.85)( Analysis 1.3). This difference was not clinically relevant. The test for subgroup difference did not show a statistically significant difference in treatment effects in patients treated in different types of health care setting (Chi² = 0.27, df = 1 (P = 0.61)).
Subgroup analysis based on study design
We performed subgroup analysis based on study design and compared RCTs (n = 1304) versus cluster-RCTs (n = 121). There was no difference in SGRQ total score between intervention and control in the cluster-RCT of Wood-Baker 2006 (MD 2.30; 95% CI -1.62 to 6.22; Analysis 1.4). Pooled meta-analysis of RCTs showed a clinically relevant effect in favor of the IDM group of -4.22 (95% CI -6.14 to -2.30, P < 0.0001). The test for subgroup differences showed a statistically significant difference between the pooled analysis of the RCTs and the effect in the cluster-RCT (Chi² = 8.57, df = 1 (P = 0.003)).
Subgroup analysis based on type of control group
In nine studies including 744 participants, control patients received usual care, and in four studies (n = 681) the control group received a mono-disciplinary treatment of education. Meta-analysis of the usual care studies showed a significant difference between groups of -4.09 (95% CI -6.35 to -1.84, P < 0.001) ( Analysis 1.5). Subgroup analysis of studies in which the control group received education showed no significant difference in effect between groups (MD -2.98; 95% CI -7.69 to 1.74, P = 0.022), which was neither statistically nor clinically relevant. There was no statistically significant difference in the test for subgroup difference (Chi² = 0.17, df = 1 (P = 0.68)).
Subgroup analysis based on dominant component of the program
There were four studies including 942 patients (Bourbeau 2003; Wood-Baker 2006; Koff 2009; Rice 2010) in which self management was the dominant component, and six studies including 373 patients in which exercise training was the dominant component (Engstrom 1999; Boxall 2005; Theander 2009; Fernandez 2009; van Wetering 2010; Gottlieb 2011). One study (Wakabayashi 2011) evaluated an individual tailored education program and one study (Dheda 2004) focused mainly on structured follow-up with nurses and GPs. Subgroup analysis of the self management studies revealed neither a statistically nor a clinically relevant mean difference: MD -2.76 (95% CI -5.88 to 0.36, P = 0.08). Subgroup analysis of exercise studies showed a statistically and clinically relevant difference of -4.74 in favor of IDM (95% CI -7.05 to -2.43, P < 0.0001). There was no statistically significant difference between subgroups (Chi² = 1.00, df = 1 (P = 0.32)) ( Analysis 1.6).
22.214.171.124. SGRQ - long-term
Two studies including 189 participants measured the long-term effect on the SGRQ total score: at 18 (Gottlieb 2011) and 24 (van Wetering 2010) months follow-up. There was no statistically significant difference between groups (MD -0.22; 95% CI -7.43 to 6.99, P = 0.95; I² = 54%, P = 0.14)( Analysis 1.2).
126.96.36.199 SGRQ domain scores - short-term
Eleven studies with a total population of 1377 patients reported scores on the SGRQ domains of symptoms, activity and impact. For all domains, there was no significant heterogeneity (I² between 35% and 28%) ( Analysis 1.1). We found the following results:
- Symptom domain: MD -2.39 (95% CI -5.31 to 0.53, P = 0.11)
- Activity domain: MD -2.70 (95% CI -4.84 to -0.55, P = 0.01)
- Impact domain: MD -4.04 (95% CI -5.96 to -2.11, P < 0.0001)
188.8.131.52. SGRQ domain scores - long-term
184.108.40.206. CRQ domain scores - short-term
The Chronic Respiratory Disease Questionnaire (CRQ), with a scale from 0 to 7 and a MCID of 0.5, was reported in eight trials (Wijkstra 1994; Bendstrup 1997; Cambach 1997; Güell 2000; Farrero 2001; Rea 2004; Güell 2006; Sridhar 2008). Three of these (Bendstrup 1997; Farrero 2001; Rea 2004) could not be used in a meta-analysis. Bendstrup 1997 and Rea 2004 reported insufficient data and the authors could not provide us with additional data. In addition, Farrero 2001 administered the CRQ in the first 40 consecutive patients and therefore outcomes were not published.
The pooled results of four studies including 160 participants (Wijkstra 1994; Cambach 1997; Güell 2000; Güell 2006) measuring the CRQ until 12 months follow-up are shown in Figure 4 and Analysis 1.7. For each of the CRQ domains, the MD was well above the MCID of 0.5 units and differences in scores were statistically significant: dyspnoea (MD 1.02; 95% CI 0.67 to 1.36, P < 0.0001), fatigue (MD 0.82; 95% CI 0.46 to 1.17, P < 0.0001), emotion (MD 0.61; 95% CI 0.26 to 0.95, P < 0.0005) and mastery (MD 0.75; 95% CI 0.38 to 1.12, P < 0.0001). The results showed homogeneity across studies.
|Figure 4. Forest plot of comparison: 1 Integrated disease management versus control, outcome: 1.7 CRQ: short-term (3 to 12 months).|
220.127.116.11. CRQ domain scores - long-term
Two studies (n = 151) (Güell 2000; Sridhar 2008) measured the long-term effectiveness on CRQ domain scores at 24 months follow-up( Analysis 1.8). There was no difference between groups on the CRQ dyspnoea domain: MD 0.47 (95% CI -0.31 to 1.25, P = 0.24). Pooled data showed substantial heterogeneity (I² = 70%, P = 0.07), which was related to differences in the type of intervention (exercise in the Güell 2000 study versus structured follow-up with a respiratory nurse and exacerbation plan in Sridhar 2008). Güell 2000 demonstrated a significant difference in favor of IDM (MD 0.92; 95% CI 0.19 to 1.65, P = 0.01). In contrast, there was no statistically significant difference between groups on the CRQ dyspnoea domain in Sridhar 2008 (MD 0.12; 95% CI -0.32 to 0.58, P = 0.61).
Pooled mean differences on the domains fatigue, emotion and mastery showed homogeneity across studies. On the CRQ fatigue domain, there was a statistically significant but not clinically relevant difference of 0.45 in favor of IDM (95% CI 0.05 to 0.85, P = 0.03). On the CRQ emotion and mastery domain, the statistically and clinically relevant effect was in favor of IDM: emotion MD 0.53 (95% CI 0.10 to 0.95, P = 0.02) and mastery MD 0.80 (95% CI 0.37 to 1.23, P < 0.01).
1.2 General health-related QoL
General HRQoL was measured with the SF-36 in three studies (Dheda 2004; Rea 2004; Aiken 2006). The authors of these studies could not provide us with sufficient data for pooling in a meta-analysis. Neither study found a significant effect between groups. Two of these studies (Dheda 2004; Aiken 2006) suffer from small sample sizes varying from 15 to 10 patients per group per study, which makes it difficult to detect an effect (underpowered studies).
We pooled the data from two studies (Littlejohns 1991; Engstrom 1999) reporting data on the SIP ( Analysis 1.9). No between-group differences in any domain of the SIP were found. One other study used the York Quality of Life Questionnaire (Bendstrup 1997) and reported no significant difference. Smith 1999 used a modified version of the Dartmouth Primary COOP. In this study, the authors analyzed only the data from the intervention group (n = 30) due to lack of data in the control group. The authors concluded that the total COOP scores in the intervention group significantly improved HRQoL at 12 months.
2. Exercise capacity
Seventeen studies measured exercise capacity using either the 6MWD or the cycle ergometer test. The MCID on the 6MWD is estimated at 35 meters (Puhan 2008). There is no MCID reported in the current literature for the cycle ergometer test. Results are shown in Figure 5.
|Figure 5. Forest plot of comparison: 1 Integrated disease management versus control, outcome: 1.10 Functional exercise capacity: 6MWD mean difference.|
2.1.1 Functional exercise capacity - short-term
We pooled data from 14 studies using the 6MWD including 871 participants. One study could not be pooled, as the authors reported no data because there was no significant difference between groups at 12 months follow-up (Bourbeau 2003).
Patients treated with IDM improved their 6MWD by a statistically and clinically relevant 43.86 meters (95% CI 21.83 to 65.89)(Figure 5; Analysis 1.10). There was heterogeneity between the results of the studies (I² = 83%). This heterogeneity is explained by differences in the quality of studies. We performed sensitivity analysis on studies with adequate allocation concealment, which reduced heterogeneity (I² = 0%) and reduced the effect to a MD of 15.15 meters, which was still statistically significant (95% CI 6.37 to 23.93, P < 0.001), however no longer clinically relevant. Furthermore, we performed subgroup analysis based on type of setting, type of control group and dominant component of the intervention.
Subgroup analysis based on type of setting
There were seven studies with 427 participants (Wijkstra 1994; Cambach 1997; Boxall 2005; Fernandez 2009; van Wetering 2010; Mendes 2010; Gottlieb 2011) conducted in primary care, seven studies with 438 participants (Littlejohns 1991; Bendstrup 1997; Engstrom 1999; Güell 2000; Theander 2009; Mendes 2010; Wakabayashi 2011) in secondary care and one study in tertiary care with 35 participants (Güell 2006). Both subgroup analyses showed similar statistically and clinically relevant improvements: exercise training in primary care revealed a MD of 45.16 meters (95% CI 8.65 to 81.67, P = 0.02), whereas in the secondary care setting the MD was 49.18 meters (95% CI 14.28 to 84.08, P = 0.006). The tertiary care study showed a significant effect in favor of IDM of 85 meters (95% CI 30.43 to 139.57). Results are shown in Analysis 1.11 and Figure 6.
|Figure 6. Forest plot of comparison: 1 Integrated disease management versus control, outcome: 1.11 Subgroup analysis 6MWD based on type of setting.|
Subgroup analysis based on control group
We pooled four studies with 180 participants in which control patients received a treatment with optimal medication (Cambach 1997; Güell 2006) or an education session (Fernandez 2009; Wakabayashi 2011) in a subgroup analysis. In the same way, we pooled 10 studies (Littlejohns 1991; Wijkstra 1994; Bendstrup 1997; Engstrom 1999; Güell 2000; Boxall 2005; Theander 2009; Mendes 2010; van Wetering 2010; Gottlieb 2011) including 691 participants in which the control group consisted of usual care.
Subgroup analysis in which one component of treatment was used showed no difference between groups (MD 35.99; 95% CI -5.34 to 77.31, P = 0.09)( Analysis 1.12). In studies in which the control group consisted of usual care, the 6MWD improved clinically and statistically significantly by 46.59 meters in favor of IDM (95% CI 19.68 to 73.51, P = 0.0007). However, the test for subgroup differences did not show any difference between control groups (Chi² = 0.18, df = 1 (P = 0.67)).
Subgroup analysis based on dominant component of intervention
Twelve out of the 14 studies (n = 653) measuring exercise capacity incorporated some kind of exercise training in their IDM programs. We performed subgroup analysis, which showed that the 6MWD improved by 51.47 meters (95% CI 26.53 to 76.40). This effect was statistically and clinically relevant. In the remaining two studies (n = 218), exercise was not part of the IDM programs. In one study (Wakabayashi 2011), which consisted of individually tailored education sessions, there was no difference between groups (MD 0.40; 95% CI -39.64 to 40.44, P = 0.98). The other study (Littlejohns 1991), in which there was a focus on structured follow-up with GP and nurses, revealed no effect (MD 3.50; 95% CI -28.31 to 35.31, P = 0.83). In conclusion, studies incorporating exercise training in their IDM programs demonstrated larger effect sizes; this was statistically significant using the test for subgroup difference (Chi² = 7.49, df = 2 (P = 0.02))( Analysis 1.13).
2.1.2 Functional exercise capacity - long-term
Two studies on 184 participants published long-term results on the 6MWD (van Wetering 2010; Gottlieb 2011). Both studies showed that IDM statistically significantly improved exercise capacity measured on the 6MWD by 16.8 meters (MD 16.84; 95% CI 3.01 to 30.67) compared to the control group. However, this effect did not exceed the MCID. There was no heterogeneity present. Results are shown in Figure 5 and Analysis 1.10.
2.2. Maximal exercise capacity
Four studies on 298 participants assessed the maximal exercise capacity (in Watts) using the cycle ergometer test. Both studies showed that IDM statistically significantly improved the maximal exercise capacity by 7 Watts (MD 6.99; 95% CI 2.96 to 11.02, P < 0.0001)( Analysis 1.14).
3.1.1 Number of patients experiencing at least one exacerbation - short-term
Two studies (Bourbeau 2003; Trappenburg 2011) including 407 patients reported on the number of patients experiencing at least one exacerbation during 12 months of follow-up. Both studies used the same definition and defined an exacerbation as an increase in symptoms, with deterioration of dyspnoea or purulent sputum. Pooled meta-analysis showed homogeneity and a pooled OR of 1.21 (95% CI 0.77 to 1.91) ( Analysis 1.15), which showed no statistically or clinically relevant difference between groups. The trial authors of the Bourbeau 2003 study reported that although there were more patients experiencing at least one exacerbation in the intervention group (85 versus 81), the total number of exacerbations was higher in the control group (362) compared to the intervention group (299). This was of borderline significance (P = 0.06). Similarly, the number of patients experiencing three or more exacerbations during 12-month follow-up was higher in the control group (67.9%), compared to the action plan group (62.3%). Exacerbations in the intervention group were treated successfully at an early stage, which probably resulted in fewer patients with a hospital admission (17.2% versus 36.3%, P < 0.01). Trappenburg 2011 reported similar findings: although exacerbation rates did not differ between groups, exacerbations in the action plan group were perceived as substantially milder by patients, and they reported on average three days faster than those in the control group.
3.1.2. Number of patients experiencing at least one exacerbation - long-term
Two studies (Sridhar 2008; van Wetering 2010) including 301 patients assessed the number of patients experiencing at least one exacerbation at 24 months follow-up. Both studies related the definition of an exacerbation to health care. Sridhar 2008 stated they defined an exacerbation as the "unscheduled need for healthcare, or need for steroid tablets, or antibiotics for worsening of their COPD". Similarly, van Wetering 2010 defined a moderate exacerbation as "a visit to the general practitioner or respiratory physician in combination with a prescription of antibiotics and/or prednisolone or a visit to the emergency department or day care of a hospital, which according to the patient, was related to a COPD exacerbation. A severe exacerbation was defined as a hospitalisation for a COPD exacerbation". Pooled meta-analysis demonstrated no difference between groups (OR 1.53; 95% CI 0.90 to 2.60, P = 0.12) ( Analysis 1.16). There was homogeneity between studies. Sridhar 2008 stated that patients in the intervention group were more likely to have exacerbations treated with oral steroids alone or oral steroids and antibiotics than the control group. The initiator of treatment was statistically more likely to be the patient themselves compared to the GP in the control group.
3.1.3 Mean exacerbation rate - long-term
Two studies (Güell 2000; van Wetering 2010) including 226 participants reported on the exacerbation rate in both groups at 24 months follow-up. Data on exacerbations were skewed in the van Wetering study, therefore we decided not to pool both studies in a meta-analysis. In Güell 2006, control group patients (n = 23) experienced 207 exacerbations, with an average of 6.9 (3.9) exacerbations per patients, ranging from 0 to 16 exacerbations during the 24 months. The IDM group experienced 111 exacerbations, with an average of 3.7 (2.2) exacerbations per patients, ranging from 0 to 9 exacerbations during the 24 months. This difference was statistically significant (P < 0.0001) favoring IDM. In van Wetering 2010, the exacerbation rate was 2.78 in the IDM group and 2.16 in the control group, resulting in a rate ratio of 1.29 (95% CI 0.89 to 1.87), which was not statistically significant (P = 0.113).
3.2.1 Hospital admissions, all causes - short-term
Two studies on 266 participants (Littlejohns 1991; Rea 2004) reported data on the number of patients who were admitted for all causes until 12 months follow-up. There was no heterogeneity and there was no difference between groups (OR 0.62; 95% CI 0.36 to 1.07, P = 0.49) ( Analysis 1.17).
3.2.2. Hospital admissions, all causes - long-term
Two studies including a total of 283 patients (Sridhar 2008; van Wetering 2010) assessed the number of patients admitted until 24 months follow-up. Pooled results showed heterogeneity (I² = 53%), which could be explained as van Wetering 2010 showed a positive effect in favor of IDM and Sridhar 2008 showed no significant difference in effect between groups. Therefore, a pooled meta-analysis showed no difference between groups (OR 0.78; 95% CI 0.38 to 1.57)( Analysis 1.18).
3.3.1. Respiratory-related admissions - short-term
We pooled data from seven studies (Smith 1999; Bourbeau 2003; Rea 2004; Boxall 2005; Koff 2009; Rice 2010; Trappenburg 2011) measuring respiratory-related admissions until 12 months follow-up in a meta-analysis. Studies were homogeneous. Pooled estimates showed a statistically significant difference in favor of IDM (OR 0.68; 95% CI 0.47 to 0.99, P = 0.04)( Analysis 1.19). In the control group 27 people out of 100 had a respiratory-related hospital admission over 3 to 12 months, compared to 20 (95% CI 15 to 27) out of 100 in the integrated disease management group, as presented in Figure 7. Over the course of a year, the number needed to treat with IDM to prevent one hospital admission was NNT(B) 15 (95% CI 9 to 506).
|Figure 7. In the control group 27 people out of 100 had a respiratory-related hospital admission over 3 to 12 months, compared to 20 (95% CI 15 to 27) out of 100 for integrated disease management group.|
3.3.2. Respiratory-related admissions - long-term
Data from one trial (van Wetering 2010) presented data on the number of patients admitted until 24 months follow-up. There was no difference between the control and IDM group on the number of respiratory-related admissions (OR 0.59; 95% CI 0.28 to 1.22, P = 0.16)( Analysis 1.20).
3.4.1 Hospital days per patient - short-term
Six studies on 741 patients (Engstrom 1999; Farrero 2001; Bourbeau 2003; Rea 2004; Boxall 2005; Trappenburg 2011) reported the difference in mean hospitalisation days per patient per group (intervention versus control). Patients treated with IDM were on average discharged from the hospital nearly four days earlier compared to control patients, with a confidence interval from six to two days (MD -3.78; 95% CI -5.90 to -1.67, P < 0.001) ( Analysis 1.21). There was heterogeneity in the results (I² = 55%). Inspection of the forest plot shows that this was the result of one outlying study (Engstrom 1999), which reported more days for intervention patients. The authors stated that the data on admission days in his study were skewed, as one patient accounted for 50% of the increase in the IDM group. Reanalysis with exclusion of this trial did not change the significance, direction or effect of the mean difference.
3.4.2. Hospital days per patient - long-term
One trial with 175 patients (van Wetering 2010) reported the difference in mean number of total hospital days per patient per group at 24 months follow-up. There was no difference between groups (MD 0.60; 95% CI -3.01 to 4.21, P = 0.74) ( Analysis 1.22).
3.5 Emergency Department (ED) visits
Six trials (Smith 1999; Farrero 2001; Bourbeau 2003; Rea 2004; Rice 2010; Wakabayashi 2011) assessed in various ways the number of ED visits. We were able to pool the data from four studies with 1161 patients (Smith 1999; Bourbeau 2003; Rea 2004; Rice 2010), which revealed no difference between groups with high heterogeneity (OR 0.64; 95% CI 0.33 to 1.25; I² = 71%)( Analysis 1.23). Sensitivity analysis on two studies which analyzed by intention-to-treat and which blinded outcome assessors revealed a mean difference of 0.49 in favor of the control group (MD 0.49; 95% CI 0.36 to 0.67, P < 0.0001, I² = 0%). Three studies could not be pooled, due to lack of required data. Of these excluded studies, Trappenburg 2011 and Wakabayashi 2011 reported the mean ED visits per patient at baseline and follow-up. Both studies concluded no statistically significant difference between groups compared to baseline. On the other hand, Farrero 2001 reported a significant decrease in ED visits per patient in favor of the IDM group (0.45 ± 0.83 for intervention group, 1.58 ± 1.96 for control group; P = 0.0001). There were no data presented on the number of ED visits at long-term follow-up.
3.6 Patients using at least one course of oral steroids
We pooled data from three studies including 348 patients (Littlejohns 1991; Farrero 2001; Rea 2004) on the number of patients using at least one course of oral steroids until 12 months follow-up. Results were homogeneous and there was no difference between groups (OR 1.13; 95% CI 0.64 to 2.01, P = 0.66) ( Analysis 1.24).
3.7. Patients using at least one course of antibiotics
There were two studies with 236 participants (Littlejohns 1991; Rea 2004) reporting on the number of patients using at least one course of antibiotics. The studies presented conflicting results and heterogeneity was large, as Rea 2004 was a primary care, cluster-randomized trial and Littlejohns 1991 was a RCT in the secondary care setting. The number of patients using at least one course of antibiotics was not different between groups, and the OR had a wide confidence interval (OR 1.43; 95% CI 0.24 to 8.48, P = 0.69)( Analysis 1.25).
Four studies reported the MRC Dyspnea Scale as an outcome (Mendes 2010; van Wetering 2010; Gottlieb 2011; Wakabayashi 2011), however Gottlieb failed to publish any results. We pooled data from the remaining three studies, including 345 patients. Dyspnea was improved in the IDM group by -0.30 points (MD -0.30; 95% CI -0.48 to -0.11, I² = 0%, P < 0.001)( Analysis 1.26).
Furthermore, three studies on 145 patients used the Borg score to detect changes in perceived dyspnoea (Güell 2000; Boxall 2005; Gottlieb 2011). These data were pooled and revealed no change in dyspnoea (MD 0.14; 95% CI -0.70 to 0.98, P = 0.74, I² = 39%)( Analysis 1.27).
Five trials assessing 1207 patients explicitly recorded mortality as an outcome. Of these, four trials assessed mortality at 12 months (Littlejohns 1991; Smith 1999; Farrero 2001; Rice 2010) and one study at 24 months (Sridhar 2008). There was no statistically significant difference between groups at short- (OR 0.96; 95% CI 0.52 to 1.74, P = 0.33; I² = 59%) and long-term follow-up (OR 0.45; 95% CI 0.16 to 1.28, P = 0.13) ( Analysis 1.28). Heterogeneity in the short-term studies is due to different dominant components of the interventions.
6. Lung function
Lung function was measured in three different ways in 10 trials (Littlejohns 1991; Wijkstra 1994; Güell 2000; Farrero 2001;Bourbeau 2003; Wood-Baker 2006; Sridhar 2008; Fernandez 2009; van Wetering 2010; Wakabayashi 2011). Therefore, we created three different subgroups, which we pooled in two different meta-analyses: forced expiratory volume in one second (FEV1) in liters and FEV1 as per cent predicted for age, gender and height (FEV1% predicted), as well as the mean difference in FEV1% predicted from baseline. All pooled data on short- as well as on long-term outcome revealed no significant difference in lung function between groups( Analysis 1.29; Analysis 1.30).
7. Anxiety and depression
Four studies assessed depression as an outcome (Engstrom 1999; Littlejohns 1991; Güell 2006; Trappenburg 2011). Two studies (Littlejohns 1991; Trappenburg 2011) used the HADS, one study (Engstrom 1999) used the Mood Adjective Check List (MACL) and one study (Güell 2006) used a Revised Symptom Checklist. We pooled results on the HADS in a meta-analysis including 316 patients, which revealed no statistically significant difference between groups for anxiety (MD 0.22; 95% CI -0.41 to 0.85, I² = 0%) or depression (MD 0.21, 95% CI -0.39 to 0.81, I² = 0%)( Analysis 1.31). Engstrom 1999 used the MACL, a shortened 38-item version covering three basic dimensions of mood: pleasantness/unpleasantness, activation/deactivation and calmness/tension. No significant differences were found between groups. The aim of Güell 2006 was specifically to evaluate the effect of a pulmonary rehabilitation program on psychosocial morbidity (without including any specific psychological intervention), as well as effort capacity and HRQoL. Therefore, the authors used a Revised Symptom Checklist, containing 90 items, which included depression and anxiety. Following a per protocol analysis, the intervention group showed a significant improvement in depression (P ≤ 0.01) and anxiety (P ≤ 0.05).
8. Co-ordination of care
Three studies (Littlejohns 1991; Bendstrup 1997; Koff 2009) reported in some way on the co-ordination of care. However, these studies had different intervention programs and reported on co-ordination of care in different ways. Therefore, interpretation of outcomes is difficult. Bendstrup 1997 reported an attendance rate of 78% of patients following a 12-week IDM program (consisting of education, exercise training, smoking cessation and occupational therapy).
Patient satisfaction with regard to the provided health care was measured in two studies. In Koff 2009, satisfaction with a self management/action plan program was assessed on a scale from 1 to 10 in the intervention group, with 1 being strongly dissatisfied and 10 completely satisfied. Patients expressed high satisfaction with all of the equipment used, except for the pedometer. Littlejohns 1991 designed a satisfaction questionnaire for his study, which included questions on satisfaction with level of care, the information given to patients and their knowledge of medication. The questionnaire was used in both study groups. At 12 months follow-up, there was little difference in the level of satisfaction with the service provided between groups.
Summary of main results
We reviewed the results of 26 randomised controlled trials evaluating the effect of an integrated disease management (IDM) program in patients with COPD. All included studies contained a program provided by caregivers from at least two different disciplines, with two different components (for example exercise, education, self management etc) and with a duration of at least three months. Firstly, pooled data showed statistically and clinically relevant improvements in disease-specific quality of life on the CRQ in the IDM group: dyspnoea (MD 1.02; 95% CI 0.67 to 1.36); fatigue (0.82; 95% CI 0.46 to 1.17); emotional (0.61; 95% CI 0.26 to 0.95) and mastery (0.75; 95% CI 0.38 to 1.12). All domains (dyspnoea, fatigue, emotional and mastery) exceeded the minimum clinically relevant difference until 12 months follow-up. Only two studies measured long-term results on the CRQ, which showed that the positive effect was maintained for the fatigue, emotion and mastery domains at 24 months follow-up. Furthermore, disease-specific quality of life was also measured with the SGRQ. There was considerable heterogeneity in the score on the SGRQ. After multiple sensitivity analyses, we concluded that there was a difference in the SGRQ total score in favor of patients treated with IDM, which lies around the minimal clinically relevant difference of four units. The effect was greatest for the impact domain. We could not find a difference in the SGRQ total score at long-term follow-up. Remarkably, only two studies could provide data.
Second, the pooled data showed statistically significant improvements in maximal and functional exercise capacity, with an improvement of 7 Watts and 44 meters in favor of the IDM group, respectively. Sensitivity analysis of the 6MWD lowered the effect to 15 meters, indicating the likelihood of an overestimated effect in the lower quality studies.
Thirdly, the total number of patients with at least one respiratory-related hospital admission decreased from 27 per 100 to 20 per 100 patients in favor of the intervention group, with a number needed to treat of 15 patients to prevent one being admitted to hospital over three to 12 months. Mean hospitalisation days decreased on average by three days in the IDM group. The effects on the aforementioned primary outcomes are summarized in the Summary of findings for the main comparison. There was no evidence of an effect on generic quality of life, the number of patients with at least one exacerbation, the number of hospital admissions for all causes, emergency department visits, courses of antibiotics/prednisolone, dyspnoea, lung function parameters or depression scores.
Overall completeness and applicability of evidence
We found sufficient studies to address the objective of this review. All studies reported at least one primary outcome, and all studies were included in at least one pooled analysis. The COPD population in the included studies ranged from mild to very severe COPD and trials were conducted across all types of healthcare settings in a range of different countries. Although the results of this review appear therefore to be applicable to all COPD patients worldwide, one should bear in mind that applicability may depend on the context of available healthcare resources. The IDM programs included in this review differed in the type of health care providers involved, type of components and duration of intervention, reflecting the diversity of daily practice. Overall, programs containing at least two health care providers and two different elements, showed improvements in quality of life and exercise capacity, and reduced the number of hospital admissions and days spent in the hospital. We found no differences in quality of life and exercise tolerance between patients treated in primary or secondary care. Although the mean differences between groups were lower in studies using a mono-disciplinary treatment as a control group compared to usual care, the subgroup difference did not reach statistical significance. Furthermore, subgroup analysis on studies focusing mainly on exercise programs showed a statistically significant greater improvement in exercise capacity. Further research is required to define the optimal combination, intensity and duration of components in IDM programs.
Quality of the evidence
We included RCTs only and found 26 trials assessing almost 3000 participants. A priori, we intended to perform meta-analyses on some outcomes when feasible. However, with this amount of data we were able to perform pooled data analysis for all outcomes. As a result of the complex intervention, there was a certain amount of clinical and statistical heterogeneity among studies. We have incorporated heterogeneity into the estimated effects by using random-effects analyses, where possible. Using the GRADE approach, we specified the levels of quality of the evidence (high, moderate, low and very low) in our 'Summary of findings' table. According to this approach, we checked if the included trials had limitations in terms of design, indirectness of the evidence, unexplained heterogeneity or inconsistency of the results, imprecision of the results or high probability of publication bias. If one of these factors was present, we downgraded the evidence. On the SGRQ, there was considerable variation in risk of bias between studies. Risk of bias tended to be lower in the more recently published trials compared to older trials. Sensitivity analyses based on studies with low quality did not change the direction, significance or magnitude of the effect. Therefore we concluded that the quality of the evidence was 'high'. For the CRQ, there were four studies which were all of moderate quality and presented with some form of bias, therefore we did downgrade the evidence to 'moderate' quality. We downgraded the evidence on functional exercise capacity for inconsistency, as substantial heterogeneity (I² = 84%) was present. After performing sensitivity analysis, the mean difference substantially decreased to 15 meters. We did not downgrade for respiratory-related admissions or hospitalisation days, as we feel the studies presented consistent, homogeneous results. We expect that additional trials with proper description of their methods and data collection could upgrade the quality of evidence and further our findings.
Potential biases in the review process
Several methodological strengths minimized the risk of bias in this review. As definitions of IDM are still under debate, we a priori strictly determined the inclusion criteria for an IDM program, which was published in our protocol. Our definition was derived from the definitions published in the literature (Peytremann-Bridevaux 2009; Schrijvers 2009). Overall, they reported on "multiple interventions, designed to manage chronic conditions, with a focus on a multidisciplinary approach". Furthermore, these definitions suggest that IDM interventions should "focus on maximum clinical outcome, regardless of treatment setting(s) or typical reimbursement patterns". As a result, we chose to include all interventions, independent of treatment setting, and to keep our definition as simple as possible, in order to be easily understandable for readers and easy to use for us as authors when checking on all relevant literature. Therefore, we restricted the inclusion of trials to multi-component, multidisciplinary programs of at least three months duration. Furthermore, we performed comprehensive searches to identify possible studies, leading to almost 4800 potentially relevant abstracts being identified. Subsequently, three different assessors assessed the abstracts. All studies that were excluded by two authors because of the type of intervention were triple-checked by a third review author to make sure all studies describing an IDM program were included. We reached consensus on all included studies. Although we followed the inclusion criteria for IDM as stated in our protocol, final decisions on the inclusion of studies are open to interpretation or criticism.
Limitations of this review include possible bias from inconsistent reporting of data from included studies. We requested additional data from 14 authors and received an answer from 11. Six of them could provide us with additional data, which could potentially have biased the results. Furthermore, only three out of 26 studies published a study protocol with which we could compare the results sections. In the other studies, we examined whether the outcomes reported in the methods section of the paper were reported in the results section. It is possible that this could have introduced bias if the authors blanked out outcomes from their methods section.
Lastly, there was heterogeneity present in the control group as we used a broad a priori definition of controls, varying from no treatment to treatment including one component of COPD care. We acknowledge the fact that controls and usual care differ between countries and between healthcare settings. Therefore, we performed subgroup analysis to investigate to what extent a difference between the control groups possibly influenced the results. From these analyses we concluded that the effect between intervention and control groups is less strong if patients in control groups receive one component of IDM compared to patients receiving no treatment or usual care.
Agreements and disagreements with other studies or reviews
This review adds to the results of four earlier systematic reviews analyzing IDM for COPD patients (Adams 2007; Niesink 2007; Peytremann-Bridevaux 2008; Lemmens 2009). The current review brings together new trials that were not included in any of these reviews. Some of these earlier reviews analyzed some of our primary outcomes. Adams 2007 examined the effectiveness of programs for COPD patients including chronic care model components and pooled six trials including at least two components. Pooled results did not demonstrate statistically significant differences on the SGRQ. Patients with COPD who received interventions with two or more chronic care model components had lower rates of hospitalisation and a shorter length of stay compared with control groups, comparable to our results. Lemmens 2009 examined the effectiveness of multiple interventions in asthma and COPD patients. The authors pooled data on the SGRQ from three studies in which two components of IDM were compared to usual care and three studies in which three components of IDM were compared to usual care. The effect on the SGRQ was larger if three components of IDM were used (MD -4.69; 95% CI -8.34 to -0.83 versus MD -0.95; 95% CI -4.23 to 2.34). Pooled data from five studies showed a decrease in the number of respiratory-related hospitalizations, with a pooled OR of 0.58, which is comparable to the OR of 0.67 found in this review. Niesink 2007 evaluated quality of life in COPD patients, but did not perform a meta-analysis; reasons for this were not clearly described. Five out of 10 studies showed a clinically relevant improvement in quality of life. Peytremann-Bridevaux 2008 examined the effectiveness of IDM in COPD patients on exercise tolerance, quality of life, hospital admissions and mortality. Only data on hospital admissions and exercise tolerance were pooled. Positive effects on exercise capacity are in line with this review. The authors demonstrated a mean improvement of 32 meters on the 6MWD in five studies, which is comparable to our results. Furthermore, a pooled odds ratio of 0.85 (95% CI 0.54 to 1.36) for mortality is comparable to our review. Differences between this review and these other reviews are related to differences in the inclusion criteria for patients and the focus of programs. All reviews used different definitions of IDM; however there was some overlap with this review. Lemmens 2009 et al also based their definition on the EPOC list (EPOC 2008), whereas Adams 2007 and Steuten 2009 based their definition of IDM on the chronic care model as reported by Wagner 1996. The definition used by Peytremann-Bridevaux 2008 was similar to our definition, with the only difference being a duration of the intervention of at least 12 months instead of three months. Finally, all the aforementioned systematic reviews included study designs other than RCTs.
Our findings from the St. George's Respiratory Questionnaire (SGRQ) showed improvements of a similar magnitude to those reported in two recent Cochrane reviews evaluating two other supposedly important pharmaceutical cornerstones of COPD treatment, tiotropium (Karner 2012a) and inhaled corticosteroids (Yang 2012). IDM resulted in a higher MD on the SGRQ of -3.71 compared to the MD of tiotropium (-2.89); however, the confidence interval for IDM is wider (95% CI -5.83 to -1.59) compared to the confidence interval (95% CI -3.35 to -2.44) for tiotropium.
Eight studies in this review are also evaluated in a Cochrane review assessing the effectiveness of pulmonary rehabilitation (Lacasse 2006) and four studies included in this review are also evaluated in a Cochrane review assessing the effect of self management programs (Effing 2007). In line with the review of Effing 2007 (OR 0.64; 95% CI 0.47 to 0.89) we found a decrease in respiratory-related hospital admissions (OR 0.64; 95% CI 0.47 to 0.89). Furthermore, both reviews demonstrated improvements in disease-specific quality of life, although the effects tended to be higher and clinically relevant in the pulmonary rehabilitation review (Lacasse 2006), whereas in the self management review the improvement was too small to be of clinical relevance (Effing 2007). A priori we determined subgroup analyses on the type of dominant intervention in the program. Subgroup analysis of studies containing some form of exercise training showed greater improvement in quality of life, which exceeded the clinically relevant threshold on almost all domains. These results are in line with the Lacasse review. However, a subgroup analysis performed on studies that mainly focused on self management did not exceed the minimum clinically important difference, in line with the Effing review.
Furthermore, Effing 2007 and Lacasse 2006 reported pooled estimates for functional exercise capacity. Not surprisingly, as the focus in most included pulmonary rehabilitation studies lies on exercise training, the 6MWD improved significantly by 48 meters in the Lacasse review. This effect size is comparable to our overall estimate of 44 meters and our subgroup analyses on studies including an exercise program in which we found a mean difference of 50 meters. In contrast to these results, Effing did not find any significant differences in exercise capacity at all (weighted mean difference -6.25; 95% CI -24.05 to 11.05).
We did not find a difference between groups in the number of patients with at least one exacerbation. However, we concluded that there was a reduction in the number of patients admitted and the mean number of hospital days related to exacerbations. Self management education including the use of action plans might lead to more and better self treatment of exacerbations. As a result, hospital admissions will decrease (Effing 2007). In our included studies, a self management program caused patients to respond three days sooner on complaints (Trappenburg 2011). Furthermore, patients more often initiated treatment by themselves, which could then be successfully treated with oral steroids at an early stage (Sridhar 2008). As a result, perceived exacerbations were rated as substantially milder (Trappenburg 2011) and were less likely to result in an admission (Bourbeau 2003).
In the past few years, several systematic reviews evaluating IDM for various other chronic conditions have been published (Norris 2002; Badamgarav 2003; Gonseth 2004; Neumeyer-Gromen 2004; Knight 2005; Roccaforte 2005; Pimouguet 2010). Overall, quality of care improved with these programs, however some of the differences were in fact clinically modest (Peytremann-Bridevaux 2008). We found that the results of this review were most comparable to a systematic review evaluating patients with heart failure, which demonstrated that all-cause and heart failure-related hospitalisation rates were significantly reduced: OR 0.76 (CI 0.69 to 0.94, P < 0.0001) and OR 0.58 (CI 0.50 to 0.67, P < 0.0001), respectively (Roccaforte 2005). In studies evaluating depression and diabetes, differences in health care use and quality of care were less clear (Neumeyer-Gromen 2004; Knight 2005).
Implications for practice
This meta-analysis provides evidence for the efficacy of integrated disease management (IDM) programs of at least three months duration for chronic obstructive pulmonary disease (COPD) patients, for up to 12 months follow-up. We found positive effects on disease-specific quality of life and exercise capacity in studies containing an exercise program, suggesting that exercise training is an important element in an IDM program. Long-term effects are still unclear, as only a few studies evaluated these. The magnitude of improvement in disease-specific quality of life was clinically relevant, especially using the Chronic Respiratory Questionnaire (CRQ).
We calculated that seven hospital admissions related to respiratory problems can be prevented for every 100 patients treated with IDM for three to 12 months, giving to a number needed to treat of 15 patients to prevent one being admitted. Furthermore, hospitalisation decreased by three days in patients treated with IDM compared to controls. This is of utmost importance, as hospitalizations contribute to the highest burden and costs in patients with COPD. The effects of IDM on the total number of patients suffering at least one exacerbation still remain unclear. It is possible that patients who have learned from education and have an action plan may recognize exacerbations at an early stage and can start medical treatment directly. It is therefore likely that further worsening of health status and hospital admissions can be prevented in these patients.
Implications for research
The following issues could be assessed if authors are planning future trials regarding the effectiveness of IDM:
Finally, given the heterogeneity of interventions, there is a need to reach consensus on which interventions are likely to yield the best results when applying integrated care programs for COPD.
The authors would like to thank Liz Stovold for her help with the development of the search strategy. We acknowledge the authors of the studies who provided additional data.
Julia Walters was the Editor for this review. Julia commented critically on the review and assisted the Co-ordinating Editor with signing off the review for publication.
Data and analyses
- Top of page
- Summary of findings [Explanations]
- Authors' conclusions
- Data and analyses
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Appendix 1. MEDLINE search strategy
1. Pulmonary Disease, Chronic Obstructive/
3. Chronic Obstructive Pulmonary Disease.mp.
4. Chronic Obstructive Airway Disease.mp.
5. Chronic Obstructive Lung Disease.mp.
6. pulmonary emphysema.mp.
7. chronic bronchitis.mp.
9. Chronic Airflow Obstruction.mp.
11. disease management/
12. Disease management.mp.
13. exp Managed Care Programs/
14. managed care.mp.
15. (insurance and "case management").mp.
16. exp Patient Care Planning/
17. "patient care plan$".mp.
18. "nursing care plan$".mp.
19. "goals of care".mp.
20. "care goal".mp.
21. exp "Delivery of Health Care, Integrated"/
22. (integrated and (health$ or care$ or delivery or system$)).mp.
23. disease state management.mp.
24. Comprehensive Health Care/
25. "comprehensive health care".mp.
26. ((interdisciplin$ or multidisciplin$) and (care or health$ or delivery or system$)).mp.
27. Primary Nursing/
28. "primary nursing".mp.
29. "community based".mp.
30. Patient-Centered Care/
31. Patient Care Management/
32. (patient adj3 (care or management)).mp.
33. practice guideline/
34. education, medical, continuing/ or education, nursing, continuing/
35. exp community health services/
36. Primary Health Care/
37. "patient care team".mp.
38. "critical pathways".mp.
39. "case management".mp.
40. Self Care/
41. (continuity adj3 "patient care").mp.
43. "clinical protocol".mp.
44. "patient education".mp.
45. (self-care or "self care").mp.
46. reminder systems.mp. or Reminder Systems/
47. Health Education/
48. Health Promotion/
49. (health adj3 (education or promotion)).mp.
50. Community Health Planning/
51. ambulatory care.mp.
54. 10 and 53
55. (clinical trial or controlled clinical trial or randomised controlled trial).pt.
56. (randomised or randomised).ab,ti.
65. 63 not (63 and 64)
66. 62 not 65
67. 54 and 66
[Limited to pub. Date > = 1990]
Appendix 2. EMBASE search strategy
1. chronic obstructive lung disease/
2. COPD.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
3. Chronic Obstructive Pulmonary Disease.mp.
4. Chronic Obstructive Airway Disease.mp.
5. Chronic Obstructive Lung Disease.mp.
6. pulmonary emphysema.mp.
7. chronic bronchitis.mp.
8. COAD.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
9. Chronic Airflow Obstruction.mp.
11. disease management/
12. Disease management.mp.
13. managed care/
14. managed care.mp.
15. (insurance and "case management").mp.
16. patient care planning/
17. "patient care plan$".mp.
18. "nursing care plan$".mp.
19. "goals of care".mp.
20. "care goal".mp.
21. integrated health care system/
22. (integrated adj5 (health$ or care$ or delivery or system$)).mp.
23. disease state management.mp.
24. health care/
25. "comprehensive health care".mp.
26. ((interdisciplin$ or multidisciplin$) adj5 (care or health$ or delivery or system$)).mp.
27. primary nursing/
28. "primary nursing".mp.
29. "community based".mp.
30. patient care/
31. (patient adj3 (care or management)).mp.
32. practice guideline/
33. medical education/
34. exp community care/
35. primary health care/
36. "patient care team".mp.
37. "critical pathways".mp.
38. "case management".mp.
39. self care/
40. (continuity adj3 "patient care").mp.
42. "clinical protocol".mp.
43. "patient education".mp.
44. (self-care or "self care").mp.
45. reminder system/
46. reminder systems.mp.
47. health education/
48. health promotion/
49. (health adj3 (education or promotion)).mp.
50. health care planning/
51. ambulatory care.mp.
54. 10 and 53
55. Randomized Controlled Trial/
57. Controlled Study/
58. Clinical Trial/
59. controlled clinical trial/
60. Double Blind Procedure/
61. Single Blind Procedure/
62. Crossover Procedure/
64. (clinica$ adj3 trial$).mp.
65. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (mask$ or blind$ or method$)).mp.
66. exp Placebo/
69. ((control$ or prospectiv$) adj3 (trial$ or method$ or stud$)).mp.
70. (crossover$ or cross-over$).mp.
72. 63 or 71
73. exp ANIMAL/
76. 73 or 74
77. 76 not 75
78. 72 not 77
79. 54 and 78
[Limited to pub. Date >=1990]
Appendix 3. CINAHL search strategy
S1 (MH "Pulmonary Disease, Chronic Obstructive+")
S3 "chronic Obstructive Pulmonary Disease"
S4 "Chronic Obstructive Airway Disease"
S5 "Chronic Obstructive Lung Disease"
S6 "pulmonary emphysema"
S7 "chronic bronchitis"
S9 "Chronic Airflow Obstruction"
S10 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9
S11 (MH "Disease Management")
S12 "Disease management"
S13 (MH "Managed Care Programs+")
S14 "managed care"
S15 insurance and "case management"
S16 (MH "Patient Care Plans+")
S17 "patient care plan*"
S18 "nursing care plan*"
S19 "goals of care"
S20 "care goal"
S21 (MH "Health Care Delivery, Integrated")
S22 (integrated and (health* or care* or delivery or system*))
S23 "disease state management"
S24 "Comprehensive Health Care"
S25 ((interdisciplin* or multidisciplin*) and (care or health* or delivery or system*))
S26 (MH "Primary Nursing")
S27 "primary nursing"
S28 "community based"
S29 (MH "Patient Centered Care")
S30 "patient care"
S31 "patient management"
S32 (MH "Education, Medical, Continuing")
S33 Education, Nursing, Continuing
S34 (MH "Community Health Services+")
S35 (MH "Primary Health Care")
S36 "patient care team"
S37 (MH "Critical Path")
S38 "case management"
S39 (MH "Self Care")
S40 (MH "Continuity of Patient Care")
S42 "clinical protocol"
S43 "patient education"
S44 self-care or "self care"
S45 (MH "Reminder Systems")
S46 "reminder system*"
S47 (MH "Health Education")
S48 (MH "Health Promotion+")
S49 (health N3 educat*) or (health N3 promot*)
S50 "Community Health Planning"
S51 "ambulatory care"
S53 S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or S34 or S35 or S36 or S37 or S38 or S39 or S40 or S41 or S42 or S43 or S44 or S45 or S46 or S47 or S48 or S49 or S50 or S51 or S52
S54 S10 and S53
S55 (DE "RANDOMIZED CONTROLLED TRIALS")
S56 (MH "Double-Blind Studies")
S57 (MH "Random Assignment")
S58 (MH "Placebos")
S61 crossover* or cross-over*
S62 clinical* and (trial* or study or studies)
S63 (single* or double* or triple*) and blind*
S64 S55 or S56 or S57 or S58 or S59 or S60 or S61 or S62 or S63
S65 S54 and S64 [Limiters - Exclude MEDLINE records; Published Date from: 19900101-20111231 ]
Appendix 4. CENTRAL search strategy
#1 MeSH descriptor Pulmonary Disease, Chronic Obstructive explode all trees
#3 "chronic Obstructive Pulmonary Disease"
#4 "Chronic Obstructive Airway Disease"
#5 "Chronic Obstructive Lung Disease"
#6 "pulmonary emphysema"
#7 "chronic bronchitis"
#9 "Chronic Airflow Obstruction"
#10 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9)
#11 MeSH descriptor Disease Management, this term only
#12 "Disease management"
#13 MeSH descriptor Managed Care Programs explode all trees
#14 "managed care"
#15 insurance and "case management"
#16 MeSH descriptor Patient Care Planning explode all trees
#17 "patient care plan*"
#18 "nursing care plan*"
#19 "goals of care"
#20 "care goal"
#21 MeSH descriptor Delivery of Health Care, Integrated explode all trees
#22 (integrated and (health* or care* or delivery or system*))
#23 "disease state management"
#24 MeSH descriptor Comprehensive Health Care, this term only
#25 "comprehensive health care"
#26 ((interdisciplin* or multidisciplin*) and (care or health* or delivery or system*))
#27 MeSH descriptor Primary Nursing, this term only
#28 "primary nursing"
#29 "community based"
#30 MeSH descriptor Patient-Centered Care explode all trees
#31 MeSH descriptor Patient Care Management, this term only
#32 "patient care"
#33 "patient management"
#34 MeSH descriptor Education, Medical, Continuing, this term only
#35 MeSH descriptor Education, Nursing, Continuing, this term only
#36 MeSH descriptor Community Health Services explode all trees
#37 MeSH descriptor Primary Health Care, this term only
#38 "patient care team"
#39 "critical pathways"
#40 "case management"
#41 MeSH descriptor Self Care, this term only
#42 continuity NEAR/3 "patient care"
#44 "clinical protocol"
#45 "patient education"
#46 self-care or "self care"
#47 MeSH descriptor Reminder Systems explode all trees
#48 "reminder system*"
#49 MeSH descriptor Health Education, this term only
#50 MeSH descriptor Health Promotion explode all trees
#51 health NEAR/3 (educat* or promot*)
#52 MeSH descriptor Community Health Planning, this term only
#53 "ambulatory care"
#55 (#11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54)
#56 (#55 AND #10)
#57 (#56), from 1990 to 2013
Appendix 5. Cochrane Airways Group Register search strategy
("disease management" or "managed care" or insurance* or "case management" or "care plan" or (goal* and care) or (integrat* and (system* or delivery or care or health*)) or (comprehensive and "health care") or ((interdisciplin* or multidisciplin*) and (care or health* or delivery or system*)) or "primary nursing" or patient-cent* or "patient care" or "patient manag*" or "practice guideline*" or "community health" or "primary health care" or "critical pathway*" or self-care or "self care" or "clinical protocol*" or "patient educat*" or reminder* or (health and (educat* or promot*)) or ((community or health) and plan*) or "ambulatory care" or feedback)
[Limited to pub. date>=1990]
Contributions of authors
AK, NC and NS wrote the protocol.
All authors contributed to and approved the protocol.
AK, NS and NC selected trials.
AK and NC extracted data and assessed risk of bias.
AK was responsible for data management in RevMan.
All authors contributed to and approved the final version of the review.
Declarations of interest
AK, NC, WA, JG, MB and MR are part of the ongoing RECODE trial, which investigates the cost-effectiveness of integrated care in primary care COPD patients in a cluster-randomized controlled trial. The Leiden University Medical Centre received a grant from ZonMW (Dutch governmental agency) for the RECODE trial and the Erasmus University (iMTA) received additional financial support from Achmea (Dutch Healthcare Insurer) for the economic evaluation of the intervention in the RECODE trial. In the future, our RCT will be included in this Cochrane Review.
MR is involved in cost-effectiveness studies of various COPD interventions, both pharmacological and non-pharmacological. She was the project leader of the cost-effectiveness study of the INTERCOM trial, a trial that will be included in this review.
NC is a senior researcher in the field of integrated disease management programs and involved in several initiatives promoting education, developing software applications and providing e-health solutions, which may be considered as a potential conflict of interest.
NS: none known.
Sources of support
- LUMC, Leiden, Netherlands.Leiden University Medical Centre
- iMTA, Rotterdam, Netherlands.Institute for Medical Technology Assessment
- ZonMW, Netherlands.The Netherlands Organisation for Health Research and Development
Differences between protocol and review
We added Borg score next to the MRC Dyspnea Score as an instrument to measure dyspnoea under 'Secondary outcomes'.
We did not search the DARE database for non-Cochrane reviews.
Medical Subject Headings (MeSH)
*Disease Management; *Quality of Life; Delivery of Health Care, Integrated [*methods]; Exercise Tolerance; Hospitalization [statistics & numerical data]; Patient Care Team; Pulmonary Disease, Chronic Obstructive [physiopathology; *therapy]; Randomized Controlled Trials as Topic
MeSH check words
Aged; Female; Humans; Male
* Indicates the major publication for the study